Effect of Antecedent Exercise on the

Glycaemia-Increasing Response of a Short

Sprint: Implications for Blood Glucose

Management for Individuals with Type 1

Diabetes Mellitus

Tara Dawn Justice, BSc, BPHE

This thesis is presented in partial fulfilment for the degree of

Master of Science of The University of Western Australia

 

 

 

School of Sport Science, Exercise and Health

Faculty of Life and Physical Sciences

December 2011

ii

“Good, better, best. Never let it rest. Until your good is better

and your better is best” ~ Tim Duncan

iii

Executive Summary

Individuals with type 1 diabetes mellitus (T1DM) manage their blood glucose levels by

maintaining a careful balance between carbohydrate intake and exogenous insulin

administration. Although regular exercise affords numerous benefits to individuals with

T1DM, it can further complicate this balance, making management of blood glucose

levels more difficult. For example, moderate-intensity activity causes a rapid decline in

blood glucose levels both during exercise and early recovery, discouraging many

individuals with T1DM from participating in exercise due to the increased risk of

hypoglycaemia, a potentially life threatening condition. However, it is important to note

that not all types of exercise cause a decline in blood glucose levels. For instance, it has

recently been found that performance of short maximal sprints can attenuate the fall in

blood glucose levels both during (Guelfi et al., 2005) and after moderate-intensity

exercise (Bussau et al., 2006; Bussau et al., 2007; Guelfi et al., 2005) in individuals with

T1DM. However, before short maximal sprints can be safely added to exercise

guidelines for individuals with T1DM, factors that may reduce the glycaemia-increasing

benefit of a sprint need to be considered. In particular, the effect of an antecedent bout

of moderate-intensity exercise on the glycaemia-increasing response to a 30-second

maximal sprint performed several hours later needs to be investigated given that

previous research has shown a blunted counterregulatory hormone response to a second

bout of moderate-intensity exercise after an identical bout of exercise performed several

hours prior (Galassetti et al., 2001b).

To address this issue, eight healthy, physically active men without type 1 diabetes were

recruited. All individuals participated in three sessions, each separated by at least one

week. The first visit was a familiarization session in which baseline characteristics and

peak oxygen consumption ( O2peak) were determined. The second and third sessions

were administered following a randomized counterbalanced design, with participants

either cycling at 65% O2peak for 60 minutes (EX) or resting for an equivalent period

(CON). Following this, participants rested for 3 hours and 15 minutes prior to

performing a 30-second maximal sprint on a cycle ergometer. During the first hour of

recovery from the sprint, blood samples were taken and analyzed for blood glucose,

glucose kinetics, insulin, and the counterregulatory hormones: glucagon, epinephrine,

norepinephrine, cortisol, and growth hormone.

iv

In response to the 30-second maximal sprint, blood glucose levels increased

significantly and similarly above baseline following both trials, reaching a peak at 10

minutes of recovery. After this point, blood glucose levels began to steadily decline

towards baseline, with a more rapid decline following EX. Consequently, blood glucose

levels were significantly lower at 45 minutes of recovery (p = 0.024) following EX

compared to CON, and also tended to be lower in EX at 30 (p = 0.067) and 60

(p = 0.072) minutes of recovery. The increase in blood glucose levels in response to the

maximal sprint effort may be explained by a greater increment in glucose rate of

appearance (Ra) compared with glucose rate of disappearance (Rd) in early recovery (p

< 0.05), but may also be attributed to some extent to a large fluid shift out of the plasma.

However, the more rapid decline in blood glucose after the initial increase in EX cannot

be explained by a shift in plasma volume since the magnitude of plasma volume shift

was similar in both trials. Rather, this was associated with a higher Rd than Ra early

after the peak in blood glucose during recovery following EX compared with CON.

This is likely explained, at least in part, by the blunted growth hormone response and

increased insulin sensitivity in EX. Plasma insulin levels peaked similarly in both trials

at 30 minutes of recovery following the sprint, but were significantly lower in EX at 45

(p = 0.042) minutes of recovery. In addition, 60 minutes of antecedent exercise was

associated with significantly lower levels of growth hormone at 15 (p = 0.048), 30

(p = 0.025), and 45 (p = 0.028) minutes of recovery. There was no difference in cortisol

or norepinephrine between trials, while there was a small significant difference in

epinephrine at 15 minutes of recovery between trials, with slightly higher levels

following EX (p = 0.036). Glucagon increased at 60 minutes of recovery from EX,

likely in response to the rapid decline in blood glucose levels in this trial.

In summary, performance of antecedent exercise several hours prior to a 30-second

sprint does not affect the magnitude of the initial blood glucose increase, but does

accelerate the decline of blood glucose levels back to baseline. This raises the question

of whether antecedent exercise would have a similar effect in individuals with T1DM. If

so, individuals with T1DM should be cautious when performing a sprint after a bout of

antecedent exercise, as it may not be as effective as a sprint alone. Therefore, further

investigation of this phenomenon in individuals with T1DM is warranted before

complete guidelines can be given.

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DECLARATION FOR THESES CONTAINING PUBLISHED WORK AND/OR WORK PREPARED FOR PUBLICATION

The examination of the thesis is an examination of the work of the student. The work must have been substantially conducted by the student during enrolment in the degree.

Where the thesis includes work to which others have contributed, the thesis must include a statement that makes the student’s contribution clear to the examiners. This may be in the form of a description of the precise contribution of the student to the work presented for examination and/or a statement of the percentage of the work that was done by the student.

In addition, in the case of co-authored publications included in the thesis, each author must give their signed permission for the work to be included. If signatures from all authors cannot be obtained, the statement detailing the student’s contribution to the work must be signed by the coordinating supervisor.

Please sign one of the statements below.

1. This thesis does not contain work that I have published, nor work under review for publication.

Student Signature…………………………………………………………………………………..

2. This thesis contains only sole-authored work, some of which has been published and/or prepared for publication under sole authorship. The bibliographical details of the work and where it appears in the thesis are outlined below.

Student Signature…………………………………………………………………………………...............

3. This thesis contains published work and/or work prepared for publication, some of which has been co-authored. The bibliographical details of the work and where it appears in the thesis are outlined below. The student must attach to this declaration a statement for each publication that clarifies the contribution of the student to the work. This may be in the form of a description of the precise contributions to the student to the published work and/or a statement of percent contribution by the student. This statement must be signed by all authors. If signatures from all the authors cannot be obtained, the statement detailing the student’s contribution to the published work must be signed by the coordinating supervisor.

Chapter 2 – “Effect of Antecedent Moderate-Intensity Exercise on the Glycaemia-Increasing Effect of a 30-second Maximal Sprint” will be prepared for publication in the near future.

Student Signature………………………………………………………………………………….

Coordinating Supervisor Signature………………………………………………………………..

vi

Statement of Candidate Contribution

The work involved in designing and conducting the study described in this thesis has

been conducted primarily by Tara Justice (the candidate). The thesis outline and

experimental design of the study was developed and planned by the candidate, in

consultation with Dr Kym Guelfi, Dr Paul Fournier, Dr Raymond Davey, & Dr Tim

Jones (the candidates supervisors). All participant recruitment and management was

carried out entirely by the candidate, along with the actual organization, implementation

and performance of the experiments, with the assistance of nursing staff for the purpose

of cannulation and infusion procedures, as well as research associates for blood

analysis. In addition, the candidate was responsible for all data analysis and original

drafting of the thesis. Dr Kym Guelfi, Dr Paul Fournier, Dr Raymond Davey, and Dr

Tim Jones have provided feedback for further drafts and polishing of the thesis and

manuscript.

Student Signature………………………………………………………………………………….

Coordinating Supervisor Signature………………………………………………………………..

vii

Table of Contents

Executive Summary………………………………………………………………. iii

Declaration for Thesis Containing Published Work And/Or Work Prepared for Publication………………………………………………………………………… v

Statement of Candidate Contribution……………………………………………... vi

Table of Contents…………………………………………………………………. vii

List of Tables……………………………………………………………………… xi

List of Figures……………………………………………………………………... xii

List of Abbreviations……………………………………………………………… xiii

Acknowledgments………………………………………………………………… xv

Chapter One: Introduction and Review of the Literature

1.1 Introduction……….. …………………………………………………….. 2

1.2 Type 1 Diabetes Mellitus………………………………………………... 3

1.3 Management of Type 1 Diabetes Mellitus………………………………. 5

1.4 Hyperglycaemia in Type 1 Diabetes Mellitus…………………………… 7

1.5 Hypoglycaemia in Type 1 Diabetes Mellitus……………………………. 8

1.5.1 Prevention and Correction of Hypoglycaemia in

Non-Diabetic Individuals……………………………………. 9

1.5.1.a Glucagon…………………………………………... 10

viii

1.5.1.b Catecholamines……………………………………. 10

1.5.1.c Growth Hormone and Cortisol…………………….. 11

1.5.2 Prevention and Correction of Hypoglycaemia in Individuals

with Type 1 Diabetes………………………………………….. 13

1.5.2.a Influence of Gender on the Response to

Hypoglycaemia…………………………………….. 14

1.5.2.b Influence of Prior Exercise on the Response to

Hypoglycaemia…………………………………….. 15

1.6 Exercise and Type 1 Diabetes Mellitus…………………………………... 16

1.6.1 Current Exercise Guidelines for Individuals

with Type 1 Diabetes………………………………………….. 17

1.7 Regulation of Blood Glucose Levels during Moderate-Intensity

Exercise and Recovery…………………………………………………… 18

1.7.1 Regulation of Blood Glucose Levels during Moderate-

Intensity Exercise in Non-Diabetic Individuals……………….. 18

1.7.2 Regulation of Blood Glucose Levels during Moderate-

Intensity Exercise in Individuals with Type 1 Diabetes………. 20

1.8 Regulation of Blood Glucose Levels during High-Intensity Exercise

and Recovery…………………………………………………………….. 23

1.8.1 Regulation of Blood Glucose Levels during High-Intensity

Exercise in Non-Diabetic Individuals………………………… 24

1.8.2 Regulation of Blood Glucose Levels during High-Intensity

Exercise in Individuals with Type 1 Diabetes………………… 26

1.9 Clinical Implications of High-Intensity Exercise as a Tool to Reduce

the Risk of Hypoglycaemia………………………………………………. 27

ix

1.10 Factors that May Influence the Glycaemia-Increasing Effect of a

Sprint in Individuals with Type 1 Diabetes……………………………… 29

1.10.1 Antecedent Hypoglycaemia…………………………………... 29

1.10.2 Antecedent Exercise…………………………………………... 30

1.11 Summary…………………………………………………………………. 32

1.12 Aims……………………………………………………………………… 32

1.13 Research Hypotheses…………………………………………………….. 33

1.14 Significance of the Study………………………………………………… 33

1.15 References………………………………………………………………... 34

Chapter Two: Effect of Antecedent Moderate-Intensity Exercise on the

Glycaemia-Increasing Effect of a 30-second Maximal Sprint

2.1. Abstract…………………………………………………………………... 50

2.2. Introduction………………………………………………………………. 51

2.3. Research Design and Methods…………………………………………… 53

2.3.1. Participants……………………………………………………. 53

2.3.2. Experimental Design………………………………………….. 54

2.3.3. Familiarization Session……………………………………….. 55

2.3.4. Experimental Trials…………………………………………… 55

2.3.5. Measurement of Blood Metabolites and Hormones…………... 58

2.3.6. Measurement of [6,6-2H] glucose enrichment, and glucose

Ra and Rd calculations………………………………………… 59

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2.3.7. Statistical Analyses…………………………………………… 60

2.4. Results……………………………………………………………………. 60

2.4.1. Characteristics of the 60-minute antecedent bout of exercise

and maximal sprint efforts…………………………………….. 60

2.4.2. Blood glucose response to a 30-second maximal sprint………. 62

2.4.3. Glucose rate of appearance and rate of disappearance

determined without corrections in plasma volume……………. 63

2.4.4. Glucose rate of appearance and rate of disappearance when

corrected for plasma volume changes………………………… 64

2.4.5. Plasma insulin response to a 30-second maximal sprint……… 65

2.4.6. Counterregulatory hormone response to a 30-second

maximal sprint………………………………………………… 65

2.4.7. Blood lactate, blood pH, and heart rate responses to a 30-second

maximal sprint………………………………………………… 73

2.5. Discussion………………………………………………………………... 75

2.6. References………………………………………………………………... 80

Appendices

Appendix A: Testing Information Sheets and Consent Forms……………………. 87

Appendix B: Human Ethics Approval Form………………………………………. 91

Appendix C: Meal Record Sheet…………………………………………………... 96

Appendix D: Data Collection Sheets………………………………………………. 100

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List of Tables

2.1 Characteristics of Study Participants…………………………………….. 54

2.2 Response of oxygen consumption, blood lactate, and heart rate

to 60 minutes of antecedent exercise or rest (control)…………………… 61

2.3 Comparison of mean and peak power output during a 30-second

maximal sprint following 60 minutes of antecedent exercise or rest

(control)………………………………………………………………….. 62

2.4 Percent change in plasma volume (%∆PV) in response to a

30-second maximal sprint………………………………………………... 68

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List of Figures

2.1 Blood glucose response to a 30-second maximal sprint performed

after 60 minutes of exercise (EX) or rest (CON)………………………… 63

2.2a Glucose Ra and Rd in response to a 30-second maximal sprint

performed after 60 minutes of rest (CON)……………………………….. 67

2.2b Glucose Ra and Rd in response to a 30-second maximal sprint

performed after 60 minutes of exercise (EX)……………………………. 67

2.3 Change in haematocrit in response to a 30-second maximal sprint

performed after 60 minutes of exercise (EX) or rest (CON)…………….. 68

2.4a Glucose Ra and Rd in response to a 30-second maximal sprint

performed after 60 minutes of rest (CON) when corrected for plasma

volume changes………………………………………………………….. 69

2.4b Glucose Ra and Rd in response to a 30-second maximal sprint

performed after 60 minutes of exercise (EX) when corrected for

plasma volume changes………………………………………………….. 69

2.5 Plasma insulin response to a 30-second maximal sprint performed

after 60 minutes of exercise (EX) or rest (CON)………………………… 70

2.6 Plasma glucagon response to a 30-second maximal sprint performed

after 60 minutes of exercise (EX) or rest (CON)………………………… 70

2.7a Plasma epinephrine response to a 30-second maximal sprint performed

after 60 minutes of exercise (EX) or rest (CON)………………………… 71

2.7b Plasma norepinephrine response to a 30-second maximal sprint

performed after 60 minutes of exercise (EX) or rest (CON)…………….. 71

2.8 Plasma growth hormone response to a 30-second maximal sprint

performed after 60 minutes of exercise (EX) or rest (CON)…………….. 72

2.9 Plasma cortisol response to a 30-second maximal sprint performed

after 60 minutes of exercise (EX) or rest (CON)………………………… 72

2.10 Blood lactate response to a 30-second maximal sprint performed after

60 minutes of exercise (EX) or rest (CON)………………………………. 74

2.11 Blood pH response to a 30-second maximal sprint performed after

60 minutes of exercise (EX) or rest (CON)……………………………… 74

xiii

Abbreviations

alpha ANS autonomic nervous system ATP adenosine triphosphate beta BMI body mass index (weight/height2) bpm beats per minute BW body weight

°C degrees celsius CGMS continuous glucose monitoring system cm centimeter CON control (rest) condition

DKA diabetic ketoacidosis EX exercise condition

g gram GCMS gas chromatography mass spectrometry GLUT 2 glucose transporter type 2 GLUT 4 glucose transporter type 4 h hour H+ hydrogen ion HbA1C glycated haemoglobin HR heart rate HRmax maximal heart rate kg kilogram L liter m meter

xiv

mM millimolar mg milligram min minute mIu/L milli-international units per liter ml milliliter

nmol/L nanomoles per liter Pi inorganic phosphate pg/mL picograms per milliliter pmol/L picomoles per liter

Ra rate of appearance of glucose

Rd rate of disappearance of glucose

rpm revolutions per minute SD standard deviation SEM standard error of the mean

T1DM type 1 diabetes mellitus µU/ml microunits per milliliter

O2 rate of oxygen consumption

O2peak peak rate of oxygen consumption W watt

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Acknowledgements

There is no doubt that this thesis would not exist without the support, guidance, and hard work of several people.

To Kym – I am speechless. I honestly don’t think I could have asked for a more outstanding supervisor! I’m eternally grateful to be the student of a supervisor with

never-ending guidance, support, and encouragement like yours. You’ve made this year nothing short of a great experience, and I don’t think I can thank you enough!

To Paul – Your endless enthusiasm and love for research is highly contagious and has

fueled me all year long. When I think I have all the answers, you ask the question that I can’t answer. Thanks for your guidance and support over the year!

To “Butler” Ray – The number of hours we have worked together does not do justice to

the effort and dedication you had to my project. Between editing, drawing award-winning kinetics diagrams, and catering to the every need of my participants, I’m not too sure how you had time for your own work. Thank you for absolutely everything!!

To Tim – Your expertise and feedback regarding the experimental design

and final thesis has been greatly appreciated. Thanks so much!

To my Participants – You were the backbone of this thesis! Thank you for your time, sweat, oxygen, veins, blood, and feel-good-state. I appreciate your flexibility and dedication to my study. You kept me entertained and on my toes at the same time!

To Niru, Adam, & Heather at PMH – This study could not have happened without all of you! Your guidance, expertise, and humor have been invaluable throughout the research process. You’ve challenged me to improve my critical thinking and

scrabble skills. Every day in the lab had some good to it!

To Ang, Katherine, Dan, Elisa, Annie, and James – Thanks so much for the Redbull offers, technical support, coffee dates, pep talks, opportunities to procrastinate,

and advice. You’ve been an amazing support network and I can’t imagine a graduate program without people like you. I’ll miss you all!

To my housemates – Thanks for your endless support and entertainment when I

don’t want to think about school anymore. Remember, haters gonna hate!

To Chloe & my Camp Huronda family – Thank you for continuing to inspire me and giving me a reason to find answers. This thesis is dedicated to all of you!

To my family – Although you may be thousands of miles away, you never fail to support me in my pursuits. Although none of you understand my research at all,

your ability to smile and nod is always appreciated!

 

 

 

Chapter One 

Introduction and Review of the Literature 

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1.1 Introduction

Individuals with type 1 diabetes mellitus aim to maintain blood glucose levels within

the normal physiological range of 4 to 8 mM. To achieve this goal, these individuals

must carefully balance their diet, physical activity, and exogenous insulin

administration. Regular blood glucose monitoring provides feedback to these

individuals and assists with decision-making regarding carbohydrate intake and insulin

administration. However, a balance is hard to achieve and blood glucose levels can

often deviate from the desired target range. A high blood glucose level

(hyperglycaemia) is a common occurrence for individuals with type 1 diabetes.

Unfortunately, chronic hyperglycaemia increases the risk of developing long-term

complications such as blindness, cardiovascular disease, and kidney failure. On the

other hand, a decline in blood glucose, often caused by the administration of too much

insulin, can lead to the onset of hypoglycaemia, a potentially life-threatening condition.

Another factor that increases the risk of hypoglycaemia is moderate-intensity exercise.

Regular exercise is a key component of any treatment plan for an individual with type 1

diabetes, but unfortunately moderate-intensity exercise causes a steady decline in blood

glucose levels thereby increasing the risk of hypoglycaemia during both exercise and

early recovery. However, it is often overlooked that different types of exercise have

different impacts on blood glucose levels. For instance, it has been shown that high-

intensity exercise causes blood glucose levels to increase, raising the possibility that this

type of exercise may be useful for the prevention of hypoglycaemia. As evidence for

this, the performance of a short 10-second maximal sprint before or after moderate-

intensity exercise has been shown to have a stabilizing effect on blood glucose levels

during early recovery, thereby reducing the risk of hypoglycaemia at this time.

However, before a short maximal sprint can be recommended as a tool for the

prevention of exercise-mediated hypoglycaemia, several factors that may alter the

glycaemia-increasing effect of a sprint, such as antecedent exercise, must be

investigated. Consequently, the primary goal of this thesis was to examine the effect of

antecedent moderate-intensity exercise on the blood glucose response to a short

maximal sprint performed later in the day. This issue was examined in non-diabetic

individuals to investigate how this factor influences the glycaemia-increasing effect of

sprinting under non-pathological conditions. The information obtained will form the

3

basis for future studies on individuals with type 1 diabetes and should provide valuable

information for management of blood glucose levels during exercise.

1.2 Type 1 Diabetes Mellitus

Type 1 diabetes mellitus (T1DM) represents 10-15% of all cases of diabetes in Australia

(Australian Diabetes Council, 2010). It currently affects 122,300 Australians, with 6

new cases diagnosed each day (Juvenile Diabetes Research Foundation, 2010a). T1DM

is most commonly diagnosed in children 15 years or younger and is the second most

common chronic disease in school-aged children, preceded only by asthma

(Strawhacker, 2001). However, diagnosis at an older age is still a possibility with

approximately 50% of patients diagnosed older than 20 years of age (Juvenile Diabetes

Research Foundation, 2006; Khardori, 2011).

T1DM is an autoimmune disease with onset occurring following destruction of the beta

cells of the pancreas, which are responsible for producing insulin. It is currently not

fully understood what triggers this autoimmune reaction, but it has been suggested that

both genetics and the environment may play a role (Juvenile Diabetes Research

Foundation, 2010a). Insulin is a key glucoregulatory hormone, which, in conjunction

with glucagon, helps to regulate blood glucose and circulating fatty acid levels.

Insulin’s primary role is to lower blood glucose levels by stimulating uptake of glucose

by insulin-sensitive cells and suppressing hepatic glucose production (Strawhacker,

2001). With respect to glucose uptake, insulin stimulates translocation of the glucose

transporter GLUT 4 from the intracellular storage site to the plasma membrane where it

readily transports glucose out of the bloodstream and into the cells, especially those of

skeletal muscle (Tuch et al., 2000). Insulin further decreases blood glucose by inhibiting

glycogenolysis and gluconeogenesis in the liver (Cherrington et al., 1998).

In individuals without diabetes, the level of circulating insulin is tightly regulated.

Insulin secretion by the pancreas is regulated primarily, but not exclusively, by the

blood glucose level itself (Henquin, 2000). As the blood glucose level rises, glucose

enters the beta cells of the pancreas via GLUT 2 transporters and is subsequently broken

down to produce adenosine triphosphate (ATP). The build-up of ATP within the beta

cells stimulates the secretion of insulin, which works through a negative feedback loop

4

to decrease the blood glucose level (Tuch et al., 2000). In this manner, insulin and blood

glucose work together to maintain euglycaemia in the bloodstream. For example, as

blood glucose levels rise, insulin secretion increases in an attempt to bring blood

glucose levels back to the euglycemic range, whereas low blood glucose levels inhibit

insulin secretion to conserve the limited supply of blood glucose.

In contrast, individuals with T1DM lack the ability to produce insulin. Insulin

deficiency in the body results in increased hepatic glucose production and a lack of

peripheral glucose uptake, causing glucose to accumulate in the bloodstream. A chronic

state of hyperglycaemia ensues, further exacerbated by an excessive increase in some

counterregulatory hormones (Goldstein et al., 1995). These counterregulatory hormones

include glucagon, epinephrine, norepinephrine, cortisol, and growth hormone. These

hormones normally function to oppose the action of insulin and some stimulate a rise in

blood glucose levels by activating hepatic glycogenolysis, inhibiting glucose uptake by

the tissues, and promoting the conversion of gluconeogenic precursors (i.e. lactate,

alanine, and glycerol) into glucose (Goldstein et al., 1995). However, the lack of insulin

production in T1DM means the actions of the counterregulatory hormones are

unopposed, with some such as glucagon reaching extremely high levels and causing

blood glucose levels to rise as a result. High levels of glucose in the blood cause glucose

to spill into the urine, causing increased urine output, which results in dehydration and

electrolyte loss (Lumb & Gallen, 2009). Consequently, hyperglycaemia presents with

symptoms of excessive thirst (polydipsia), excessive urination, (polyuria), and excessive

hunger (polyphagia), along with weight loss and blurred vision.

The absence of circulating insulin combined with excessively high levels of glucagon

results in a marked increase in plasma fatty acid levels. These factors in turn stimulate

hepatic ketogenesis, which causes ketone bodies (i.e. acetoacetate, acetone, and 3-ß-

hydroxybuturate) to accumulate in the blood, causing metabolic acidosis due to their

weak acidic properties. The combination of high blood glucose levels, high ketone

levels, and metabolic acidosis is often referred to as diabetic ketoacidosis (DKA), and is

often present at the time of diagnosis of T1DM (American Diabetes Association, 2011).

Left untreated, DKA can lead to a diabetic coma or even death (Kitabchi et al., 2001).

Another acute complication of high blood glucose is increased risk of septicemia

(Kitabchi et al., 2001). Hyperglycaemic conditions are conducive to the growth of

bacteria and can aggravate what might have been a minor infection otherwise. For these

reasons, individuals with T1DM die often within 1 to 2 years if left untreated.

5

1.3 Management of Type 1 Diabetes Mellitus

There is currently no cure for T1DM. However, the discovery of insulin in 1921 has

greatly enhanced the quality of life and life expectancy of those individuals living with

the disease. Currently, treatment of the condition involves maintaining blood glucose

within the normal physiological range (4 to 8 mM) with the administration of

exogenous insulin, typically via multiple daily injections with a syringe or insulin pen.

Initially, several varieties of animal-sourced insulin, such as bovine (cow) and porcine

(pig), were used for treatment. Today, most varieties of administered insulin are

biosynthetic recombinant ‘human’ insulin or its analogs.

There are currently a number of different insulin analogs with various pharmacokinetic

properties (i.e. absorption rate, duration, and time of peak action) available to

individuals with T1DM to optimize their blood glucose control. Most individuals

combine a rapid-acting insulin (e.g. insulin Aspart or Lispro), typically absorbed within

5 to 15 minutes of administration and peaking 30 to 90 minutes later, with a long-acting

insulin (e.g. insulin Glargine or Detemir) that has a delayed absorption and peaks

between 4 to 12 hours after administration (Shalitin & Phillip, 2008). The rapid-acting

insulin is used to combat the large and rapid postprandial rises in blood glucose,

attempting to mimic the normal insulin secretion following a meal. For this reason, it is

typically administered just prior to eating. On the other hand, long-acting insulins are

designed to mimic the basal secretion of insulin over the course of the day and

throughout the night. This form of insulin is responsible for combating small

fluctuations in blood glucose as a result of stress and daily activities, and is

administered once or twice daily at a predetermined time (Shalitin & Phillip, 2008).

Two therapeutic approaches have been used in the treatment of diabetes, with intensive

therapy more widely used than conventional therapy today (Strawhacker, 2001).

Intensive therapy incorporates three or more daily insulin injections, comprising one or

two daily injections of long-acting insulin and multiple daily injections of rapid-acting

insulin in conjunction with meals to mimic the natural secretion of insulin (The

Diabetes Control and Complications Trial, 1993). Frequent blood glucose monitoring

and strict glycaemic targets accompany intensive therapy. On the other hand,

conventional therapy involves twice-daily insulin injections, which contain a mixture of

short and long acting insulins, and a wider range of acceptable blood glucose levels

(Strawhacker, 2001). The general adoption of intensive therapy is the result of The

6

Diabetes Control and Complications Trial, which found marked reductions in several

diabetic complications following intensive therapy aimed at normalizing blood glucose

levels in T1DM (The Diabetes Control and Complications Trial Group, 1993).

Recently, however, the development of the subcutaneous insulin pump has removed the

need for injections for those on intensive regimens. The insulin pump delivers rapid-

acting insulin at a basal rate throughout the day through a catheter inserted

subcutaneously into the abdomen, and has the ability to deliver a bolus of insulin when

carbohydrates are consumed (Strawhacker, 2001). These devices attempt to match the

activity of a healthy pancreas and are a big step towards a closed-loop regulation

system, the ultimate goal of diabetic technological advances.

Although exogenous administration of insulin greatly helps to maintain blood glucose

levels within a reasonable range, it is important to note that an excess of insulin can

have potentially fatal consequences. For this reason, individuals with T1DM must

undergo regular blood glucose monitoring prior to making any decisions about insulin

administration, food intake, or exercise. The advent of portable blood glucose meters

makes this a relatively simple process, with most meters requiring only a single drop of

capillary blood from the fingertip and giving results within seconds (American Diabetes

Association, 1997). It is generally recommended that individuals following an intensive

therapeutic regimen monitor their blood glucose level 3 to 4 times per day

(Strawhacker, 2001). Strategically placing these checks before meals and sleep allows

an individual to make informed decisions about carbohydrate intake and insulin

administration. However, a shortcoming of blood glucose monitoring is that it only

provides the immediate blood glucose level and does not show any possible fluctuations

between tests. The recent development of continuous glucose monitoring systems

(CGMS) overcomes this shortcoming, providing nearly continuous estimates of blood

glucose. The small, lightweight sensor measures subcutaneous tissue interstitial glucose

levels every 5 minutes, and transmits this information to a monitor worn on clothing or

a belt (Kaufman et al., 2001). The data can then be uploaded onto a computer where

glucose values and trends can be seen, providing a guide for individuals with T1DM.

Unfortunately, the current sensors only have a recommended lifespan of a few days,

making CGMS a very expensive system and, consequently, not accessible to everyone

with T1DM.

Patients’ success at maintaining blood glucose levels within the physiological range is

assessed indirectly by the measurement of their glycosylated haemoglobin, otherwise

7

known as HbA1C, a commonly used test and currently the gold standard measurement of

long-term glycaemic control. As glucose circulates in the blood, some glucose

glycosylates haemoglobin, which remains this way until the death of the red blood cell.

Since the red blood cell has an approximate lifespan of 120 days, a measurement of

HbA1C provides an indication of the average blood glucose level over the preceding 120

days (American Diabetes Association Position Statement, 2011; Sacks et al., 2002;

Shemin & Rittenberg, 1946). For example, a high HbA1C reading (>7.5%) indicates that

blood glucose levels were often above the desired target range during the 120 days. In

this manner, HbA1C tests can highlight poor glycaemic control even if regular blood

glucose monitoring suggests that the individual is in good control.

1.4 Hyperglycaemia in Type 1 Diabetes Mellitus

Consistently achieving the perfect balance between administered insulin and

carbohydrate intake is very difficult, and blood glucose fluctuations outside of the

normal physiological range (4 to 8 mM) often occur. Hyperglycaemia, defined as blood

glucose in excess of 8 mM, is often the result of inadequate insulin intake for a specified

amount of carbohydrate. The occurrence of chronic hyperglycaemia over a number of

years carries an increased risk of long-term health complications (The Diabetes Control

and Complications Trial Group, 1993). These include vision problems, nerve damage,

kidney disease, and cardiovascular problems (Juvenile Diabetes Research Foundation,

2010b).

A common long-term complication of T1DM is proliferative retinopathy, which

accounts for most cases of lost vision in the Western Hemisphere (Chiarelli et al.,

2005). This condition results from impaired regulation of blood flow in the microvessels

of the eye due to chronic hyperglycaemia, eventually causing small reductions in vision

which may progress to complete blindness (Chiarelli et al., 2005). Another complication

associated with chronic hyperglycaemia is the development of kidney disease, otherwise

known as nephropathy, which holds the highest mortality rate of all complications

(Jabbour, 2007). High levels of blood glucose stress the kidneys over time and cause

irreversible damage, ultimately resulting in end-stage renal disease (The Diabetes

Control and Complications Trial Research Group, 1995). Furthermore, T1DM

8

accelerates the progression of macrovascular disease. Mortality and morbidity from

various forms of cardiovascular disease (myocardial infarction, stroke, and

hypertension) is markedly increased in individuals with T1DM when compared to non-

diabetic individuals (Soedamah-Muthu et al., 2006). This is the result of high blood

glucose levels accelerating the progression of early atherosclerotic lesions (Krolewski et

al., 1987). Finally, chronic hyperglycaemia causes the development of both peripheral

and autonomic neuropathy. High levels of blood glucose cause atrophy of nerve fibers,

loss of myelinated and unmyelinated nerve fibers, and blunting of nerve fiber

regeneration (Greene et al., 1992). This results in abnormal nerve function in a number

of body systems. Peripheral neuropathy predisposes individuals with diabetes to skin

ulceration, gangrene, and potential amputation (Peirce, 1999). It is often sensed as a

feeling of coldness, tingling, or numbness in the extremities. On the other hand,

autonomic neuropathy can cause postural hypotension, vomiting, bladder paresis, and

sudden death (Chiarelli et al., 2005). The risk of developing any of these complications

can be greatly reduced by the use of intensive therapy to keep blood glucose levels

within the normal physiological range of 4 to 8 mM (The Diabetes Control and

Complications Trial, 1993).

1.5 Hypoglycaemia in Type 1 Diabetes Mellitus

Although the use of intensive therapy greatly reduces the risk of the longer-term

complications associated with hyperglycaemia, it is not without its disadvantages.

Intensive therapy is associated with an approximate threefold increase in the incidence

of severe hypoglycaemia, limiting the widespread implementation of this treatment

paradigm (The Diabetes Control & Complications Trial, 1993). Hypoglycaemia is a

condition characterized by blood glucose levels below 3.0 – 3.8 mM and is experienced

often by individuals with T1DM (Chiarelli et al., 1999). The average person with

T1DM experiences numerous asymptomatic episodes, thousands of symptomatic

episodes, and several severe (i.e. temporarily disabling) episodes of hypoglycaemia in

their lifetime (Chiarelli et al., 1999). Hypoglycaemia occurs since individuals with

T1DM cannot control their circulating level of insulin; rather, it is determined solely by

the amount, timing, and pharmacokinetics of the administered insulin. For this reason, a

9

relative insulin excess, as a result of insulin doses that are excessive or ill timed, can

cause hypoglycaemia (Rattarasarn et al., 1994).

The onset of hypoglycaemia is accompanied by a number of symptoms that can be

generally classified into one of two categories. Neurogenic symptoms, which include

anxiety, palpitations, hunger, sweating, irritability, tachycardia, and tremors, are caused

by hypoglycaemia-induced activation of the ANS (Bolli, 2003; Cryer et al., 2003). On

the other hand, neuroglycopenic symptoms are a result of glucose deprivation in the

brain. The brain is heavily reliant upon the delivery of glucose as it stores little in the

form of glycogen (Bolli, 2003; Cryer et al., 2003). Neuroglycopenic symptoms include

dizziness, tingling, blurred vision, difficulty thinking, and loss of coordination, and can

extend to convulsions, unconsciousness, brain damage, and even death when

hypoglycaemia is severe (Bolli, 2003). Detection of hypoglycaemia is largely due to

perception of these symptoms and recognition that they are indicative of hypoglycaemia

to allow for appropriate action to be taken.

1.5.1 Prevention and Correction of Hypoglycaemia in Non-Diabetic Individuals

In non-diabetic individuals, insulin and the counterregulatory hormones act

antagonistically to prevent hypoglycaemia. A negative feedback system involving

glucose and the glucoregulatory hormones allows for tight control and minimal

fluctuation of the blood glucose level from the normal physiological range. When blood

glucose levels decline to 4.5 mM, decreasing the circulating level of insulin is the first

corrective measure taken (Cryer et al., 2003). Insulin secretion by the pancreas virtually

ceases during hypoglycaemia in non-diabetic individuals, helping to restore

euglycaemia by stimulating increased hepatic glucose production and inhibiting glucose

uptake by the insulin-sensitive tissues (Cryer et al., 2003). If blood glucose levels

continue to decline to 3.6 to 3.9 mM, the counterregulatory hormones begin to play a

vital role. Glucagon and the catecholamines are the most important counterregulatory

hormones, followed by growth hormone and cortisol, which have been shown to have

lesser but longer-lasting effects (Rizza et al., 1979; Rosen et al., 1984). The

counterregulatory hormones help restore euglycaemia by stimulating endogenous

glucose production, increasing lipolysis, and limiting glucose uptake by tissues other

than the brain (Cryer et al., 2003).

10

1.5.1.a Glucagon

Glucagon is the primary counterregulatory hormone in non-diabetic individuals.

Glucagon is a single chain 29-amino acid polypeptide hormone that is secreted by the

alpha cells of the Islets of Langerhans of the pancreas (Jiang & Zhang, 2003). It is

secreted in a pulsatile fashion in response to low circulating levels of blood glucose as it

plays a role in returning blood glucose to the normal physiological range (Jiang &

Zhang, 2003; Opara et al., 1988). Glucagon acts by decreasing glycogen synthesis and

increasing the rate of hepatic glucose production via activation of glycogenolysis and

gluconeogenesis (Cryer et al., 2003; Jiang & Zhang, 2003). The primary role of

glucagon in glucose counterregulation has been demonstrated in studies where glucagon

secretion is impaired, resulting in reduced hepatic glucose production (Bolli et al., 1984;

Jiang & Zhang, 2003; Rizza et al., 1979). The importance of glucagon is further

supported by its clinical usage in treating insulin-induced hypoglycaemia in individuals

unable to self-treat with sugary drinks or snacks (Davis et al., 2000b; Draznin, 2000;

Haymond & Schreiner, 2001). An emergency injection of glucagon subcutaneously or

intramuscularly during an episode of severe hypoglycaemia quickly increases blood

glucose levels, primarily through the conversion of liver glycogen stores to glucose

(Fonjallaz & Loumaye, 2000; Unger & Orci, 1994).

Glucagon’s importance mainly lies in its acute effect on hypoglycaemia. Fortunately,

only a small amount of glucagon is needed to significantly raise blood glucose levels

(Myers et al., 1991; Sandoval et al., 2004; Strawhacker, 2001). The glucose-rising effect

of glucagon occurs within minutes and dissipates rapidly, highlighting the need for

pulsatile secretion (Dobbins et al., 1998). However, the main factor of interest for the

maintenance of blood glucose levels is the ratio of insulin to glucagon. A high ratio of

insulin to glucagon will cause blood glucose levels to decline through stimulation of

glucose uptake by the tissues and inhibition of hepatic glucose production, and vice

versa when the ratio is low (Boyle et al., 1989).

1.5.1.b Catecholamines

The catecholamines, namely epinephrine and norepinephrine, are part of the

sympathetic nervous system and play a secondary role to glucagon in glucose

11

counterregulation. The catecholamines are released in response to stress and form part

of the body’s fight-or-flight response. The adrenal medulla is the main site of

production, secreting 80% epinephrine and 20% norepinephrine, with norepinephrine

also being secreted from the endings of sympathetic neurons (Klabunde, 2008).

Like glucagon, the catecholamines are secreted in response to low blood glucose levels

(Porcellati et al., 2003). They increase blood glucose levels by stimulating increased

hepatic glucose production via glycogenolysis and gluconeogenesis and decreasing

glucose uptake by the tissues (Cryer et al., 2003). A rise in plasma epinephrine has been

shown to initially increase hepatic glycogenolysis and later hepatic gluconeogenesis

when the hepatic glycogen stores begin to deplete (Goldstein et al., 1995). Furthermore,

epinephrine has been shown to decrease glucose clearance from the blood and thus

further stimulate a rise in blood glucose (Rizza et al., 1979).

However, the catecholamines are not essential for acute glucose counterregulation in

non-diabetic individuals. Their importance in glucose counterregulation emerges when

glucagon secretion is deficient. A number of studies have found increased

catecholamine levels when somatostatin and insulin have been infused to suppress

glucagon secretion. Under these conditions, catecholamine levels rise in an attempt to

compensate for the lack of glucagon and return blood glucose back to the normal

physiological range (Boyle et al., 1989; Cryer et al., 2003; Rizza et al., 1979; Rosen et

al., 1984). Although not essential, the catecholamines do still play a role when glucagon

is present. A substantial decrease in blood glucose elicits secretion of the

catecholamines, which work in conjunction with glucagon to prevent hypoglycaemia

and return blood glucose back to the normal physiological range (Rosen et al., 1984).

1.5.1.c Growth Hormone & Cortisol

Growth hormone and cortisol are counterregulatory hormones that make small

contributions to glucoregulation. Growth hormone is released from the anterior pituitary

gland while cortisol is released from the adrenal cortex, both being released in a

pulsatile pattern (Kanaley & Hartman, 2002). These hormones have a more progressive

and longer lasting-effect on blood glucose level than glucagon or epinephrine, with their

main benefit lying in their contribution to preventing prolonged hypoglycaemia (Boyle

& Cryer, 1991). Both hormones limit glucose uptake and support glucose production

12

over a longer time frame (hours) (Cryer et al., 2003). Conversely, these hormones are

unlikely to play a role in acute recovery from hypoglycaemia since recovery from

hypoglycaemia has been observed in the absence of these hormones (Boyle & Cryer,

1991; Rizza et al., 1979). Furthermore, when growth hormone and cortisol are the only

two hormones present, hypoglycaemia still progresses, again suggesting that they do not

have an important role (Boyle et al., 1989). Previous studies have shown that 3 to 4

hours of hypoglycaemia is required before growth hormone or cortisol has a significant

effect on blood glucose regulation (Rizza et al., 1979). This has been shown with the

combined infusion of somatostatin and growth hormone, which causes inhibition of

glucagon and insulin secretion and allows the effects of growth hormone and cortisol to

be isolated (Rizza et al., 1979). When growth hormone and cortisol do take effect, they

begin by acting on the liver to increase hepatic glucose production, with further delayed

effects on glucose uptake (De Feo et al., 1989a; De Feo et al., 1989b). For this reason, it

has been proposed that both hormones have a more pronounced effect on glucose

production than uptake (De Feo et al., 1989a; De Feo et al., 1989b). However, research

performed over the past decade has shown that a sudden increase in growth hormone

levels can acutely inhibit peripheral glucose utilization rate (Møller et al., 1990; Møller

et al., 1992).

Of note, although cortisol appears to play a role in long-term prevention of

hypoglycaemia, it may also play a role in increasing the risk of hypoglycaemia under

certain conditions. Cortisol is potentially responsible for the blunting of

counterregulatory responses to hypoglycaemia after an antecedent stress. Exercise and

hypoglycaemia, both stresses to the body, have been shown to increase cortisol levels,

which subsequently blunt autonomic hormone responses to any subsequent

hypoglycaemic episodes (Bao et al., 2009; Davis et al., 1996; Galassetti et al., 2001a;

Sandoval et al., 2004). When cortisol levels are suppressed during the initial stressor,

responses to the subsequent hypoglycemic episode are preserved (Davis et al., 1996).

However, it is important to note that not all studies support a role for cortisol in the

blunting of counterregulatory responses (Goldberg et al., 2006; Raju et al., 2003).

13

1.5.2 Prevention and Correction of Hypoglycaemia in Individuals with Type 1 Diabetes

In comparison to non-diabetic individuals, the defense against hypoglycaemia is not as

well coordinated in individuals with T1DM. Impairments in several of the basic

components of the counterregulatory response cause a 25-fold increased risk for severe

hypoglycaemia in this population compared to non-diabetic individuals (Gosmanov et

al., 2005). First and foremost, individuals with T1DM lose the ability to endogenously

decrease their circulating level of insulin, which is normally the first line of defense

against an episode of hypoglycaemia (Cryer et al., 2003). Their circulating level of

insulin is instead determined by the rate of passive absorption from the site of

administration and the pharmacokinetics of the administered insulin. As a result, a fall

in blood glucose cannot be attenuated by a decline in insulin secretion, and the level of

hypoglycaemia worsens.

Furthermore, the release of counterregulatory hormones has been shown to be

suboptimal in this population (Cryer et al., 2003; Ertl & Davis, 2004; Galassetti et al.,

2003). The second line of defense against hypoglycaemia, the increase in glucagon

secretion, is usually lost early in the course of the disease (Gosmanov et al., 2005). In

healthy individuals, it is the decrease in the beta cell secretion of insulin that causes an

increase in glucagon secretion by the alpha cells (Gosmanov et al., 2005). For this

reason, it is suggested that the lack of a change in the beta cell activity in individuals

with T1DM might explain the impaired glucagon response. As a result of the impaired

glucagon response to hypoglycaemia, the catecholamine response becomes essential in

individuals with T1DM (Bolli, 1990). However, this response may also be attenuated in

individuals with T1DM, causing the clinical syndrome of defective glucose

counterregulation (Amiel et al., 1988; Bolli et al., 1983; Bolli et al., 1984). In addition,

the glycemic threshold for a counterregulatory response is often shifted to a lower blood

glucose level in this population, making the risk of severe hypoglycaemia even greater

(Amiel et al., 1988). The shift in the glycemic threshold to a lower level is a result of

intensive therapy and antecedent episodes of hypoglycaemia, which are responsible for

making the body accustomed to lower blood glucose levels (Dagogo-Jack et al., 1993).

Fortunately, most individuals with T1DM are able to recognize the warning signs and

symptoms of hypoglycaemia and can treat themselves immediately by ingesting sugary

drinks or snacks. Hypoglycaemia is usually treated with fast-acting carbohydrates to

14

prevent any further decline in blood glucose levels, and occasionally with intramuscular

injection of glucagon if oral intake of carbohydrates is not possible (Davis et al., 2000b;

Draznin, 2000, Haymond & Schreiner, 2001). However, some intensively treated

patients lose the ability to detect the neurogenic symptoms of hypoglycaemia and suffer

from hypoglycaemia-associated autonomic failure (Bolli, 2003; Cryer et al., 2003;

Dagogo-Jack et al., 1993). Hypoglycaemia unawareness, one part of hypoglycaemia-

associated autonomic failure, can be the result of recurrent episodes of hypoglycaemia.

It increases the risk of experiencing severe hypoglycaemia as the individual cannot

detect and thus treat episodes of hypoglycaemia (Rattarsarn et al., 1994). Recurrent

episodes of hypoglycaemia also impair the autonomic counterregulatory responses,

specifically the catecholamine response, to subsequent episodes of hypoglycaemia

(Davis et al., 1997; Fanelli et al., 1993; Heller & Cryer, 1991). Of interest, several

studies have shown that 2 to 3 weeks of avoiding hypoglycaemia can reverse

hypoglycaemia-associated autonomic failure in most patients. This includes a return of

the epinephrine counterregulatory response, an improved ability to detect neurogenic

symptoms, and a normalization of the threshold at which symptoms occur (Cryer et al.,

2003; Fanelli et al., 1993). Unfortunately, the responses of glucagon and norepinephrine

remain attenuated.

1.5.2.a Influence of Gender on the Response to Hypoglycaemia

Gender has been determined to be a key factor in the response to hypoglycaemia.

Firstly, it has been suggested that women have a lower blood glucose threshold for

counterregulatory hormone release since blood glucose must drop even lower than in

men before a response is evoked (Davis et al., 1993; Davis et al., 2000d; Widom et al.,

1991). Furthermore, in response to a given level of hypoglycaemia with equivalent

insulinemia, women display a lesser counterregulatory response than men (Amiel et al.,

1993; Davis et al., 1993; Diamond et al., 1993). Compared to men, women also show

reduced epinephrine, norepinephrine, and growth hormone responses to equivalent

levels of hypoglycaemia (Davis et al., 2000a). Based on these responses, it might be

assumed that the incidence of hypoglycaemia would be higher in women with T1DM

compared to men with T1DM since this population is highly reliant on epinephrine

(Davis et al., 2000a). However, the incidence of severe hypoglycaemia is gender neutral

possibly in part from women having greater resistance to the blunting effects of

15

antecedent hypoglycaemia (Davis et al., 2000d). A study completed with several levels

of antecedent hypoglycaemia (3.9 mM, 3.3 mM, and 2.9 mM) showed that women only

had limited blunting of their counterregulatory responses after antecedent

hypoglycaemia of 2.9 mM, while men exhibited blunted responses after all levels of

antecedent hypoglycaemia (Davis et al., 2000d). In fact, antecedent hypoglycaemia of

2.9 mM in women and 3.9 mM in men produced equivalent counterregulatory failure

(Davis et al., 2000d). Thus, women’s resistance to the blunting of these responses by

antecedent hypoglycaemia may balance out their innate reduced autonomic responses to

hypoglycaemia and explain the similar incidence of hypoglycaemia in both genders.

1.5.2.b Influence of Prior Exercise on the Response to Hypoglycaemia

Antecedent exercise may also blunt the counterregulatory response to subsequent

episodes of hypoglycaemia (Galassetti et al., 2001a). In a study involving non-diabetic

individuals, epinephrine, norepinephrine, glucagon, and growth hormone responses to

next-day hypoglycaemia were blunted after two 90-minute bouts of antecedent

moderate-intensity exercise at 50% O2max separated by 180 minutes (Galassetti et al.,

2001a). These effects have also been observed using low- (30% O2max) and

moderate- (50% O2max) intensity exercise in individuals with T1DM (Sandoval et al.,

2004). After two 90-minute bouts of antecedent exercise at either intensity separated by

180 minutes, individuals with T1DM exhibited blunted autonomic, epinephrine, and

symptomatic responses to subsequent hypoglycaemia compared to a resting control

condition (Sandoval et al., 2004). However, no differences in the norepinephrine,

growth hormone, or cortisol responses to hypoglycaemia were noted. Of interest, the

epinephrine response to hypoglycaemia also appeared to be blunted to a greater extent

in individuals with T1DM compared to non-diabetic individuals, suggesting that

individuals with T1DM may experience slightly greater counterregulatory failure after

an antecedent stressor (Galassetti et al., 2001a; Sandoval et al., 2004). In spite of the

various reported amounts of blunting, it is clear that antecedent exercise does act as a

stressor and exerts some blunting effect on the counterregulatory hormone response to

subsequent hypoglycaemia.

16

1.6 Exercise and Type 1 Diabetes Mellitus

Although antecedent exercise may blunt the counterregulatory response to subsequent

hypoglycaemia, regular exercise remains a key component of any T1DM management

plan. The American Diabetes Association’s position statement on exercise states that,

“all patients with diabetes should have the opportunity to benefit from the many

valuable effects of exercise” (American Diabetes Association Position, 1999). Regular

exercise affords many health benefits, including lower risk of macrovascular disease,

obesity, hypertension, certain cancers, and all-cause mortality (Colberg & Swain, 2000).

Exercise has also been shown to have psychological benefits, including improved self-

esteem, reduced anxiety, and lower levels of depression (Morgan, 1985; Sonstroem &

Morgan, 1989). Furthermore, exercise confers many additional benefits that are specific

to individuals with T1DM such as improved insulin sensitivity and enhanced glucose

uptake, which can reduce the requirement for exogenous insulin and assist in the

management of blood glucose levels (White & Sherman, 1999).

For these reasons, many individuals with T1DM could greatly benefit from exercise;

however, they are often discouraged from engaging in a physically active lifestyle

because of the increased risk of hypoglycaemia (Choi & Chisholm, 1996). The risk of

hypoglycaemia is increased both during (Tsalikian et al., 2005; Tuominen et al., 1995)

and for up to 31 hours after moderate-intensity exercise (Macdonald, 1987; McMahon

et al., 2007). The increased risk of hypoglycaemia during exercise is the result of an

inability of individuals with T1DM to both decrease the circulating level of insulin and

mount an adequate counterregulatory hormone response. High circulating insulin levels,

when combined with exercise-mediated glucose uptake, causes accelerated uptake of

glucose into the peripheral tissues, resulting in a lowering of blood glucose levels

(Lumb & Gallen, 2009). Although the risk of exercise-induced hypoglycaemia is a

legitimate fear, the benefits of regular physical activity almost certainly outweigh the

risks in the majority of individuals with T1DM, including those with some

complications (Riddell & Perkins, 2006). This is because it is possible to effectively

manage blood glucose levels during exercise and recovery by adjusting exogenous

insulin administration and nutrition to minimize the risk of hypoglycaemia (Guelfi et

al., 2007a).

17

1.6.1 Current Exercise Guidelines for Individuals with Type 1 Diabetes

The American College of Sports Medicine recommends that individuals with T1DM

participate in aerobic exercise on a minimum of 3 to 5 days a week for 20 to 60 minutes

as well as resistance training that includes one set of 8 to 10 exercises using the major

muscle groups on 2 to 3 days per week (American College of Sports Medicine, 1998;

Hornsby & Albright, 2009). In an attempt to encourage participation, numerous

researchers and physicians have published specific exercise guidelines and

recommendations for individuals with T1DM to help minimize the risk of

hypoglycaemic episodes (Colberg, 2000a; Dawson, 2002; Draznin, 2000; Draznin,

2010; Lumb & Gallen, 2009; Riddell & Perkins, 2006). Many guidelines suggest a

decrease in the amount of insulin given prior to exercise and additional ingestion of

carbohydrates before, during, and after exercise. In a study performed by Rabasa-Lhoret

and colleagues (2001), a 50-75% reduction in the amount of rapid-acting insulin

administered with a meal 90 minutes prior to exercise at 25, 50, or 75% O2max

reduced the incidence of exercise-induced hypoglycaemia by 75%. However, utilization

of this strategy requires that the exercise be planned, which is often not the case. In this

respect, carbohydrate supplementation is a useful alternative. The American Diabetes

Association (2004) recommends ingestion of carbohydrates if blood glucose is below

5.5 mM prior to exercise, and the consumption of additional carbohydrates throughout

exercise as needed to prevent hypoglycaemia.

While such guidelines provide a useful starting point, specific recommendations for

avoiding hypoglycaemia during exercise are lacking. This is because a number of

factors can influence the glycaemic response to exercise, including the time elapsed

since the last meal, individual variability in the glycaemic response to exercise, and the

insulin regimen followed (Colberg, 2000b; Riddell & Perkins, 2006). Furthermore, not

all types of exercise increase the risk of hypoglycaemia. A limitation of the current

recommendations is that they often do not differentiate between moderate- and high-

intensity exercise, which have been shown to have contrasting effects on blood glucose

levels, and thus require different management strategies if hypoglycaemia is to be

avoided (Guelfi et al., 2007a; Riddell & Perkins, 2006). In general, most

recommendations suggest a trial and error approach to learn the glycaemic responses to

different types of exercise through frequent blood glucose monitoring in a variety of

activities (Colberg & Swain, 2000). The trial and error approach is worthwhile for these

18

individuals since it has been found that blood glucose responses to exercise have some

degree of reproducibility (Temple et al., 1995). However, there remains a considerable

need to individualize and add to these recommendations, specifically addressing

different intensities of activity. Since different intensities of exercise produce different

glycaemic responses, an understanding of the metabolic and hormonal responses to

different intensities of exercise is necessary to avoid exercise-induced hypoglycaemia

and to ensure usage of the correct blood glucose management strategies.

1.7 Regulation of Blood Glucose Levels during Moderate-Intensity Exercise and Recovery

Most published exercise guidelines for individuals with T1DM address moderate-

intensity exercise. Moderate-intensity exercise is defined as exercise at 40-59% of an

individual’s maximal oxygen consumption ( O2max) or 55-69% of maximal heart rate

(HRmax), and includes continuous aerobic activities such as jogging, swimming, and

cycling (American Diabetes Association Position Statement, 2004). It is principally this

intensity of activity that carries an increased risk of hypoglycaemia, both during

(Tuominen et al., 1995) and for up to 31 hours of recovery (Macdonald, 1987). This

increased risk of hypoglycaemia with moderate-intensity exercise is a result of a

mismatch between glucose production and glucose uptake, as well as a defective

counterregulatory hormone response (Macdonald, 1987; McMahon et al., 2007). For

this reason, individuals with T1DM should frequently monitor their blood glucose and

often need to make adjustments in insulin administration and carbohydrate intake

before, during, and after this type of exercise.

1.7.1 Regulation of Blood Glucose Levels during Moderate-Intensity Exercise in Non-Diabetic Individuals

In order to understand how moderate-intensity exercise increases the risk of

hypoglycaemia in individuals with T1DM, mechanisms of blood glucose regulation

during this type of exercise should be first examined in the healthy non-diabetic

population. With the exception of prolonged bouts of moderate intensity exercise (> 90

19

minutes in duration), non-diabetic individuals generally maintain euglycaemia

throughout moderate-intensity exercise and recovery (Brun et al., 2001). This is

achieved as a result of a precise match between the rate of endogenous glucose

production and the rate of glucose uptake by the tissues.

The onset of moderate-intensity exercise in non-diabetic individuals is accompanied by

a 2-fold increase in glucose uptake by the muscles (Davis et al., 2000c). This 2-fold

increase in glucose uptake by the exercising muscle would stimulate a decrease in blood

glucose if it were not matched by an equal increase in hepatic glucose production

(Davis et al., 2000c). Fortunately, a precisely matched increase in hepatic glucose

production occurs due to activation of both hepatic glycogenolysis and gluconeogenesis,

and euglycaemia is maintained as a result (Wolfe et al., 1986). This matching of glucose

production with glucose uptake continues into recovery from exercise until both glucose

production and glucose uptake return to basal levels (Wolfe et al., 1986). As a result, the

risk of an episode of hypoglycaemia during moderate-intensity exercise is minimal in

non-diabetic individuals.

The matching of glucose production to glucose uptake during exercise in non-diabetic

individuals is coordinated by the glucoregulatory hormones. The onset of moderate-

intensity exercise is accompanied by a decline in endogenous insulin secretion, which

decreases the level of circulating insulin usually responsible for stimulating glucose

uptake and inhibiting hepatic glucose production (Riddell & Perkins, 2006; Schneider et

al., 1991). This decrease in circulating insulin, which resulted from increased

sympathetic nervous system activity, sensitizes the liver to basal levels of the

counterregulatory hormones and thus enhances the effects they may have on blood

glucose regulation (Schneider et al., 1991). With a decline in insulin secretion, the

glucagon to insulin ratio increases regardless of whether the level of glucagon increases

or remains stable (Kjaer, 1992). As the duration of exercise increases, levels of

glucagon, catecholamines, growth hormone, and cortisol rise, resulting in increased

hepatic glucose output and further suppression of insulin secretion (Kjaer, 1992;

Kozlowski et al., 1979; Riddell & Perkins, 2006; Schneider et al., 1991). In short, the

counterregulatory hormones counteract the falling blood glucose caused by exercise-

mediated glucose uptake. The concentrations of the counterregulatory hormones are a

function of exercise intensity and duration, with greater increases as intensity and

duration increase (Kjaer, 1992; Kozlowski et al., 1979; Schneider et al., 1991). Insulin,

on the other hand, continues to change in the opposite direction, removing its inhibitory

20

effects on hepatic glucose production (Kjaer, 1992). The changes in insulin and

glucagon levels are primarily responsible for the maintenance of euglycaemia during

moderate-intensity exercise. The catecholamines have a secondary role, followed by

growth hormone and cortisol, which become increasingly important as the duration of

exercise is increased (Utter et al., 1999). Shortly after the onset of recovery, all

counterregulatory hormones return to baseline levels, with continued action from

growth hormone and cortisol as their release pattern and pharmacokinetics result in

long-term effects (Kjaer, 1992).

1.7.2 Regulation of Blood Glucose Levels during Moderate-Intensity Exercise in Individuals with Type 1 Diabetes

Moderate-intensity exercise in insulin-treated individuals with T1DM stimulates a

similar increase in glucose uptake by the muscles as that observed in non-diabetic

individuals (Simonson et al., 1984). However, insulin-treated individuals with T1DM

are unable to match this increase in glucose uptake with an equivalent increase in

hepatic glucose production as demonstrated by an increasing need for exogenous

glucose infusion during moderate-intensity exercise and early recovery performed under

a euglycaemic clamp (Guelfi et al., 2007b).

The mismatch between glucose uptake and hepatic glucose production during moderate-

intensity exercise in individuals with T1DM is largely the result of the inability of these

individuals to control their circulating insulin level (McMahon et al., 2007; Riddell &

Perkins, 2006; Wasserman & Zinman, 1994). Once exogenous insulin is given, its rate

of appearance and utilization is determined primarily by the pharmacokinetics of the

particular type of insulin administered. Therefore, unlike their non-diabetic

counterparts, individuals with T1DM are unable to decrease their circulating insulin

level in response to the onset of moderate-intensity exercise, leaving most individuals

hyperinsulinemic during exercise (McMahon et al., 2007; Wasserman & Zinman,

1994). This hyperinsulinemic state increases the risk of hypoglycaemia since there is an

additive effect of high levels of circulating insulin and muscle contraction on glucose

uptake by the muscles (Douen et al., 1990; Ivy, 1987). Also, high levels of circulating

insulin inhibit the rise in hepatic glucose production, despite the rise in the

counterregulatory hormones (Tuominen et al., 1995). As a result, the sustained elevation

21

in plasma insulin during exercise in individuals with T1DM causes a fall in blood

glucose during this type of activity (Guelfi et al., 2007a).

Further complicating blood glucose regulation during exercise, individuals with T1DM

are unable to mount a sufficient counterregulatory hormone response to the decline in

blood glucose (Rizza, et al., 1979). These individuals display insufficient increases in

norepinephrine and epinephrine during exercise, which play a key role in increasing

hepatic glucose output (McMahon et al., 2007; Schneider et al., 1991). Fortunately,

unlike during hypoglycaemia, glucagon responses are preserved during exercise in

individuals with T1DM, suggesting that the loss of the glucagon response is stimulus-

specific (Galassetti et al., 2003; Gerich et al., 1973). Like non-diabetic individuals,

glucagon is the primary counterregulatory hormone responsible for increases in hepatic

glucose production during this type of exercise (Shilo et al., 1990).

The combination of contraction-mediated glucose uptake, high levels of plasma insulin,

and insufficient counterregulatory hormone responses causes blood glucose to decline

during exercise, increasing the potential for hypoglycaemia (Galassetti et al., 2003;

Macdonald, 1987; McMahon et al., 2007; Peirce, 1999). The risk of hypoglycaemia

may be further increased since exercise can mask many of the symptoms signaling a

decline in blood glucose. For instance, tachycardia and sweating are two key responses

in both hypoglycaemia and exercise given that both forms of stress include high levels

of sympathetic outflow (Choi & Chisholm, 1996; Riddell & Bar-Or, 2002). When these

symptoms are detected during exercise, individuals with T1DM may wrongly attribute

them to the exercise as opposed to hypoglycaemia. Individuals with T1DM also tend to

overestimate their blood glucose when they are hypoglycaemic and underestimate their

level when they are hyperglycaemic (Riddell & Bar-Or, 2002). Therefore, regular blood

glucose monitoring is necessary during exercise for correct knowledge of blood glucose

levels.

Other factors, such as the timing of exercise in relation to the time of peak insulin

action, the specific location of injection site, and time of day, can also increase the risk

of hypoglycaemia. Exercising during the time of peak insulin action (i.e. within 2 hours

of a meal with an insulin bolus) increases the risk of hypoglycaemia since the additive

effect of insulin and exercise on blood glucose uptake is enhanced at this time (Colberg,

2000a). Insulin can also be injected in a variety of locations, such as the abdomen, arm,

buttocks, or thigh. If insulin is injected into an exercising limb, its absorption will be

22

faster due to increased blood flow to the area and a rise in body temperature (Choi &

Chisholm, 1996; Riddell & Perkins, 2006; Wasserman & Zinman, 1994). Therefore, if

exercise is planned, administration of insulin into a non-exercising body part (such as

the abdomen) is highly recommended. Time of day can also have a large impact on the

risk of hypoglycaemia because of circadian variations in the release of the

counterregulatory hormones. As a result of low levels of circulating exogenous insulin,

greater insulin resistance, and higher levels of cortisol, morning exercise, particularly

before breakfast and morning insulin, carries a lower risk of exercise-induced

hypoglycaemia than exercise performed later in the day (Colberg, 2000a; Colberg &

Swain, 2000). However, adjustments in insulin dosage and carbohydrate intake usually

still need to be made prior to participation in moderate-intensity exercise. A reduction in

insulin dosage, mimicking a healthy pancreas during exercise, decreases the risk of

hypoglycaemia, especially when exercise is performed postprandially (Colberg &

Swain, 2000; Lumb & Gallen, 2009; Riddell & Perkins, 2006). In addition, having

supplementary carbohydrates available during exercise is crucial as a means of treating

any hypoglycemic episodes that do occur (Colberg & Swain, 2000; Riddell et al., 1999).

Of note, moderate-intensity exercise also carries a heightened risk of hypoglycaemia for

up to 31 hours of recovery (Macdonald, 1987). The risk of hypoglycaemia during

recovery is especially increased both 60 to 90 minutes after exercise and several hours

later (Lumb & Gallen, 2009). Post-exercise late onset hypoglycaemia is a result of

increased glucose uptake to replenish glycogen stores (Macdonald, 1987; Peirce, 1999),

increased insulin sensitivity (Macdonald, 1987; Peirce, 1999), and impaired

counterregulation to hypoglycaemia after exercise (Macdonald, 1987). After an

exhausting bout of exercise, muscle glycogen stores are severely depleted and rely on

the uptake of blood glucose for re-synthesis. Consuming a large amount of carbohydrate

within 30 minutes of exercise provides a large carbohydrate supply from which muscle

glycogen can be re-synthesized, decreasing the reliance on the remaining blood glucose

and helping to prevent post-exercise late-onset hypoglycaemia (Colberg & Swain,

2000). Another factor that may increase the risk of hypoglycaemia after exercise is the

timing of the exercise session in relation to sleep. Counterregulatory hormone responses

to hypoglycaemia are highly impaired during sleep (Jones et al., 1998), and may

increase the risk of late-onset post-exercise hypoglycaemia when exercise is performed

in the late afternoon (McMahon et al., 2007). For these reasons, a reduction in basal

23

insulin is highly recommended after exercise to avoid hypoglycaemia during recovery

(Lumb & Gallen, 2009).

While less likely to occur, it is also possible for individuals with T1DM to exercise

while hypoinsulinemic. When circulating levels of insulin are low, blood glucose levels

rise and a state of hyperglycaemia ensues. An elevation in the counterregulatory

hormones as a result of the exercise further exacerbates the hyperglycaemia because of

an increase in hepatic glucose production. Although it may be tempting to commence

exercise with a higher blood glucose level, widening the range over which blood

glucose can safely decline, pre-exercise hypoinsulinaemia does not in fact help and

actually increases the risk of developing ketoacidosis (Colberg, 2000b; Lumb & Gallen,

2009; Riddell & Perkins, 2006). Also, hyperglycaemic conditions cause a shift towards

carbohydrate as a fuel during exercise, accelerating the decline in blood glucose during

exercise even further (Cryer et al., 2003). For these reasons, it is generally

recommended that blood glucose should be under 16.7 mM or 13.9 mM when in

combination with the presence of ketosis before exercise is started (American Diabetes

Association Position Statement, 2004).

1.8 Regulation of Blood Glucose Levels during High-Intensity Exercise and Recovery

It is often assumed that all intensities of exercise affect blood glucose levels in the same

manner. However, unlike moderate-intensity exercise, high-intensity exercise causes

blood glucose levels to rise in individuals both with and without diabetes. High-

intensity exercise is defined as exercise that is at or above 80% O2max or 75%

HRmax and has a rating of perceived exertion above 15 on the Borg scale (Grimm,

1999; Marliss & Vranic, 2002). High-intensity exercise includes sudden, intense

activities such as sprinting or exercise at or near maximal oxygen consumption (Colberg

& Swain, 2000).

24

1.8.1 Regulation of Blood Glucose Levels during High-Intensity Exercise in Non-Diabetic Individuals

In non-diabetic individuals, participation in 10 to 15 minutes of high-intensity exercise

(>80% O2max) is associated with a marked rise in blood glucose concentration

(Mitchell et al., 1988; Purdon et al., 1993). This rise in glycaemia is the result of an

imbalance between glucose production and glucose uptake, with a 7- to 8-fold increase

in the rate of hepatic glucose production, but only a 4-fold increase in the rate of

glucose uptake from the circulation (Marliss et al., 2000; Marliss & Vranic, 2002; Sigal

et al., 1994b). Since the rate of glucose production continually exceeds the rate of

glucose uptake, blood glucose continues to rise throughout exercise and early recovery,

resulting in transient hyperglycaemia (Kreisman et al., 2000; Mitchell et al., 1988;

Purdon et al., 1993, Sigal et al., 1994b). Of interest, short maximal sprint efforts of both

6 and 30-seconds in duration have also been shown to produce a marked rise in blood

glucose in non-diabetic individuals (Moussa et al., 2003).

Unlike moderate-intensity exercise, insulin and glucagon are not the key regulators of

the blood glucose response to high-intensity exercise. Rather, high-intensity exercise is

associated with a marked rise in the catecholamines, epinephrine and norepinephrine,

suggesting that they play an important role in blood glucose regulation during this type

of exercise (Kjaer, 1992; Lumb & Gallen, 2009; Marliss et al., 2000; Moussa et al.,

2003; Purdon et al., 1993). In comparison to the 2-fold increase in glucagon and the

slight, if any, increase in insulin, plasma norepinephrine and epinephrine levels increase

15-fold during high-intensity exercise (Kreisman et al., 2000; Kreisman et al., 2003;

Marliss et al., 2000; Sigal et al., 1994b). Therefore, it is unlikely that insulin and

glucagon contribute given their relative responses as well as their inappropriate timing

to explain the increase in glucose production (Kreisman et al., 2003; Marliss et al.,

2000; Purdon et al., 1993; Sigal et al., 1994b). In a study by Sigal and colleagues

(1996), a similar increase in glucose production was observed during high-intensity

exercise regardless of whether insulin and glucagon secretion were suppressed by

somatostatin and infused at basal levels, or allowed to respond as normal, suggesting

mechanisms other than the glucagon:insulin ratio control the glycaemic response to

high-intensity exercise. On the other hand, the rise in the catecholamines associated

with high-intensity exercise is significantly correlated with hepatic glucose production

(Kjaer, 1992; Kreisman et al., 2003; Purdon et al., 1993). To further support a role of

catecholamines in high-intensity exercise, Kreisman and colleagues (2003) infused high

25

levels of epinephrine and norepinephrine during moderate-intensity exercise to simulate

the hormonal response to high-intensity exercise. The result was a glycaemic response

similar to that seen in high-intensity exercise (Kreisman et al., 2003). In addition, it has

been shown that individuals who produce greater catecholamine responses to a given

level of high-intensity exercise display greater hyperglycaemia (Purdon et al., 1993).

The mechanism by which epinephrine and norepinephrine raise blood glucose levels

during high-intensity exercise involves the stimulation of hepatic glucose production via

the activation of glycogenolysis and gluconeogenesis, as well as the inhibition of

insulin-mediated glucose uptake by the tissues (Lumb & Gallen, 2009; Marliss et al.,

2000; Sigal et al., 1994b). These hormones operate in a feedforward manner without

any input from the rising blood glucose level (Marliss et al., 2000). Meanwhile, the high

levels of catecholamines inhibit insulin secretion, avoiding any potential effect insulin

may have on the rising blood glucose levels (Lumb & Gallen, 2009). The rise in the

catecholamines dominates and consequently glycaemia continues to rise (Riddell &

Perkins, 2006). However, it is important to note that not all studies necessarily support

a role for the catecholamines. Work performed using and receptor blockades has

shown that the increment in the glucose rate of appearance (Ra) during high-intensity

exercise was not dependent on adrenergic receptor stimulation (Coker et al., 1997;

Kjaer et al., 1993; Kjaer et al., 1995; Sigal et al., 1994a).

In non-diabetic individuals, recovery from high-intensity exercise is associated with an

initial increase in blood glucose, followed by a return to euglycaemia. By 10 minutes of

recovery, epinephrine and norepinephrine levels have declined by 80%, with a

subsequent fall in glucose production and rise in insulin secretion (Mitchell et al., 1988;

Sigal et al., 1994b). Likewise, glucagon, a potent stimulator of hepatic glucose

production during moderate-intensity exercise, returns to baseline within the first hour

of recovery, while growth hormone and cortisol, known for their long-term effects on

hepatic glucose production, rise during recovery from high-intensity exercise (Kraemer

et al., 2002; Pritzlaff et al., 2000). Of primary importance, insulin secretion reacts to the

high level of blood glucose and lower levels of circulating catecholamines, by nearly

doubling the circulating level of insulin (Purdon et al., 1993; Sigal et al., 1994b). This

hyperinsulinemic state accelerates glucose uptake by the tissues to rapidly replenish

muscle glycogen stores, causing glucose uptake to surpass glucose production and

return blood glucose levels to normal within 40 minutes of recovery (Lumb & Gallen,

2009; Purdon et al., 1993; Riddell & Perkins, 2006).

26

1.8.2 Regulation of Blood Glucose Levels during High-Intensity Exercise in Individuals with Type 1 Diabetes

High-intensity exercise (10-15 minutes at >80% O2max) produces a similar

glycaemia-increasing effect in individuals with T1DM (Moussa et al., 2003; Purdon et

al., 1993). Like non-diabetic individuals, the continued rise in glycaemia associated

with high-intensity exercise in individuals with T1DM is the result of a disproportionate

increase in glucose production relative to that of glucose uptake (Purdon et al., 1993;

Sigal et al., 1994b). The proposed mechanism underlying this disproportionate increase

in glucose production relative to glucose uptake is a 15-fold increase in the

concentrations of the catecholamines, epinephrine and norepinephrine (Colberg, 2000a;

Deibert & DeFronzo, 1980; Kreisman et al., 2003; Nonogaki, 2000; Purdon et al.,

1993). On the other hand, glucagon levels remain unchanged (Hübinger et al., 1985;

Mitchell et al., 1988) or increase slightly (Purdon et al., 1993; Sigal et al., 1994b) during

this type of exercise. Furthermore, high-intensity exercise elicits similar rises in cortisol

and growth hormone as in non-diabetic individuals (Hübinger et al., 1985, Purdon et al.,

1993). The similarity in the glycemic response to high-intensity exercise between

individuals with T1DM and non-diabetic individuals is consistent with the relative

unimportance of plasma insulin in the glycaemic response to this type of exercise.

However, a marked difference exists between non-diabetic individuals and those with

T1DM in the glycaemic response during recovery from high-intensity exercise. Within

a few minutes of the onset of recovery, catecholamine levels return to baseline and

hepatic glucose production declines as a result (Sigal et al., 1994b). At this point,

plasma insulin secretion begins to rise in non-diabetic individuals, stimulating glucose

uptake, glycogen re-synthesis, and the return of blood glucose to euglycaemic levels.

However, individuals with T1DM are unable to control the level of circulating insulin

and, as a result, are unable to mount a rise in circulating insulin in response to the

existing hyperglycaemia (Purdon et al., 1993; Riddell & Perkins, 2006; Wasserman &

Zinman, 1994). Consequently, insulin-mediated glucose uptake does not increase and

the hyperglycaemic state persists well into recovery (Mitchell et al., 1988; Purdon et al.,

1993; Sigal et al., 1994b). The role of insulin in recovery from high-intensity exercise is

supported by a study by Marliss & Vranic (2002), in which insulin was infused into

individuals with T1DM throughout high-intensity exercise and early recovery. The level

of infused insulin was doubled during recovery in one group and kept constant in the

other. It was found that doubling the insulin infusion rate during recovery restored

27

euglycaemia in individuals with T1DM. However, the glycaemic decline in these

individuals often started from a higher blood glucose level and declined slower than in

non-diabetic individuals, indicating the importance of an acute insulin response in

restoring euglycaemia (Marliss & Vranic, 2002). In the constant insulin infusion group,

the increase in blood glucose persisted for the 2-hour recovery period. Overall, the

inability of individuals with T1DM to increase the level of circulating insulin post-

exercise translates into a sustained increase in blood glucose during recovery from high-

intensity exercise, thereby decreasing the risk of post-exercise hypoglycaemia in

individuals with T1DM after high-intensity exercise, unlike moderate-intensity exercise

(Purdon et al., 1993). However, the effect of high-intensity exercise on late-onset post-

exercise hypoglycaemia, which occurs several hours later, has yet to be established.

1.9 Clinical Implications of High-Intensity Exercise as a Tool to Reduce the Risk of Hypoglycaemia

The glycaemia-increasing effect of high-intensity exercise may provide a promising tool

for decreasing the risk of hypoglycaemia in individuals with T1DM. However,

continuous high-intensity exercise above 80% O2max lasting 10 to 15 minutes may

be too strenuous for the majority of the T1DM population, which limits its application

in practice. For this reason, the effect of a much shorter bout of maximal intensity

exercise on blood glucose levels was recently investigated in this population. Harmer

and colleagues (2006) demonstrated that high-intensity exercise at 130% O2max,

lasting approximately 78 ± 21 seconds, causes a transient increase in blood glucose

levels throughout exercise and recovery in individuals with T1DM. However, since a

10-second sprint is generally better tolerated by the majority of individuals, Bussau and

colleagues (2006) examined the glycaemic response to a 10-second maximal sprint

performed immediately following the completion of 20 minutes of moderate-intensity

exercise in individuals with T1DM. These researchers reported that adding the 10-

second sprint to the end of a bout of moderate-intensity exercise opposed a further

decline in blood glucose levels for 120 minutes of recovery, despite plasma insulin

being well above basal levels. This stabilization of blood glucose levels during recovery

was partially explained by a marked rise in the catecholamines, growth hormone, and

cortisol resulting from the sprint (Bussau et al., 2006). Building upon these results,

28

Bussau and colleagues (2007) performed a further study to investigate whether

performing a 10-second sprint immediately before a 20-minute bout of moderate-

intensity exercise would have the same effect. It was found that although sprinting had

no effect on the decline in blood glucose levels during subsequent moderate-intensity

exercise, the sprint did prevent blood glucose levels from falling for at least the first 45

minutes of recovery after the exercise (Bussau et al., 2007). Once again, the

stabilization of blood glucose was attributed to the increased norepinephrine levels in

conjunction with increased lactate levels from the sprint.

The risk of hypoglycaemia during and after moderate-intensity exercise may also be

reduced by performing repeated short maximal sprints throughout continuous moderate-

intensity exercise (Guelfi et al., 2005). In a study by Guelfi and colleagues (2005),

individuals with T1DM performed either 30 minutes of moderate-intensity activity at

40% O2peak either with or without the addition of 4-second sprints every 2 minutes.

The results showed that blood glucose declined significantly less during moderate-

intensity exercise that included repeated short sprints compared to moderate-intensity

exercise alone. This provides further support for the need to develop better exercise

guidelines as small transient differences in exercise intensity and duration occur

regularly and without intent in reality, and can evidently have an impact on

glucoregulation. Furthermore, blood glucose levels remained stable during recovery

from moderate-intensity exercise with repeated short sprints, while levels continued to

decline after moderate-intensity exercise alone (Guelfi et al., 2005). This attenuated

decrease in blood glucose level when adding repeated short sprints to moderate-

intensity exercise was associated with a significantly greater increase in growth

hormone and norepinephrine with this type of exercise (Guelfi et al., 2005). These

hormonal changes were associated with a more rapid and greater increment in Ra,

together with a more rapid decline in the rate of peripheral glucose disposal (Rd) in early

recovery from this type of exercise (Guelfi et al., 2007b).

Taken together, these findings indicate that one or many short maximal sprints

performed before, during, or after moderate-intensity exercise may reduce the risk of

hypoglycaemia during early recovery in individuals with T1DM. This highlights the

potential usefulness of short sprints as an additional tool to prevent hypoglycaemia

associated with exercise. Accordingly, this could possibly be a preferred method of

raising blood glucose levels for competitive athletes when carbohydrate is not available

or they do not wish to stop exercising.

29

1.10 Factors that May Influence the Glycaemia-Increasing Effect of a Sprint in Individuals with Type 1 Diabetes

The discovery that a short sprint may provide a possible tool to decrease the risk of

hypoglycaemia is very promising for the development of improved exercise guidelines

for individuals with T1DM. However, more extensive research needs to be performed

to identify potential factors that could impair the glycaemic benefit of a sprint so that

safe and accurate guidelines can be given. For example, it has been shown that a prior

bout of hypoglycaemia diminishes the counterregulatory hormone responses to a

subsequent bout of moderate-intensity exercise in individuals with T1DM (Galassetti et

al., 2003). Moreover, bouts of antecedent moderate-intensity exercise have been shown

to blunt the counterregulatory hormone responses to both future hypoglycaemia

(Galassetti et al., 2001a; Sandoval et al., 2004) and moderate-intensity exercise,

impairing the glycaemic response to these events (Galassetti et al., 2001b). Since the

catecholamines play a central role in the glycaemic benefit of a sprint, it is possible that

antecedent hypoglycaemia and moderate-intensity exercise may also impair the

counterregulatory hormone response and glycaemic benefit of sprinting.

1.10.1 Influence of Antecedent Hypoglycaemia

An acute bout of hypoglycaemia has been shown to diminish the counterregulatory

response to a subsequent bout of moderate-intensity exercise in both non-diabetic

individuals (Davis et al., 2000b) and individuals with T1DM (Galassetti et al., 2003).

Davis and colleagues (2000b) demonstrated that two episodes of antecedent moderate

hypoglycaemia reduced the counterregulatory hormone responses to moderate-intensity

exercise performed the following day by 50% in non-diabetic individuals. More

specifically, they observed blunted epinephrine, norepinephrine, glucagon, growth

hormone, and cortisol responses compared to the same exercise performed following

two episodes of antecedent euglycaemia (Davis et al., 2000b). Likewise, antecedent

hypoglycaemia has been shown to blunt the counterregulatory hormone responses to a

subsequent bout of moderate-intensity exercise performed by individuals with T1DM

(Galassetti et al., 2003). In response to 90-minutes of moderate-intensity exercise

following two 2-hour periods of hypoglycaemia on the previous day, individuals with

30

T1DM showed a reduced glucagon response in addition to attenuated epinephrine,

norepinephrine, and cortisol responses that were blunted by 40-80% compared to an

antecedent euglycaemia condition (Galassetti et al., 2003).

The proposed explanation for the blunting of the counterregulatory responses caused by

antecedent hypoglycaemia is a reduction in the ANS drive to the pancreas, adrenal

gland, and sympathetic nerve endings. A series of studies have suggested that an

increase in cortisol can reduce the neuroendocrine and ANS counterregulatory

responses to a variety of subsequent stressors (Brown & Fisher, 1986; Davis et al.,

1996; Komesaroff & Funder, 1994; Udelsman et al., 1987). As evidence for this, one

study infused participants with a level of cortisol that mimicked the cortisol rise during

hypoglycaemia before measuring the responses to hypoglycaemia on the following day

(Davis et al., 1996). When compared to the antecedent euglycaemia and hypoglycaemia

groups, ANS responses were similarly blunted after the infused cortisol and the

antecedent hypoglycaemia (Davis et al., 1996). Since this blunting occurs in the

counterregulatory hormone response, it is possible that other stressors that increase the

level of cortisol (i.e. moderate-intensity exercise) may also affect any subsequent events

that rely on a counterregulatory hormone response. Since the glycaemic benefit of a

sprint is likely to be mediated by an increase in catecholamine levels, a bout of

antecedent hypoglycaemia, which raises the cortisol levels, could potentially blunt the

catecholamine response to a short sprint and reduce the glycaemic benefit of the sprint.

However, it is important to note that not all studies support a role for cortisol in the

blunting caused by antecedent stressors (Goldberg et al., 2006; Raju et al., 2003).

1.10.2 Influence of Antecedent Exercise

Another factor that may influence the glycaemic benefit of a sprint is prior exercise. Of

interest, a single bout of moderate-intensity exercise has been shown to cause

significant blunting of the counterregulatory response to a subsequent moderate-

intensity exercise bout. In a study performed by Galassetti and colleagues (2001b), non-

diabetic participants were either required to rest or complete a 90-minute bout of

exercise at 50% O2max, followed by a 3-hour break and then a subsequent 90-minute

exercise bout at the same intensity. Reduced epinephrine, norepinephrine, cortisol, and

growth hormone responses were observed during the second exercise bout following

31

antecedent exercise (Galassetti et al., 2001b). In addition, the glucose infusion rate

required to maintain euglycaemia was almost 5 times greater during the second exercise

bout after antecedent exercise compared to when no prior exercise was performed,

suggesting that endogenous glucose production was substantially lower following a

prior bout of moderate-intensity exercise.

Furthermore, Galassetti and colleagues (2001b) investigated gender differences in the

effect of an antecedent bout of exercise on the counterregulatory responses to a second

bout of exercise. Individuals without diabetes exercised for 90-minutes at 80% of

anaerobic threshold followed by a 3-hour break before a second identical bout of

exercise was performed. During the first bout of exercise, men showed a greater

counterregulatory response than women, attaining significantly higher absolute levels of

epinephrine, norepinephrine, cortisol, and growth hormone in response to moderate-

intensity exercise (Galassetti et al., 2001b). It has been suggested that this is a reflection

of women displaying a greater sensitivity to ANS drive (Davis et al., 1993). However,

during the second exercise bout, men had reduced epinephrine, norepinephrine, cortisol,

and growth hormone responses compared to their previous bout (Galassetti et al.,

2001b). In contrast, the counterregulatory responses to exercise were unchanged or

increased in women when compared to their first bout of exercise, leading to a

statistically significant gender difference in the change of these parameters between the

two exercise bouts (Galassetti et al., 2001b). So although men had greater

counterregulatory responses to the first bout of exercise, they experienced significantly

greater blunting than women during the second bout of exercise.

Since antecedent moderate-intensity exercise is known to reduce the catecholamine

response to subsequent moderate-intensity exercise, it is possible that antecedent

exercise may similarly reduce the catecholamine response, and therefore the glycaemia-

increasing response, to a subsequent sprint. Whether the glycaemia-increasing response

to a subsequent maximal sprint is blunted by antecedent exercise has yet to be

determined. This may have implications for the efficacy of sprinting as a safe and

reliable means to reduce the risk of exercise-mediated hypoglycaemia.

32

1.11 Summary

Treatment of T1DM involves balancing diet and administered insulin in order to

achieve acceptable blood glucose levels. In spite of this, many individuals with T1DM

lead full, normal lives and participate in many of the same activities as individuals

without diabetes. Exercise is one such activity, with regular exercise affording

numerous health benefits to both the healthy and T1DM populations. However, it must

be acknowledged that exercise does complicate management of blood glucose levels. It

is well established that different intensities of exercise have different effects on blood

glucose levels and that certain types of exercise may increase the risk of

hypoglycaemia. Moderate-intensity exercise causes blood glucose levels to continually

decline during exercise and recovery, increasing this risk of hypoglycaemia, a

potentially life threatening condition. In contrast, high-intensity exercise has been

shown to raise blood glucose levels. In fact, a maximal sprint effort as short as 10

seconds can delay the decline of blood glucose during exercise and short-term recovery.

This suggests that a short maximal sprint may be a promising tool for decreasing the

risk of exercise-mediated hypoglycaemia in individuals with T1DM. However, before

sprinting can be safely and accurately added to clinical exercise guidelines, factors that

may impair the efficacy of a sprint need to be investigated. Therefore, the purpose of

this thesis was to investigate whether a bout of antecedent moderate-intensity exercise

attenuates the glycaemia-increasing as well as the counterregulatory hormone response

to a short maximal sprint performed hours later in non-diabetic individuals. Non-

diabetic individuals were studied in order to firstly understand how antecedent exercise

influences the glycaemia-increasing effect of sprinting under non-pathological

conditions.

1.12 Aims

The primary goal of this thesis was to investigate the effect of an antecedent exercise

bout on the blood glucose and counterregulatory hormone response to a short, maximal

sprint in non-diabetic individuals. A short, maximal sprint has been recommended as a

tool in the prevention of exercise-induced hypoglycaemia; however, factors that may

33

alter its efficacy must be established before safe and accurate guidelines can be given.

The objective of this study was to investigate whether antecedent exercise affects the

glycaemia-increasing effect of sprinting in non-diabetic individuals. The information

obtained will form the basis for future research on individuals with T1DM.

1.13 Research Hypotheses

The hypotheses relating to these aims were that;

- 60 minutes of antecedent moderate intensity exercise (65% O2max) would reduce

the glycaemia-increasing effect of a 30-second maximal sprint performed 3 hours

later

- This predicted reduced glycaemia-increasing response after antecedent exercise

would be associated with blunted counterregulatory responses to the maximal

sprint.

1.14 Significance of the Study

The use of a short maximal sprint has been proposed as a tool to reduce the risk of

hypoglycaemia in individuals with T1DM; accordingly, this study will highlight

whether this benefit persists after antecedent exercise. The results of this study will

form the basis for future studies on individuals with T1DM and may have implications

for existing guidelines for exercise for these individuals.

34

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Unger, R.H., & Orci, L. (1994). Glucagon. In C.R. Kahn & G.C. Weir (Eds.), Joslin’s

Diabetes Mellitus (pp 170). Philadelphia, PA: Lea & Febiger.

Utter, A.C., Kang, J., Nieman, D.C., Williams, F., Robertson, R.J., Henson, D.A.,

Davis, J.M., & Butterworth, D.E. (1999). Effect of carbohydrate ingestion and

hormonal responses on ratings of perceived exertion during prolonged cycling and

running. European Journal of Applied Physiology, 80, 92-99.

Wasserman, D.H., and Zinman, B. (1994). Exercise in individuals with IDDM. Diabetes

Care, 17, 924-937.

White, R.D., & Sherman, C. (1999). Exercise in diabetes management: Maximizing

benefits, controlling risks. The Physician and Sportsmedicine, 27(4), 63-76.

Widom, B., Kinsley, B.T., & Simonson, D. (1991). Women and men differ in

counterregulatory hormone responses to hypoglycaemia (Abstract). Diabetes, 40,

543.

Wolfe, R.R., Nadel, E.R., Shaw, J.H.F., Stephenson, L.A., & Wolfe, M.H. (1986). Role

of changes in insulin and glucagon in glucose homeostasis in exercise. Journal of

Clinical Investigations, 77, 900-907.

 

 

 

 

 

 

 

Chapter Two 

Effect of Antecedent  

Moderate‐Intensity Exercise on  

the Glycaemia‐Increasing Effect of 

 a 30‐second Maximal Sprint 

50

2.1 Abstract

Recently, the glycaemia-increasing effect of a short sprint has been proposed as a

potential clinical tool for minimizing the risk of exercise-mediated hypoglycaemia in

individuals with type 1 diabetes. However, previous research has shown that an

antecedent bout of moderate-intensity exercise may blunt the counterregulatory

hormone responses to a second bout of moderate-intensity exercise performed several

hours later. Consequently, the purpose of the present study was to investigate whether

an antecedent bout of moderate-intensity exercise also attenuates the counterregulatory

hormone and glycaemia-increasing responses to a maximal 30-second sprint. Eight

healthy young males (age 21.8 1.8 years; BMI 23.9 2.2 kg·m-2; O2peak 48.6 6.6

ml·kg-1·min-1; mean SD) visited the laboratory on two occasions during which they

either rested for 60 minutes (CON) or performed 60 minutes of moderate-intensity

cycling at ~65% O2peak (EX). Following EX or CON, each participant rested for 3

hours and 15 minutes before performing a 30-second maximal cycling sprint. The

response of blood glucose and the counterregulatory hormones was monitored for one

hour of recovery. Mean blood glucose concentrations prior to the 30-second sprint were

similar between trials (4.46 0.20 mM CON; 4.44 0.15 mM EX). In response to the

sprint, blood glucose levels significantly increased, reaching similar maximal levels at

10 minutes of recovery (5.44 0.38 mM CON; 5.43 0.23 mM EX). However, blood

glucose then declined at a faster rate following EX, resulting in significantly lower

blood glucose levels at 45 minutes of recovery compared to CON (4.98 0.15 mM

CON; 4.50 0.10 EX; p = 0.024). The faster fall in blood glucose levels in EX

compared to CON was associated with a more consistent rise in glucose rate of

disappearance (Rd) above the rate of appearance (Ra) during recovery. This might be

explained, at least in part, by the lesser post-exercise rise in growth hormone levels in

EX (p < 0.05). Furthermore, plasma insulin levels were significantly lower at 45

minutes of recovery (p = 0.042) in EX compared to CON. These results suggest that a

prior bout of moderate-intensity exercise does not affect the glycaemia-increasing

response of a 30-second sprint; however, the subsequent decline in blood glucose to

baseline is more rapid. This highlights the need for further investigations in individuals

with type 1 diabetes before sprinting can be safely recommended as a tool for

decreasing the risk of exercise-mediated hypoglycaemia.

51

2.2 Introduction

Individuals with type 1 diabetes mellitus (T1DM) strive to achieve optimal blood

glucose levels by balancing carbohydrate intake with exogenous insulin administration.

Unfortunately, an ideal balance is often hard to achieve because external factors, such as

exercise, make management of blood glucose levels more difficult. Regular exercise has

many well-documented benefits for healthy individuals, as well as those with T1DM,

including lowered risk of cardiovascular disease, obesity, and hypertension, as well as

improved self-esteem and reduced anxiety (Colberg & Swain, 2000; Morgan, 1985;

Sonstroem & Morgan, 1989). Despite these benefits, moderate-intensity exercise causes

a decline in blood glucose levels in individuals with T1DM and consequently carries an

increased risk of hypoglycaemia, both during exercise (Tuominen et al., 1995) and for

up to 31 hours of recovery (Macdonald, 1987; McMahon et al., 2007). This is of great

concern given that an episode of severe hypoglycaemia can lead to convulsions,

unconsciousness, and even death (Bolli, 2003; Chiarelli et al., 1999). As a result of the

increased risk of hypoglycaemia, many individuals with T1DM are advised to be

cautious and continually monitor their blood glucose levels while being physically

active (Choi & Chisholm, 1996).

Current guidelines for individuals with T1DM to avoid hypoglycaemia during exercise

are very general as a result of the wide variety of prescribed insulin regimens, range of

activities pursued, and individual variability in the blood glucose response to exercise

(Colberg, 2000). Furthermore, many guidelines do not acknowledge that different

intensities of exercise produce different glycaemic responses, with not all types of

exercise necessarily increasing the risk of hypoglycaemia (Guelfi et al., 2007). For

example, 10 to 15 minutes of sustained high-intensity exercise has been shown to

stimulate a rise in blood glucose levels both during exercise and recovery, thereby

carrying little to no risk of acute hypoglycaemia for individuals with T1DM (Purdon et

al., 1993; Riddell & Perkins, 2006). Of even greater significance, a bout of high-

intensity cycling at 130% O2max for as little as 78 seconds has been shown to elicit a

marked rise in blood glucose levels in both individuals with and without T1DM, with a

greater and more transient increase in individuals with T1DM (Harmer et al., 2006).

This glycaemic response can be explained, in part, by an increase in the catecholamine

hormones, epinephrine and norepinephrine, which stimulate a large rise in glucose

52

production that far exceeds the rise in glucose uptake (Marliss et al., 2000; Marliss &

Vranic, 2002; Moussa et al., 2003; Purdon et al., 1993).

The glycaemia-increasing effect of high-intensity exercise may provide a promising tool

for minimizing the risk of exercise-induced hypoglycaemia. However, 10 to 15 minutes,

and possibly even 78 seconds, of sustained high-intensity exercise is likely too

strenuous for the majority of the T1DM population to adopt as a regular form of

exercise. For this reason, Bussau and colleagues (2006; 2007) investigated the

glycaemic response to a maximal sprint as short as 10 seconds, performed immediately

before or after 20 minutes of moderate-intensity exercise in individuals with T1DM. It

was found that the inclusion of a sprint did not alter the decline in blood glucose during

exercise; however, it did lead to a stabilization of blood glucose levels during the first

hour of recovery, while levels continued to decline in recovery when no sprint was

performed, thereby decreasing the risk of early post-exercise hypoglycaemia (Bussau et

al., 2006; Bussau et al., 2007). This blood glucose response was attributed to a marked

rise in the catecholamines, growth hormone, and cortisol resulting from the sprint

(Bussau et al., 2006). The risk of hypoglycaemia during and after moderate-intensity

exercise may also be reduced by performing repeated short maximal sprints throughout

continuous moderate-intensity exercise. In a study by Guelfi and colleagues (2005),

individuals with T1DM performed 30 minutes of moderate-intensity exercise either

with or without the addition of 4-second sprints performed every 2 minutes. In

comparison to moderate-intensity exercise alone, blood glucose declined significantly

less during moderate-intensity exercise when the sprints were added. Furthermore, the

addition of sprints caused a stabilization of blood glucose levels during recovery, while

levels continued to decline after moderate-intensity exercise alone (Guelfi et al., 2005).

Although the beneficial effects of sprinting on blood glucose levels may be an

encouraging breakthrough for decreasing the risk of hypoglycaemia during exercise,

factors that may impair the efficacy of a sprint need to be investigated before it can be

safely recommended for individuals with T1DM. For instance, it is well established that

a bout of antecedent moderate-intensity exercise can blunt the counterregulatory

hormone responses to subsequent moderate-intensity exercise performed hours later on

the same day (Galassetti et al., 2001). Whether prior exercise influences the glycaemia-

increasing response of a maximal sprint effort is not known. Since the glycaemia-

increasing effect of a sprint is mediated by an increase in the counterregulatory

hormones, any blunting of the counterregulatory hormone response by antecedent-

53

moderate intensity exercise may reduce the beneficial effects of sprinting on blood

glucose levels. Therefore, the purpose of this study was to investigate the blood glucose

and counterregulatory hormone responses to a 30-second maximal sprint performed

approximately 3 hours after a bout of antecedent moderate-intensity exercise. This issue

was examined in non-diabetic participants to better understand how antecedent exercise

affects the glycaemia-increasing effect of sprinting under non-pathological conditions.

The information thus obtained will form the basis for future research on individuals

with T1DM and hopefully contribute to the publication of more complete exercise

guidelines for this population.

2.3 Research Design and Methods

2.3.1 Participants

Eight healthy, physically active men between the ages of 18 and 25 (See Table 2.1 for

characteristics of participants) were recruited from the local community. Participation in

a minimum of 30 minutes of moderate-intensity activity on 3 days a week was required

to be considered physically active. No participants suffered from any exercise-limiting

musculoskeletal injuries or were taking any form of medication. All participants were

informed of the purpose of the study and any possible risks associated with exercise and

blood sampling. Informed consent was obtained in accordance with the Princess

Margaret Hospital Ethics Committee (Appendix A). Ethics approval was granted by

the Princess Margaret Hospital Ethics Committee and also by The University of

Western Australia Human Research Ethics Committee (Appendix B).

54

Table 2.1. Characteristics of Study Participants (n = 8)

Characteristic Mean ± SD

Age (years) 21.8 ± 1.8

Height (cm) 177.6 ± 7.7

Body Mass (kg) 75.6 ± 10.4

Body Mass Index (kg/m2) 23.9 ± 2.2

O2peak (ml/kg/min) 48.6 ± 6.6

O2peak, peak oxygen consumption

2.3.2 Experimental Design

Each participant was required to attend the Clinical and Metabolic Research Unit at

Princess Margaret Hospital on three occasions, each separated by at least one week. The

first visit was a familiarization session during which the participant was familiarized

with the equipment and procedures to be used, as well as with the research team. Each

participant also completed an incremental exercise test on a cycle ergometer to measure

his peak oxygen consumption ( O2peak) and to determine the exercise workload for

the subsequent experimental trial. The subsequent two visits involved an exercise trial

(EX) and a control rest trial (CON) in order to determine the effect of an antecedent

bout of exercise on the glucose and counterregulatory responses to a maximal sprint

effort. To avoid any order effects, the EX and CON trials were administered in a

randomized counterbalanced design, with each participant acting as his own control. On

one occasion, the participant performed 60 minutes of moderate-intensity exercise (EX)

on a cycle ergometer and then rested for 3 hours and 15 minutes before performing a

30-second maximal sprint. On the other occasion, the participant rested on the bike for

60 minutes (CON) prior to resting for a further 3 hours and 15 minutes before

performing the 30-second maximal sprint.

55

2.3.3 Familiarization Session

The primary goal of the familiarization session was to ensure that each participant was

comfortable with the research team, equipment, and procedures that were to be used

during the subsequent experimental trials. All participants were instructed to avoid

caffeine, alcohol and physical activity in the 24 hours prior to the familiarization

session. Upon arrival to the lab, standing height was measured, without shoes, against a

wall using a measuring tape (SECA, Model 240). Body mass was also measured with

the participant centered on an electronic scale (SECA Alpha, Model 770), with no shoes

and minimal clothing. An incremental exercise test, lasting approximately 20 minutes,

was then performed on a Front Access Cycle Ergometer (Exertech, Repco, Melbourne

Australia) to establish each participant’s peak oxygen consumption ( O2peak). Briefly,

this involved measuring resting oxygen consumption for 3 minutes for familiarization,

followed by initiation of cycling at 50-90 W, depending on the participant’s current

level of physical activity. The intensity of cycling was increased by 40 W every 3

minutes until volitional exhaustion was reached. During exercise, participants breathed

through a calorimetry mask so that the volume of expired gas, as well as the fractions of

oxygen and carbon dioxide in the expired air, could be measured using a computerized

gas analysis system (VMax Spectra, SensorMedics Corporation, USA). These

parameters were used to calculate each participant’s O2peak, which was subsequently

used to determine the appropriate workload (65% O2peak) for the EX trial. Heart rate

(HR) (Polar Heart Rate Monitor) was also measured throughout the exercise test as an

additional indicator of exercise intensity.

2.3.4 Experimental Trials

Three days prior to each experimental trial, each participant came to the Laboratory to

be briefed on the study restrictions and fitted with an accelerometer (Activity Monitor

GT1M, Actigraph, Florida USA) to be worn for the 3 days leading up to the trial. This

was to ensure that no vigorous physical activity was done during the 24 hours prior to

56

the trial as antecedent exercise has been shown to blunt the counterregulatory responses

to subsequent exercise (Galassetti et al., 2001). Participants were also asked to abstain

from caffeine and alcohol in the 24 hours prior to each trial. Finally, participants were

asked to record their food and drink intake (types and amounts) on the day before the

first trial in a self-recorded food diary (Appendix C). The participants were asked to

consume the same food and drink on the day prior to the subsequent trial so that food

intake was standardized between trials.

On the morning of each experimental trial, participants consumed a small liquid

breakfast (Sanitarium Up & Go Liquid Breakfast; 61% carbohydrate, 19% fat, 20%

protein, 16.3 kJ/kg body mass) approximately 40 minutes prior to arrival at the

laboratory following a 10-hour overnight fast. This breakfast was provided to minimize

the risk of hypoglycaemia throughout the trial as a result of the overnight fast. The

amount of carbohydrate in the liquid meal was standardized for each participant based

on body mass (0.6 ± 0.1 g/kg body mass) and matched between trials. Participants were

also required to apply a localized anaesthetic cream (EMLA) and Tegaderm to the left

and right antecubital fossae 1 hour prior to arrival in preparation for cannulation. When

participants arrived in the laboratory at 8:00 am, the localized anesthetic cream (EMLA)

was removed to avoid excessive vasoconstriction as one hour of application was

sufficient for the anesthetic to take effect. The participant then began either cycling on

the Front Access Cycle Ergometer for 60 minutes at 65% O2peak (EX) or resting for

60 minutes while sitting stationary on the cycle ergometer (CON). This exercise

intensity was chosen based on previous research by Galassetti and colleagues (2001)

showing attenuated counterregulatory responses to subsequent exercise after a 90-

minute bout of exercise at 50% O2peak. A reduction in the exercise duration and

increase in intensity was employed to reflect more likely ‘real world’ practices and

current exercise guidelines (American College of Sports Medicine, 1998). Blood lactate

was sampled from the fingertip at 15 and 45 minutes of exercise or the resting control

using a Lactate Pro meter (Arkray Inc., Kyoto, Japan). These lactate samples were used

to ensure that participants were replicating the below anaerobic threshold exercise

conditions used by Galassetti so that the exercise was challenging, but could still be

sustained for a prolonged period of time.

Immediately after this 60-minute period of either exercise or rest, a 20-gauge cannula

(BD InsyteTM) was inserted for blood sampling and kept patent with regular infusion of

0.9% saline. A baseline blood sample was taken at this time to measure the background

57

deuterated glucose enrichment levels. Next, a 22-gauge cannula (BD InsyteTM) was

inserted into the antecubital vein of the contralateral arm for the infusion of the non-

radioactive stable isotope [6,6-2H] glucose using an ASENA Syringe Driver (Alaris

Medical System, Basingstoke, UK). This infusion was commenced 30 minutes after the

cessation of the 60 minutes of exercise or rest with an initial priming bolus of 3 mg.kg-1

body mass, accompanied by a constant infusion of 2.4 mg.kg-1.h-1 for the remainder of

the study. This infusion was necessary for measurement of the rate of appearance (Ra)

and the rate of disappearance (Rd) of glucose to determine whether changes in blood

glucose were a result of glucose production or glucose uptake. Participants were then

required to rest for a further 2 hours and 30 minutes for isotopic equilibrium to be

reached, during which time they watched light movies or read. Water intake was ceased

45 minutes prior to the sprint so that the plasma volume shift in response to the 30-

second sprint could be assessed.

Five minutes prior to the sprint, the participant moved to the cycle ergometer to prepare

for exercise. A 30-second maximal sprint was then performed. Each participant started

the sprint in the standing ready position with their feet strapped into the pedals and their

dominant leg raised at a 45-degree angle, ready to push down. Participants started

sprinting after a three second countdown and were told to cycle as hard as they could

from the start of the sprint, rather than to pace themselves. A high level of verbal

encouragement was provided to maximize the motivation and sprint effort of the

participant. A 30-second sprint was used because the glycaemia-increasing effect of

sprinting is more pronounced after a 30-second sprint compared to a 10-second sprint

(Moussa et al., 2003).

Following the sprint, each participant dismounted the bike and was required to rest for 1

hour in the Laboratory so that the response of glucose kinetics and counterregulatory

hormones to the sprint could be measured. Venous blood samples (23 ml) were taken 15

and 5 minutes before the sprint, as well as at 0, 5, 10, 15, 30, 45, and 60 minutes of

recovery. Prior to each sample, the participant’s hand was warmed in a hot box (Omega

CN 370, Sydney, Australia) at 55-60˚C so that arterialized-venous blood could be

obtained. This is important given that blood glucose concentration varies between the

arteries and veins, and the composition of arterialized venous blood is more indicative

of arterial blood (Liu et al., 1992).

58

Expired air was also collected at periods throughout the study, with each collection

lasting ten minutes. This required participants to breathe into a calorimetry mask, with

their expired gases analyzed by the same Vmax Spectra respiratory analysis system

(SensorMedics Corporation, USA) used during the maximal exercise test. Two gas

samples were taken during the 60 minutes of antecedent exercise or rest, collecting from

15-25 minutes and 40-50 minutes. These gas samples were used to confirm whether the

prescribed exercise workload was accurate (65% O2peak) and any necessary

adjustments to the workload were made accordingly.

After the 1-hour recovery period, the cannulas were removed and the participants were

given a meal before leaving the laboratory. Participants were asked to return to the

Laboratory at least 1 week later to have the accelerometer re-fitted and worn for the

three days prior to their next trial. Three days later, the participant returned to the

Laboratory to complete the alternative trial.

2.3.5 Measurement of Blood Metabolites and Hormones

A number of blood samples were collected throughout the experimental protocol to

measure the blood glucose and counterregulatory response to exercise. Blood glucose

and lactate levels were determined using a YSI Analyzer (YSI Life Sciences, Yellow

Springs, Ohio, USA). The remaining blood was aliquotted to appropriate collection

tubes prior to centrifugation at 4ºC at 3500 rpm (Eppendorf Centrifuge 5810 R,

Hamburg, Germany), with the resultant serum or plasma collected and stored at -40ºC

(with the exception of the deuterated glucose and catecholamines which were stored at

-80ºC). Insulin was assayed from plasma in a lithium heparin tube by non-competitive

chemiluminescent immunoassay (Abbott Architect i2000, Illinois USA). Plasma was

collected for the assay of pancreatic-specific glucagon in a K-EDTA tube with a

Benzamidine HCL additive, and subsequently assayed using a non-competitive radio-

immunoassay (Siemens Medical Solutions Diagnostics Ltd, California, USA). Growth

hormone was assayed from serum collected in a serum clot activator tube by a non-

competitive enzyme immunoassay with a chemiluminescent substrate (Siemens

Immulite 2000 XPi; Siemens Medical Solutions Diagnostics Ltd, California, USA).

Serum was also collected for the assay of cortisol in a serum clot activator tube before

being subsequently assayed using a competitive chemiluminescent immunoassay

59

(Abbott Architect i2000, Illinois USA). Epinephrine and norepinephrine were collected

in a lithium heparin tube with a sodium metabisulfite additive before being extracted on

alumina and eluted with acetic acid. The extracted catecholamines were separated on a

reverse phase column (Ultrasphere; Beckman Coulter, Albany North Shore City, New

Zealand) using a Shidmadzu HPLC system (Shidmadzu Scientific Instruments,

Australia) with an ESA Coulochem-II Electrochemical Detector (California, USA).

Additionally, haemoglobin levels were measured using a Hemocue analyzer (HemoCue

Hb 201+, Ängelholm, Sweden), while haematocrit was measured using a

microhaematocrit reader (Clements) after centrifuging for 4 minutes (H.I. Clements Pty

Ltd. Sydney, Australia). Measurements of haemoglobin and haematocrit were used to

determine any plasma volume changes resulting from the sprint, using the methods of

Dill and Costill (1974). In addition, blood pH was measured using an ABLTM 725 Blood

Gas Analysis System (Radiometer, Copenhagen).  

2.3.6 Measurement of [6,6-2H] glucose enrichment, and glucose Ra and Rd calculations

The level of plasma enrichment of [6,6-2H] glucose was determined from plasma

collected in a standard lithium heparin tube using gas chromatography mass

spectrometry (GCMS; Agilent Selective Detector, Agilent technologies, Ryde, NSW,

Australia). This method, as previously described by Hannestad and Lundblad (1997),

involved the conversion of [6,6-2H] glucose to its aldonitrile derivative, which was

subsequently measured using GCMS. Glucose Ra and Rd were then calculated using the

one-compartment fixed-volume non-steady state model of Steele (Wolfe & Chinkes,

2005). This model assumes that the [6,6-2H] glucose distribution volume is stable, and

that changes in plasma glucose concentration only result from changes in glucose Ra

and Rd. However, these assumptions may not be valid during a maximal sprint effort.

This is because it has been repeatedly shown that performance of exercise, particularly

at a high-intensity, is associated with a marked fluid shift out of the vasculature and into

the active muscles (Raja et al., 2006; Ward et al., 1996; Watson et al., 1993; Sjøgaard et

al., 1985; Sjøgaard & Saltin, 1982). This is due in part to the large increase in the levels

of lactate, hydrogen ions, and inorganic phosphates within the muscle cell which creates

a large osmotic gradient that causes a marked shift of fluid out of the vasculature and

into the active muscles (Raja et al., 2006; Ward et al., 1996; Watson et al., 1993,

60

Sjøgaard et al., 1985, Sjøgaard & Saltin, 1982). Therefore, some of the change in

plasma glucose concentration may be attributed to a shift in plasma volume, rather than

to a change in glucose Ra and Rd. Consequently, glucose Ra and Rd were re-calculated

after correcting for any changes in plasma glucose concentration that could be explained

by a shift in plasma volume, assuming that any relative change in plasma volume

reflects a change in the [6,6-2H] glucose distribution volume.

2.3.7 Statistical Analyses

The data from this study were analyzed for changes over time and between treatments

using SPSS 17.0 Software for Windows. Two-way (time x trial) Repeated-Measures

Analysis of Variance was used to determine whether differences existed, followed by

post-hoc pairwise comparisons to determine where the differences lay. Area under the

curve (AUC) was calculated using the trapezoidal rule, with one-way repeated-measures

ANOVA used to compare between trials. In addition, a Pearson correlation was

undertaken between relative mean power output in the 30-second sprint and the

maximum change in blood glucose, as well as AUC for blood glucose. Statistical

significance was accepted at the p < 0.05 level. With the exception of tables (mean ±

SD), all data are expressed as mean ± SEM.

2.4 Results

2.4.1 Characteristics of the 60-minute antecedent bout of exercise and maximal sprint efforts

During the EX trial, participants worked at 65 ± 6% of their O2peak during the 60

minutes of antecedent exercise, compared to the equivalent rest period in which oxygen

consumption remained at basal levels (Table 2.2). Blood lactate remained at a low level

throughout the 60 minutes of exercise (p > 0.05 compared to control). Furthermore, the

61

antecedent bout of exercise was accompanied by a significant rise in heart rate when

compared to antecedent rest (p < 0.05; Table 2.2). With respect to the number of steps

taken in the 3 days preceding each trial as determined from accelerometry, there was no

significant difference between trials in the total number of steps taken over the entire 3

day period (19,385 ± 3,176 steps CON; 22,540 ± 1,663 steps EX; p = 0.397), or when

the day preceding each trial was considered in isolation (4,980 ± 2,632 steps CON;

6,268 ± 825 steps EX; p = 0.327), suggesting antecedent activity levels were matched

between trials.

Participants displayed no significant difference between trials in the absolute or relative

mean power output during the 30-second sprint performed after 60 minutes of

antecedent exercise or rest (Table 2.3). There was also no significant difference in the

absolute or relative peak power output during the 30-second sprint between trials.

Table 2.2. Response of oxygen consumption, blood lactate, and heart rate to

60 minutes of antecedent exercise or rest (control)

Variable Exercise Control

Mean O2 (ml·kg·min-1) 30.5 ± 3.6* 4.8 ± 0.7

Mean % O2peak 65 ± 6* 9 ± 7

Blood lactate (mM)

at 15 minutes 4.5 ± 1.7 3.4 ± 2.3

Blood lactate (mM)

at 45 minutes 3.5 ± 1.7 2.2 ± 1.0

Mean heart rate (bpm) 143 ± 10* 78 ± 6

Data are means ± SD. O2, oxygen consumption. % O2peak, percentage of peak oxygen consumption. *Statistically significant difference (p < 0.05) vs. control.

62

Table 2.3 Comparison of mean and peak power output during a 30-second maximal

sprint following 60 minutes of antecedent exercise or rest (control)

Variable Exercise Control

Absolute (W) Relative (W/kg) Absolute (W) Relative (W/kg)

Mean Power

815 ± 180 10.9 ± 1.4 818 ± 170 10.7 ± 1.3

Peak Power

1,359 ± 336 18.2 ± 3.1 1,335 ± 316 17.9 ± 2.6

Data are means ± SD. No significant differences between trials (p > 0.05).

2.4.2 Blood glucose response to a 30-second maximal sprint

Prior to the 30-second maximal sprint, baseline blood glucose concentrations were 4.46

± 0.07 mM and 4.44 ± 0.05 mM in CON and EX, respectively (p = 0.724; Fig 2.1). In

response to the 30-second maximal sprint, blood glucose levels increased significantly

and similarly in both trials, reaching a peak at 10 minutes of recovery (5.44 ± 0.13 mM

and 5.43 ± 0.08 mM in CON and EX, respectively; p = 0.86). After this time, blood

glucose levels began to steadily decline, returning to baseline in EX by 45 minutes of

recovery (p = 0.619) and in CON by 60 minutes of recovery (p = 0.147). The more

rapid decline in blood glucose levels following EX resulted in significantly lower blood

glucose levels at 45 minutes of recovery compared to CON (4.98 ± 0.15 CON; 4.50 ±

0.10 EX; p = 0.024), and a tendency for lower blood glucose levels following EX at 30

(p = 0.067) and 60 (p = 0.072) minutes of recovery. Accordingly, the AUC for blood

glucose approached significance (p = 0.057), with a tendency for lower levels following

EX.

63

There were no relationships between relative mean power output in the 30-second sprint

and the maximum change in blood glucose (r = 0.55, p = 0.157) and between relative

power output and the AUC for glucose (r = 0.40, p = 0.327).

Figure 2.1 Blood glucose response to a 30-second maximal sprint (represented by

vertical bar) performed after 60 minutes of antecedent exercise (EX) or rest (CON). All

data are means ± SEM. aStatistically significant difference (p < 0.05) from baseline

(time -5 minutes). bStatistically significant difference (p < 0.05) between CON and EX.

2.4.3 Glucose rate of appearance and rate of disappearance determined without corrections in plasma volume

Immediately following the 30-second maximal sprint, Ra remained at baseline levels in

both trials (Fig 2.2a; Fig 2.2b). This was followed by a significant increase in Ra above

baseline at 5 minutes post-sprint in both CON (p = 0.044) and EX (p < 0.001), before

returning to baseline levels at 10 minutes post-sprint where Ra remained for the duration

of recovery. In contrast, Rd declined immediately following the 30-second sprint in both

trials, dropping significantly below baseline levels in CON at 0 minutes of recovery

(p = 0.009). After this initial decline, Rd quickly returned to baseline, where it remained

for the rest of recovery in CON, while for EX levels increased significantly above

64

baseline at 5 (p = 0.006) and 45 minutes of recovery (p = 0.013). There was no

significant difference in Ra or Rd between trials (p > 0.05).

Within each trial, Ra rose significantly above Rd immediately following the 30-second

sprint. Ra was significantly greater than Rd at 0 (p < 0.001) and 10 (p = 0.010) minutes

of recovery following CON and 0 (p < 0.001) and 5 (p = 0.002) minutes of recovery

following EX. Following this, Ra was matched by Rd until 15 and 45 minutes of

recovery in EX and CON, respectively. At 15 minutes of recovery following EX, Rd

rose significantly above Ra for the next 45 minutes of recovery (p = 0.044, p = 0.010,

and p < 0.001 at 15, 30, and 45 minutes, respectively). Rd also increased above Ra

following CON, but not until 45 (p < 0.001) and 60 (p = 0.004) minutes of recovery.

2.4.4 Glucose rate of appearance and rate of disappearance when corrected for plasma volume changes

The 30-second maximal sprint caused a significant shift in plasma volume and

associated increase in haematocrit (Figure 2.3; Table 2.4). Immediately following the

sprint, the change in plasma volume decreased significantly below 0 in both the CON

(p < 0.001) and EX trials (p < 0.001). After this initial shift, plasma volume began to

return towards baseline levels through the accumulation of several small changes in

plasma volume throughout the remainder of recovery. There was no significant

difference in the shift in plasma volume between trials, with the exception of between

45 and 60 minutes of recovery where a significantly greater shift was observed

following EX (p = 0.033). The 30-second maximal sprint also resulted in a significant

increase in haematocrit above pre-sprint levels, followed by a return to pre-sprint levels

at 30 minutes of recovery before declining below baseline levels in both trials. There

was no significant difference in the haematocrit response between trials (p > 0.05).

After correcting Ra and Rd for these changes in plasma volume, there was still no

difference in glucose Ra or Rd between trials (p > 0.05; Fig 2.4a; Fig 2.4b). The plasma

volume shift did not affect the pattern of Ra response compared to that which was

previously described when no correction for plasma volume was made, with a

significant increase above baseline at 5 minutes of recovery in both trials (p = 0.045 in

CON; p < 0.001 in EX). In comparison, glucose Rd was highly influenced by the shift in

65

plasma volume. During CON, Rd did not decline at the onset of recovery, with no

significant difference from baseline seen at any time point after the application of a

plasma volume correction. Similarly, the significant difference from baseline Rd seen at

45 minutes of recovery in EX was not present after the correction.

When the glucose Ra and Rd were compared within trials using the values corrected for

plasma volume changes, Ra and Rd were no longer significantly different immediately

after the sprint in both trials. Ra was significantly higher than Rd in CON at 5 and 10

minutes of recovery, while Rd exceeded Ra at 60 minutes of recovery. Similarly, Ra

exceeded Rd at 5 and 10 minutes of recovery following EX, but Rd exceeded Ra earlier

in recovery (at 45 minutes) compared to CON.

2.4.5 Plasma insulin response to a 30-second maximal sprint

Plasma insulin levels were similar in both trials prior to the 30-second sprint (Fig 2.5).

Immediately after sprinting, plasma insulin levels were significantly lower in EX

compared to CON (p = 0.006). Plasma insulin levels then began to rise in both trials,

reaching similar peak levels at 30 minutes of recovery (10.19 ± 1.91 and 8.11 ± 1.06

µU/ml in CON and EX, respectively, p = 0.281). Insulin levels returned to baseline at

45 minutes of recovery in EX, but still remained significantly elevated above basal

levels at 60 minutes of recovery in CON. Insulin levels were significantly higher at 45

minutes of recovery in CON compared to EX (p = 0.042).

2.4.6 Counterregulatory hormone response to a 30-second maximal sprint

Plasma glucagon levels were similar in both trials prior to the 30-second sprint

(p = 0.349; Fig 2.6). Immediately following the sprint, plasma glucagon levels increased

significantly and similarly above baseline in both trials (p = 0.016 and p = 0.007 in

CON and EX, respectively), returning to baseline by 15 minutes of recovery. Plasma

glucagon levels then increased significantly above baseline in EX again at 60 minutes of

recovery, resulting in a significant difference between CON and EX at this time

(p = 0.015).

66

Plasma epinephrine was similar in both trials prior to the 30-second sprint (p = 0.387;

Fig 2.7a). Plasma epinephrine levels then increased significantly above baseline in

response to the sprint, peaking immediately post-sprint (0 minutes of recovery) before

beginning to return to baseline. A significant difference in epinephrine levels existed

between trials at 15 minutes of recovery, although this difference was minimal with

slightly higher epinephrine following EX compared to CON (p = 0.036). Plasma

norepinephrine was similar in both trials prior to the sprint (p = 0.472; Fig 2.7b).

Immediately following the sprint, plasma norepinephrine levels increased significantly

and similarly above baseline in both trials (p = 0.001 and p = 0.002 in CON and EX,

respectively). Plasma norepinephrine levels then began to decline towards baseline for

the remainder of recovery. There was no significant difference in norepinephrine levels

between trials.

Plasma growth hormone levels were similar in both trials prior to the 30-second sprint

(0.963 ± 0.287 mIu/L and 3.507 ± 3.244 mIu/L in CON and EX, respectively;

p = 0.431; Fig 2.8). Immediately after the sprint, growth hormone levels began to rise,

reaching peak levels at 30 minutes of recovery. This growth hormone response was

significantly blunted by the performance of antecedent moderate exercise, with

significantly lower growth hormone levels at 15, 30, and 45 minutes of recovery in EX

compared to CON (p = 0.048, p = 0.025, p = 0.028 at 15, 30, and 45 minutes of

recovery, respectively).

Plasma cortisol levels were also similar in both trials prior to the 30-second sprint (265

± 22 nmol/L and 238 ± 20 nmol/L in CON and EX, respectively; Fig 2.9). In response

to the sprint, plasma cortisol levels increased significantly and similarly above baseline

in both trials, reaching maximal levels at 30 minutes of recovery (p = 0.524). There was

no significant difference in plasma cortisol levels between trials at any point of

recovery.

67

Figure 2.2a Glucose Ra and Rd in response to a 30-second maximal sprint (represented

by vertical bar) performed after 60 minutes of rest (CON). All data are means ± SEM. aStatistically significant difference (p < 0.05) from baseline (time -5 minutes). bStatistically significant difference (p < 0.05) between Ra and Rd.

Figure 2.2b Glucose Ra and Rd in response to a 30-second maximal sprint (represented

by vertical bar) performed after 60 minutes of antecedent exercise (EX). All data are

means ± SEM. aStatistically significant difference (p < 0.05) from baseline (time -5

minutes). bStatistically significant difference (p < 0.05) between Ra and Rd.

68

Table 2.4 Percent change in plasma volume (%∆PV) in response to a 30-second

maximal sprint

Time (min) in

relation to sprint

-5 - 0 0 - 5 5 - 10 10 - 15 15- 30 30 - 45 45- 60

Control -10.3 ± 3.3a 0.9 ± 2.7 3.2 ± 2.0

a 2.6 ± 2.3

a 4.9 ± 3.9

a 6.3 ± 3.6

a 0.3 ± 2.4

Exercise -13.3 ± 3.4a 1.0 ± 4.8 3.2 ± 1.5

a 1.7 ± 2.2 8.1 ± 3.8

a 5.5 ± 2.3

a 2.8 ± 2.0

a,b

Data are means ± SD. The 30-second sprint occurred immediately before time 0. Reported %∆PV is

the change over the specified interval. aStatistically significant difference (p < 0.05) from 0. bStatistically significant difference (p < 0.05) between CON and EX.

Figure 2.3 Changes in haematocrit in response to a 30-second maximal sprint

(represented by vertical bar) performed after 60 minutes of antecedent exercise (EX) or

rest (CON). All data are means ± SEM. aStatistically significant difference (p < 0.05)

from baseline (time -5 minutes).

69

Figure 2.4a Glucose Ra and Rd in response to a 30-second maximal sprint

(represented by vertical bar) performed after 60 minutes of rest (CON) when

corrected for plasma volume changes. All data are means ± SEM. aStatistically

significant difference (p < 0.05) from baseline (time -5 minutes). bStatistically

significant difference (p < 0.05) between Ra and Rd.

Figure 2.4b Glucose Ra and Rd in response to a 30-second maximal sprint

(represented by vertical bar) performed after 60 minutes of antecedent exercise

(EX) when corrected for plasma volume changes. All data are means ± SEM. aStatistically significant difference (p < 0.05) from baseline (time -5 minutes). bStatistically significant difference (p < 0.05) between Ra and Rd.

70

Figure 2.5 Plasma insulin response to a 30-second maximal sprint (represented by

vertical bar) performed after 60 minutes of antecedent exercise (EX) or rest (CON). All

data are means ± SEM. aStatistically significant difference (p < 0.05) from baseline

(time -5 minutes). bStatisticallysignificantdifference (p<0.05)betweenCONand

EX.

Figure 2.6 Plasma glucagon response to a 30-second maximal sprint (represented by

vertical bar) performed after 60 minutes of antecedent exercise (EX) or rest (CON). All

data are means ± SEM. aStatistically significant difference (p < 0.05) from baseline

(time -5 minutes). bStatistically significant difference (p < 0.05) between CON and EX.

71

Figure 2.7a Plasma epinephrine response to a 30-second maximal sprint (represented

by vertical bar) performed after 60 minutes of antecedent exercise (EX) or rest (CON).

All data are means ± SEM. aStatistically significant difference (p < 0.05) from baseline

(time -5 minutes). bStatistically significant difference (p < 0.05) between CON and EX.

Figure 2.7b Plasma norepinephrine response to a 30-second maximal sprint

(represented by vertical bar) performed after 60 minutes of antecedent exercise (EX) or

rest (CON). All data are means ± SEM. aStatistically significant difference (p < 0.05)

from baseline (time -5 minutes).

72

Figure 2.8 Plasma growth hormone response to a 30-second maximal sprint

(represented by vertical bar) performed after 60 minutes of antecedent exercise (EX) or

rest (CON). All data are means ± SEM. aStatistically significant difference (p < 0.05)

from baseline (time -5 minutes). bStatistically significant difference (p < 0.05) between

CON and EX.

Figure 2.9 Plasma cortisol response to a 30-second maximal sprint (represented by

vertical bar) performed after 60 minutes of antecedent exercise (EX) or rest (CON). All

data are means ± SEM. aStatistically significant difference (p < 0.05) from baseline

(time -5 minutes).

73

2.4.7 Blood lactate, blood pH, and heart rate responses to a 30-second maximal sprint

Mean blood lactate levels at baseline prior to the 30-second sprint were 0.59 ± 0.06 mM

and 0.52 ± 0.03 mM in CON and EX, respectively (p = 0.097; Fig 2.10). In response to

the 30-second maximal sprint, blood lactate increased significantly above baseline in

both trials, reaching similar peak levels of 9.59 ± 0.67 mM and 9.33 ± 0.64 mM in CON

and EX, respectively, at 5 minutes of recovery (p = 0.505). Blood lactate levels then fell

progressively, but still remained above basal levels at 60 minutes of recovery (p < 0.05

in both CON and EX), with no significant differences between trials at any point. Mean

blood pH prior to the sprint was similar in both groups (7.36 ± 0.01 in CON; 7.38 ±

0.01 in EX; p = 0.098; Fig 2.11). Performance of the 30-second maximal sprint caused a

significant decline in blood pH in both groups, with a minimum pH of 7.08 ± 0.02 and

7.07 ± 0.01 reached in EX and CON, respectively, at 5 minutes of recovery. Afterwards,

pH increased, progressively returning to baseline in both groups at 45 minutes of

recovery. A significant difference in pH was noted between trials at 45 minutes of

recovery (p = 0.020), with EX displaying a significantly higher pH. Finally, the sprint

was associated with a significant rise in heart rate, which peaked immediately post-

sprint (150 ± 7 bpm CON; 156 ± 5 bpm EX) and returned to baseline levels by 5

minutes of recovery.

74

Figure 2.10 Blood lactate response to a 30-second maximal sprint (represented by

vertical bar) performed after 60 minutes of antecedent exercise (EX) or rest (CON). All

data are means ± SEM. aStatistically significant difference (p < 0.05) from baseline

(time -5 minutes).

Figure 2.11 Blood pH response to a 30-second maximal sprint (represented by vertical

bar) performed after 60 minutes of antecedent exercise (EX) or rest (CON). All data are

means ± SEM. aStatistically significant difference (p < 0.05) from baseline (time -5

minutes). bStatistically significant difference (p < 0.05) between CON and EX.

75

2.5 Discussion

Recently, it has been reported that the performance of one or several short maximal

sprints before, during, or after moderate-intensity exercise attenuates the decline in

blood glucose levels during recovery in individuals with T1DM (Bussau et al., 2006;

Bussau et al., 2007; Guelfi, et al., 2005). This has been attributed, in part, to the

glucose-increasing effect of high-intensity exercise (Harmer et al., 2006; Marliss &

Vranic, 2002; Moussa et al., 2003; Purdon et al., 1993). Although these findings suggest

that sprinting may be a useful tool for decreasing the risk of exercise-mediated

hypoglycaemia, factors that may impair its efficacy must be identified before this type

of exercise can be safely recommended to individuals with T1DM. Of interest,

Galassetti and colleagues (2001) found that a 90-minute bout of antecedent moderate-

intensity exercise blunted the counterregulatory hormone responses to an identical bout

of exercise performed 3 hours later. This raises the question of whether antecedent

exercise may also impair the glycaemia-increasing effect of sprinting performed hours

later. The present study shows that 60 minutes of moderate-intensity exercise does not

affect the rise in blood glucose levels associated with a 30-second maximal sprint

performed approximately 3 hours later, with a similar increase in blood glucose levels

observed in both EX and CON trials. However, as recovery progresses, the decline in

blood glucose levels is more rapid when the sprint follows a bout of moderate-intensity

exercise. These results raise the possibility that antecedent moderate-intensity exercise

might also have the potential to reduce the efficacy of sprinting in decreasing the risk of

exercise-mediated hypoglycaemia in individuals with T1DM.

Although the transient glycaemia-increasing effect of sprinting seen in our study is

supported by the findings of others in non-diabetic individuals, this is the first study to

show that antecedent exercise increases the rate of fall in blood glucose after it reaches

peak levels. Previous research has shown that a 30-second maximal sprint results in a

comparable transient rise in blood glucose levels to that seen here, with blood glucose

levels returning to pre-exercise levels within one hour of recovery (Moussa et al., 2003).

Conversely, 10 to 15 minutes of intense aerobic exercise (>80% O2max) has been

shown to produce a greater rise in blood glucose levels than a 30-second maximal sprint

(Marliss & Vranic, 2002). However, this study shows for the first time that the decline

in blood glucose levels is more rapid after a sprint if preceded by a one-hour bout of

moderate intensity exercise performed several hours earlier.

76

An initial examination of our findings suggests that, when changes in plasma volume

are not taken into consideration, the increase in blood glucose levels at the onset of

recovery in both trials results mainly from a transient fall in glucose Rd, since sprinting

appears to have no immediate effect on glucose Ra. However, over the following 5-10

minutes of recovery, there is a further rise in blood glucose levels despite the marked

increase in glucose Rd in both trials. This increase in blood glucose level is the result of

the concomitant rise in glucose Ra that significantly exceeds the rise in glucose Rd. It is

noteworthy, however, that this pattern of change in glucose Ra differs markedly from

that associated with high-intensity aerobic exercise, where glucose Ra has been shown

to be already near maximal at the onset of recovery (Kreisman et al., 2000; Marliss et

al., 2000; Marliss & Vranic, 2002; Mitchell et al., 1988; Purdon et al., 1993; Sigal et al.,

1994). Another noteworthy difference is the transient fall in glucose Rd at the onset of

recovery, compared to the reported high glucose Rd immediately after high-intensity

aerobic exercise (Kreisman et al., 2000; Marliss et al., 2000; Marliss & Vranic, 2002;

Purdon et al., 1993; Sigal et al., 1994). These differences may be due to the varied

nature of high-intensity aerobic exercise as compared to the physiological requirements

of a short maximal anaerobic sprint. Regardless, the mechanisms underlying the decline

in glucose Rd remain to be determined, it is possible that the intramuscular accumulation

of glucose 6-phosphate that typically occurs with intense exercise may inhibit the rate of

glucose uptake via a glucose 6-phosphate-mediated inhibition of hexokinase, a key

glycolytic enzyme (Gollnick et al., 1981).

It is important to stress, however, that when the marked changes in plasma volume in

response to the sprint are taken into account, the onset of recovery is no longer

accompanied by a marked decline in glucose Rd. Instead, sprinting appears to have no

immediate effect on glucose Rd. This glucose Rd response still differs from that in non-

diabetic individuals subjected to high-intensity aerobic exercise who display a marked

increase in glucose Rd at the onset of recovery (Kreisman et al., 2000; Marliss et al.,

2000; Marliss & Vranic, 2002; Purdon et al., 1993; Sigal et al., 1994). Again, it is

possible that the absence of any rise in glucose Rd in response to the sprint can be

explained by an inhibition of glucose uptake by elevated glucose 6-phosphate levels.

Furthermore, the lack of a significant difference between glucose Ra and Rd at the onset

of recovery in both trials indicates that the change in plasma volume in response to the

sprint may be high enough to completely account for the early rise in blood glucose

level, with the apparent decline in glucose Rd described above (prior to correction for

77

plasma volume shifts) likely an artifactual result of the fluid shift into the musculature.

However, the continued increase in blood glucose beyond the start of recovery in both

trials cannot be fully explained by the shift in plasma volume. Rather, the rise in

glycaemia at this time likely results, to some extent, from glucose Ra significantly

exceeding glucose Rd. Clearly, our findings show that the well-documented plasma

volume shift associated with intense exercise (Raja et al., 2006; Ward et al., 1996;

Watson et al., 1993, Sjøgaard et al., 1985, Sjøgaard & Saltin, 1982) must be considered

when examining the effect of sprinting on blood glucose levels, as this variable has the

potential to considerably influence the interpretation of glucose kinetics.

The early rise in the levels of the plasma catecholamines immediately after sprinting

suggests that these hormones might play some role in mediating the increase in

glycaemia seen 5 to 10 minutes following the sprint. Others have also reported that the

rise in blood glucose levels associated with sprinting and high-intensity exercise is

accompanied by an immediate increase in plasma epinephrine and norepinephrine levels

(Kreisman et al., 2000; Kreisman et al., 2003; Marliss et al., 2000; Sigal et al., 1994).

There is substantial evidence that such an increase in plasma catecholamine levels

contributes to the rise in blood glucose levels via stimulation of glucose Ra (Kjaer,

1992; Kreisman et al., 2003; Purdon et al., 1993). In this respect, epinephrine and

norepinephrine have been proposed to exert their effects mainly by increasing the rate

of hepatic glucose production (Cryer et al., 2003; Goldstein et al., 1995; Lumb &

Gallen, 2009; Marliss et al., 2000; Rizza et al., 1979; Sigal et al., 1994). Of note, the

absence of any clinically meaningful effect of antecedent moderate-intensity exercise on

the catecholamine response to a sprint does not support our prediction based on the

work of Galassetti and colleagues (2001), which showed that a bout of antecedent

moderate-intensity exercise blunts the epinephrine and norepinephrine responses to a

second bout of moderate-intensity exercise performed several hours later. It is possible

that this discrepancy is the result of an all-out sprint being a much greater stimulus than

moderate-intensity exercise, ultimately overriding any suppression caused by an

antecedent bout of exercise.

Later in recovery, the more rapid decline in blood glucose levels in EX compared to

CON is likely the result of glucose Rd exceeding glucose Ra earlier in recovery in EX.

Indeed, glucose Rd is significantly higher than glucose Ra from 15 to 45 minutes of

recovery in EX, while glucose Rd in CON does not exceed glucose Ra until 45 minutes

of recovery. However, when both glucose Ra and Rd are corrected for changes in plasma

78

volume, glucose Rd rises above glucose Ra much later during recovery in both trials, but

still earlier in EX (45 minutes of recovery) compared to CON (60 minutes of recovery).

Despite the close matching of glucose Ra and Rd until late in recovery, blood glucose

levels begin to decline at 15 minutes of recovery, suggesting that the increasing plasma

volume back towards baseline levels occurring at this time may be responsible for at

least part of the decline in blood glucose concentration. However, the plasma volume

shift cannot account for the faster rate of decline in blood glucose following EX

compared to CON, since the changes in plasma volume were similar between trials until

60 minutes of recovery. Instead, the more rapid decline in blood glucose in EX is most

likely to involve the earlier increment in Rd above Ra as described. Unfortunately, the

analysis described here does not allow us to determine the extent to which changes in

plasma volume must be considered in glucose kinetic analyses, particularly when

working with low rates of changes in plasma volume.

The more rapid fall in blood glucose levels in EX compared to CON is unlikely to be

associated with the levels of the plasma catecholamines, since the levels of these

hormones were similar between trials, except for a small difference in epinephrine at 15

minutes of recovery that would be unlikely to have any clinically meaningful effect on

blood glucose later in recovery. Furthermore, although the level of circulating plasma

insulin is a key mediator of the decline in blood glucose during recovery from high-

intensity exercise (Lumb & Gallen, 2009; Purdon et al., 1993; Riddell & Perkins, 2006;

Sigal et al., 1994), it is noteworthy that the more rapid decline in blood glucose levels in

EX compared to CON was associated with significantly lower plasma insulin levels in

EX at 45 minutes of recovery. The similar glucose Rd in both trials despite lower

plasma insulin levels in EX is consistent with greater insulin sensitivity in EX. Since the

level of muscle glycogen is an important determinant of insulin sensitivity (Derave et

al., 2000), the hypothesized increase in insulin sensitivity in EX may be a result of

lower post-sprint muscle glycogen levels due to the expected cumulative effect of

antecedent exercise and sprinting on muscle glycogen stores.

The more rapid decline in blood glucose levels in EX compared to CON might also be

explained by the attenuated increase in growth hormone levels in EX compared to

CON. Since a sudden increase in growth hormone levels can acutely inhibit glucose

uptake in non-diabetic individuals (Møller et al., 1990; Møller et al., 1992), the

attenuated rise in growth hormone levels in EX might explain the earlier rise of glucose

Rd above glucose Ra in EX compared to CON, thus explaining the more rapid decline in

79

blood glucose levels in EX. Of note, this is the first study to show that the growth

hormone response to a maximal sprint effort is attenuated by a bout of prior moderate-

intensity exercise. This finding is consistent with the work of Galassetti and colleagues

(2001), which demonstrated an attenuated growth hormone response to a bout of

moderate-intensity exercise performed hours after an identical bout of exercise. In

contrast, antecedent moderate-intensity exercise had no effect on the response of

cortisol to sprinting in the present study, a finding which differs from that of Galassetti

and colleagues (2001) who reported an attenuated increase in plasma cortisol levels

during a bout of moderate-intensity exercise following a prior bout of moderate-

intensity exercise. On the other hand, it is unlikely that glucagon contributed to the

more rapid decline in blood glucose in EX compared to CON, given the similar and

transient increase in both trials. With respect to the significant rise in plasma glucagon

levels in EX compared to CON at 60 minutes of recovery, this is likely an antagonistic

response to the rapidly falling blood glucose levels following EX. Since it is the

decrease in the beta cell secretion of insulin that causes an increase in glucagon

secretion by the alpha cells (Gosmanov et al., 2005), the lower level of circulating

plasma insulin as well as the rapid rate of decline in blood glucose levels following EX

may explain this late increase in plasma glucagon levels.

Regardless of the mechanism underlying the glycaemia-increasing effect of a 30-second

sprint, the faster decrease in blood glucose levels when sprinting is performed after a

bout of antecedent moderate-intensity exercise in non-diabetic individuals may have

important clinical implications for individuals with T1DM. However, since the rise in

plasma insulin plays a large role in the decline of blood glucose levels after intense

exercise in non-diabetic individuals (Purdon et al., 1993; Sigal et al., 1994), individuals

with T1DM may respond differently. Given the inability of these individuals to change

their circulating level of plasma insulin, blood glucose levels remain elevated after

intense exercise in individuals with T1DM (Mitchell et al., 1988; Purdon et al., 1993;

Sigal et al., 1994). Therefore, it is unclear to what extent our findings in non-diabetic

individuals may be relevant to individuals with T1DM. Nevertheless, the possibility

remains that although sprinting may benefit individuals with T1DM, even if performed

several hours after a bout of antecedent moderate-intensity exercise, these individuals

should be cautious because the efficacy of a sprint in reducing the risk of

hypoglycaemia later in recovery may be compromised. For this reason, the effect of

antecedent exercise on the glycaemia-increasing effect of sprinting needs to be tested in

80

individuals with T1DM before valid guidelines can be given to these individuals and to

ensure that any differences in the blood glucose response to sprinting observed in the

lab is of clinical significance and has real-life application. Moreover, it is important to

note that one limitation of our study is that it focused on young physically active non-

diabetic males, thus raising the possibility that our findings may not be generalized to

other populations and that sprinting may not be warranted for individuals with

cardiovascular or respiratory diseases. For instance, there is evidence for marked

gender-based differences in glucose counterregulation and in the amount of blunting

caused by antecedent exercise, with females showing greater resistance to the blunting

effect of antecedent exercise (Galassetti et al., 2001). For this reason, future research

should investigate the effect of antecedent exercise on the glycaemia-increasing effect

of sprinting in females with and without T1DM.

In summary, although a bout of antecedent moderate-intensity exercise does not affect

the peak increase in blood glucose levels achieved after a 30-second sprint, it does alter

the efficacy of the 30-second sprint later in recovery, causing blood glucose levels to

decline more rapidly. This faster rate of decline in blood glucose levels may result from

enhanced insulin sensitivity and/or a blunted growth hormone response to sprinting, as

all the other counterregulatory hormones responded similarly in both trials. These

findings raise the possibility that antecedent exercise may also impair the protective

effect of sprinting against hypoglycaemia in individuals with T1DM. This highlights the

need for further research in individuals with T1DM before sprinting can be safely

recommended as a means of reducing the risk of exercise-mediated hypoglycaemia.

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Appendices 

 

 

 

 

 

 

 

 

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Appendix A

Testing Information Sheet and Consent Forms 

 

 

 

 

 

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Testing Information Sheet

Effect of antecedent exercise on the glycaemia-increasing effect of a short sprint

Aim of the study Recently, our research team discovered that as little as 10 seconds of high intensity exercise can cause an increase in blood glucose levels in people with type 1 diabetes mellitus (T1DM), and thereby prevent or delay a low blood glucose event (hypoglycaemia). However, it is possible that prior exercise may reduce the protective effect of a short sprint. The goal of this study is to determine whether moderate intensity exercise will reduce the ability of a short sprint to increase blood glucose levels in non-diabetic individuals. Why are you being approached You are being invited to participate in this study because you are a healthy non-diabetic individual aged between 18 and 30 years. You also fulfil the following criteria: you are not on any medication that will interfere with the study findings and you do not suffer from a chronic muscle or joint injury or any other health problem that may affect your ability to perform exercise. The study in brief If you agree to take part in this study, you will be asked to visit the Diabetes Research Laboratory at Princess Margaret Hospital on 3 separate occasions – on your first visit, your height and weight will be measured and you will be asked to perform a maximal rate of oxygen consumption (VO2 max) test on an exercise bike to determine your levels of fitness. You will also be given an accelerometer and instructions on how and when to use it. This will monitor your physical activity level prior to the study days. No less than 1 week later, you will return to the lab for your first study day – either an exercise day, or a rest day. At least 1 week later you will return to the lab for your second study day and final visit. Your second study day will be an exercise day or a rest day depending on what you did on your first study day. You will be asked to complete both an exercise day and a rest day. It is important that before each study day you meet the following restrictions:

you must have avoided any physical activity (excluding light walking) in the previous 72 hours

you must not have consumed caffeine or alcohol in the previous 24 hours

Princess Margaret Hospital for Children Roberts Road Subiaco WA 6008 GPO Box D184 Perth WA 6840

Tel: (08) 9340 8222 Fax: (08) 9340 8111 www.cahs.health.wa.gov.au

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The study begins at 8 am and ends at approximately 2 pm, on both testing days. On arrival at the Research Unit, you will be provided with breakfast before a registered nurse will place a cannula (drip) into a vein on the back of your hand for the sampling of blood, and a second cannula will be inserted into one of the veins of your other forearm for the infusion of tagged glucose that has a heavy hydrogen attached to it. It is important to note that heavy hydrogen (also called deuterium) is harmless and that it is already present in moderate amounts in your body (close to 1g). This will allow us to keep track of the glucose inside your body. Once the cannulas are in place, you will be required to perform 60 minutes of moderate intensity exercise (equivalent to a light jog) on an exercise bike, or simply rest. Then, approximately 3 hours later, you will be required to perform a 30-second sprint on the same exercise bike. Following the sprint, you will be asked to sit comfortably for another 2 hours before the study ends. As mentioned above, you will return to the lab no less than 1 week later to perform the other treatment, either exercise or rest, before performing the 30-second sprint once more. Blood will be sampled at regular time intervals throughout the study, with a total volume of around 200 ml removed. This is far less than the volume removed when donating blood. On several occasions, we will also ask you to wear a mask to measure your rate of oxygen consumption. When you are not sprinting you can entertain yourself by watching light-hearted videos, listening to music, doing some light reading or just chatting with the research staff. We discourage any activity which will raise your adrenaline levels. Important Things to Note: 1. Your personal details and test results will be treated confidentially at all times. 2. It is important to stress that at any stage during the study you will retain the right to

withdraw your consent and to stop your participation in the study generally or in any specific aspect of it without impacting on your relationship with Princess Margaret Hospital for Children or the University of Western Australia.

Should you have any further questions concerning the study, please contact Prof Paul Fournier (6488 1356). If you have any complaints regarding the conduct of this study, please contact the Executive Director, Medical Services, PMH on 9340 8222.

Princess Margaret Hospital for Children Roberts Road Subiaco WA 6008 GPO Box D184 Perth WA 6840

Tel: (08) 9340 8222 Fax: (08) 9340 8111 www.cahs.health.wa.gov.au

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Consent Form

Effect of antecedent exercise on the glycaemia-increasing effect of a short sprint

I, the undersigned (print your name) _______________________________ do freely and voluntarily give consent to be a subject in a study aimed at assessing the effect of moderate intensity exercise on the blood glucose response to a 30-second sprint.

I declare that the purposes of this study have been fully explained to me. I realize that I will be required to undertake 60 minutes of moderate intensity exercise before performing a 30-second sprint, and I am also aware of other procedures (including the sampling of blood) that will take place during the study. I understand that blood sampling is necessary, and the risks associated with this are minor, and may include minimal discomfort and minimal pain and bruising at the site of sampling. Whilst I hereby indicate my willingness to act as a subject in this study, I retain the right to withdraw my consent at any time and to discontinue my participation in the study generally or in any specific aspect of it. I understand that my participation in this study does not prejudice any right to compensation, which I may have under statute or common law. I have read and understood the information sheet about testing and any questions I have asked have been answered to my satisfaction. Should you have any further questions concerning this project please contact: Prof Paul Fournier on 6488 1356. Finally I declare that any research obtained from the results of the test to be conducted can be published in scientific papers, provided that my name is not mentioned. ___________________________ _________________________ Signature of participant Date ________________________ _________________________ Signature of investigator Date

 

 

Princess Margaret Hospital for Children Roberts Road Subiaco WA 6008 GPO Box D184 Perth WA 6840

Tel: (08) 9340 8222 Fax: (08) 9340 8111 www.cahs.health.wa.gov.au

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Appendix B 

Human Ethics Approval Form 

 

 

 

 

 

 

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Appendix C

Meal Record Sheet 

 

 

 

 

 

 

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Instruction Sheet for Food Record Keeping 

The purpose of  filling out a  food  record  sheet  in  this  study  is  to ensure  that you consume  a  similar  diet  on  the  day  prior  to  each  experimental  trial.    This  is  an important part of  the  study and needs  to be done with  care and accuracy.   You don’t need to change your eating habits, but you need to match what you eat the day before the first trial to what you eat the day before the second trial. 

 What you need to do: 

1. Record all food and drinks that you consume. 

2. Measure your food by using cup measures or teaspoon/tablespoons. 

3. Write the time of day that you consume food or drink. 

 Remember:  You must not consume caffeine or alcohol on the day prior to each testing 

session. 

You must fast for 10 hours prior to coming into the laboratory (i.e. no food 

or drink, except water from 10pm the prior evening). 

You must consume the breakfast provided to you at 7:20am before coming 

to the laboratory. 

         

         

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MEAL RECORD: DAY BEFORE FIRST VISIT  What did you eat for breakfast? (And how much)    TIME:                                                       Drinks:                        What did you eat for morning tea? (And how much)   TIME:                                                  Drinks:                        What did you eat for lunch? (And how much)    TIME:                                                  Drinks:                         What did you eat for afternoon tea? (And how much)  TIME:                                                  Drinks:                         What did you eat for dinner? (And how much)    TIME:                                                  Drinks:                         What did you eat for dessert? (And how much)    TIME:                                 

 

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MEAL RECORD: DAY BEFORE SECOND VISIT  

What did you eat for breakfast? (And how much)    TIME:                                                       Drinks:                        What did you eat for morning tea? (And how much) TIME:                                                    Drinks:                        What did you eat for lunch? (And how much)    TIME:                                                  Drinks:                        What did you eat for afternoon tea? (And how much)  TIME:                                                  Drinks:                         What did you eat for dinner? (And how much)    TIME:                                                  Drinks:                         What did you eat for dessert? (And how much)    TIME:                             Drinks:                           

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Appendix D 

Data Collection Sheets 

        

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