Target for diabetes intervention - onderzoekinbeweging.nl Prevention Program Knowler et al., ... 2007 Exercise training and glycemic control ... Lance Armstrong Jay Cutler. 5

1

Exercise prescription in type 2 diabetes treatment

Prof. L.J.C. van Loon

Maastricht University Medical Centre+ Maastricht, the Netherlands

Maastricht, February 27 , 2016

Glycemic control in type 2 diabetes

The level of glycemia is associated with the development of cardiovascular complications Glycemic control is fundamental to type 2 diabetes treatment ADA; EASD; IDF

Therapeutic targets should be aimed at reducing

post-prandial blood glucose excursions

Standard parameters for the assessment of glycemic control

do not provide sufficient information on post-prandial

hyperglycemia

Target for diabetes intervention

Basal blood glucose and HbA1c content

Glycemic control

Self-monitored blood glucose concentration

Continuous Glucose Monitoring System

Maran et al., Diabetes Care, 2001

2

Continuous Glucose Monitoring System Glycemic control

van Dijk et al., Diabetes Res Clin Pract, 2011

Time (h)

7:00 11:00 15:00 19:00 23:00 3:00 7:00

Glucose con

centratio

n (m

mol/L)

0

4

6

8

10

12

14 Control Type 2 diabetes

Daily glycemic control

Prevalen

ce of h

yperglycem

ia (%

/ 24 h)

0

10

20

30

40

50

control type 2 diabetes

type 2 diabetes

control

A B

HbA1c <7%, (<53 mmol/mol)

*

*

van Dijk et al., Diabetes Res Clin Pract, 2011

Glycemic control in type 2 diabetes

Under standardized dietary conditions long-standing

type 2 diabetes patients are in a state of hyperglycemia

throughout the greater part of the day

Oral blood glucose lowering medication

does not provide ample protection

against (post-prandial) hyperglycemia Praet et al., Clinical Science, 2006

Type 2 diabetes treatment

Oral blood glucose lowering medication Exogenous insulin therapy

The type 2 diabetes epidemic

“100% of the increase in the prevalence of

type 2 diabetes and obesity in the United States

during the latter half of the 20th century must be

attributed to a changing environment interacting

with genes, because 0% of the human genome has

changed during this time period.”

Booth et al., JAP, 2000

3

Lifestyle changes Diabetes prevention - lifestyle

Finnish Diabetes Prevention Study Tuomiletho et al., NEJM, 2001 58% reduced risk type 2 diabetes Diabetes Prevention Program Knowler et al., NEJM, 2002 Lifestyle > Metformin > Placebo Da Qing Diabetes Prevention Pan et al., Diabetes Care, 1997 42-46% reduced risk type 2 diabetes

Malmö Preventive Trial Eriksson et al., Diabetologia, 1998 Significant reduction mortality

Diabetes treatment

Diabetes cohort studies report regular exercise to be associated with a 40-70% lower mortality rate for 8 to 14 years

Hu F. et al., Ann. Intern. Med., 1999

Wei et al., Ann. Intern. Med., 2000 Tanasescu., Circulation, 2003

Hu G. et al., Circulation, 2004

Exercise in diabetes treatment

•  whole-body insulin sensitivity (0-80%)

•  glycemic control (HbA1c : -0.7 %)

•  oxidative capacity (VO2max : 0-15%)

•  cardiovascular risk profile (LDL, TG, BP)

•  fat mass and body composition

Boulé et al., Diabetologia, 2003; Sigal et al., Diabetes Care, 2006; Praet et al., J Appl Physiol, 2007; Umpierre et al., JAMA, 2011; Chudyk et al., Diabetes Care, 2011

Position statement A

To improve glycemic control, assist with weight maintenance, and

reduce risk of CVD, at least 150 min/wk of moderate-intensity aerobic

physical activity (50-70% HRmax) is recommended and/or at least

90 min/wk of vigorous aerobic exercise (70% HRmax). The physical

activity should be distributed over at least 3 days/wk and with

no more than 2 consecutive days without physical activity.

ADA 2007 - Standards of Medical Care in Diabetes

Diabetes Care, 2007

Exercise training and glycemic control

The improvements in glycemic control with exercise training are largely

attributed to the cumulative effects of transient improvements in glucose

tolerance following each successive bout of exercise

Goodyear and Kahn, Ann Rev Med, 1998

Effects of training on glycemic control may be

lost entirely 6-10 days after cessation of training

Praet and van Loon, J Appl Physiol, 2007

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Endurance type exercise

An acute bout of endurance type exercise improves insulin sensitivity for a period up to 48 h. Schneider et al., Diabetologia, 1984

Devlin et al., Diabetes, 1987

Cusi et al., J. Clin. Invest., 2000

Wojtaszewski et al., Diabetes, 2000

Position statement A

To improve glycemic control, assist with weight maintenance, and

reduce risk of CVD, at least 150 min/wk of moderate-intensity aerobic

physical activity (50-70% HRmax) is recommended and/or at least

90 min/wk of vigorous aerobic exercise (70% HRmax). The physical

activity should be distributed over at least 3 days/wk and with

no more than 2 consecutive days without physical activity.

ADA 2007 - Standards of Medical Care in Diabetes

Diabetes Care, 2007

Acute exercise in type 2 diabetes

Praet et al., Med. Sci. Sports Exerc., 2006

Hyp

ergl

ycem

ia (

dura

tion

%/2

4h)

Exercise as therapy

Based on baseline aerobic fitness, level of co-morbidities,

appendicular skeletal muscle mass and strength, patients should

be provided with a fitting exercise intervention program to

optimize its therapeutic value.

Exercise modalities

-  type of exercise

-  intensity of exercise

-  duration of exercise

-  frequency

-  timing

Type of exercise

Lance Armstrong Jay Cutler

5


An acute bout of endurance type exercise improves insulin sensitivity for a period up to 48 h. Devlin et al., Diabetes, 1987

Mikines et al., AJP, 1988

Perseghin et al., NEJM, 1996


Long-term weight loss and weight control Feasibility in elderly patients with type 2 diabetes

Feasibility in type 2 diabetes with co-morbidities

Long-standing type 2 diabetes

Fang et al., 2005 Sayer et al., 2005

Volpato et al., 2002

Thomas et al., 2004 Meyer et al., 1990

Muscle weakness

Cardiovascular co-morbidities

Exercise intolerance

Low adherence and compliance

Aging and sarcopenia

Loss of skeletal muscle mass, strength, and function

with aging is both cause as well as a consequence

of type 2 diabetes

Proportional relationship between muscle mass

and glucose disposal capacity

Park et al., 2006; Willey et al., 2003

Resistance type exercise

Muscle mass

Muscle strength

Functional capacity


Progressive resistance type exercise training offers a safe and effective alternative to endurance type exercise training

An acute bout of resistance exercise improves insulin sensitivity to a similar extent as endurance exercise Fluckey et al.,1994 Fenicchia et al., 2004 Koopman et al., 2005

6

van Dijk et al., Diabetologia, 2012

Type of exercise, design

randomized, 3-way crossover

Type of exercise, intervention

45 min, 75% 1 RM 45 min, 50% Wmax

Time

6:00 9:00 12:00 15:00 18:00 21:00 0:00 3:00 6:00 9:00 12:00

Bloo

d glucose concen

tration (m

mol/L)

0

6

8

10

12

14

16Control: no exerciseResistance-‐type exerciseEndurance-‐type exercise

24-h glycemic profiles


Prevalen

ce of h

yperglycem

ia (%

/ 24

h)

0

10

20

30

40

50

IGT OGLM INS

* *

**

* *

#

Prevalence of hyperglycemia

Control: no exerciseResistance-‐type exerciseEndurance-‐type exercise



- improved glucose disposal

- glycogen storage capacity

- GLUT-4 content

- glycemic control (HbA1c: -1.1%)

- insulin sensitivity

- oral glucose tolerance

- cardiovascular risk profile (HDL, LDL, BP)

- body composition

Castaneda et al., 2002; Dunstan et al., 1998, 2002;

Ishii et al., 1998, Cauza et al., 2005; Willey et al., 2003

Church et al., JAMA, 2010

7

Position statement B

In the absence of contraindications, people with type 2 diabetes should be encouraged to perform resistance exercise 3 times a week, targeting all major muscle groups, progressing to 3 sets of 8-10 repetitions at a weight that cannot be lifted more than 8-10 times. ADA 2007 - Standards of Medical Care in Diabetes Diabetes Care, 2007

Exercise modalities




-  frequency

-  timing

-  interaction with pharmaceuticals

-  interaction with food intake

Low versus high-intensity exercise

Manders et al., Med Sci Sports Exerc, 2010

Exercise intensity and glycemic control

Manders et al., Med Sci Sports Exerc, 2010

60 min @ 35% Wmax

30 min @ 70% Wmax

Newsom et al., Diabetes Care, 2013

Exercise intensity and insulin sensitivity

~70 min @ 50% VO2max

~55 min @ 65% VO2max

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Exercise modalities




-  frequency

-  timing

06:00 12:00 18:00 00:00 06:00 12:00 18:00 00:00 06:00 12:00

DAILY

NON-‐DAILY

48 h analysis period

Day 1 Day 2 Day 3

CONTROL

(30 min)

(60 min)

(30 min)

randomized, 3-way crossover

Study design

van Dijk et al., Diabetes Care, 2012

Prev

alen

ce o

f hyp

ergl

ycem

ia (%

of t

he ti

me)

0

20

30

40

Total 48 h First 24 h Second 24 h

* * ** * *


Prevalence of hyperglycemia

CONTROL: no exerciseNON-DAILY exerciseDAILY exercise

Are the blood glucose lowering effects equal for all type 2 diabetic patients?

individual change in average glucose concentration over 24 h period following exercise

subject

0 10 20 30 40 50 60

delta

glu

cose

con

cent

ratio

n (m

mol

/L)

-5

-4

-3

-2

-1

0

1

2

Individual response to exercise

Well-controlled and suboptimally controlled patients

bloo

d gl

ucos

e co

ncen

tratio

n (m

mol

/L)

0

6

8

10

12

prev

alen

ce o

f hyp

ergl

ycem

ia (h

our/d

ay)

0

2

4

6

8

10

12

14control exercise

*

*

*

*

A B

-0.6 mmol/L

-1.2 mmol/L -3:24 h:min

-1:43 h:min

Hba1c <7% HbA1c ≥7% Hba1c <7% HbA1c ≥7%

9

Exercise or simply more habitual physical activity to improve blood glucose homeostasis?

Study design

12.00 12.00 0.00 18.00 6.00 0.00 18.00 6.00

day 1

6.00 18.00

day 2 day 3

12.00

Study protocol

6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00

Exercise

Habitual Physical Activity

Control

Blood

45 min

15 min 15 min 15 min

4

6

8

10

12

14

16

8:30 11:30 14:30 17:30 20:30 23:30 2:30 5:30 8:30

Blo

od g

luco

se (m

mol

/L)

Time (h)

Control Habitual Physical Activity Exercise

0

24-h blood glucose


0

1

2

3

4

5

6

7

8

9

Control Habitual Physical Activity

Exercise

Hyp

ergl

ycem

ia (h

ours

/day

)

24-h glycemic control

*


10

4

6

8

10

12

14

16

8:30 11:30 14:30 17:30 20:30 23:30 2:30 5:30 8:30

Blo

od g

luco

se (m

mol

/L)

Time (h)

Control Habitual Physical Activity Exercise

Postprandial glycemic control

0


Insulin iAUC

*

* †

-17±5%

-33±4%

10

15

20

25

30

35

40

45

Control Habitual Physical Activity

Exercise

insu

lin iA

UC

(mU

/mL/

11h)

0


Summary

Hyperglycemia is highly prevalent throughout the day in

type 2 diabetes patients.

Exercise strongly reduces the prevalence of hyperglycemia

throughout the day.

Resistance and endurance-type exercise are equally effective in

improving daily blood glucose homeostasis.

Summary II

Higher intensity exercise is not more effective than lower

intensity exercise to improve daily blood glucose homeostasis.

When total work is being matched, daily exercise does not

further improve glycemic control, when compared to exercise

performed every other day.

Even well-controlled patients can benefit from the glucose

lowering properties of exercise.

Summary III

Habitual physical activity attenuates the postprandial rise in

blood glucose and insulin concentrations.

When matched for duration, exercise is more effective than

more habitual physical activity to improve glycemic control.

The volume of physical activity seems to determine the

improvements in glycemic control.

Exercise prescription

11

Collaborators and sponsors

M3 research unit www.m3-research.nl

Documents

Target for diabetes intervention - onderzoekinbeweging.nl Prevention Program Knowler et al., ... 2007 Exercise training and glycemic control ... Lance Armstrong Jay Cutler. 5