A disease of ancient Greeks and modern men · A disease of ancient Greeks and modern men ......

Namita Jayaprakash MB BcH BAO, MCEM

A disease of ancient Greeks and modern men

The history of Diabetes

The pathophysiology behind diabetes

Definitions

Management

Diabetic emergencies

Diabetes mellitus is a syndrome of chronic hyperglycemia due to relative insulin deficiency, resistance, or both

Ebers papyrus 1550 B.C

Galen and Arateus further delineated the disease 130 – 201 A.D

Arateus coined the term diabetes 150 A.D

Diabetes = ‘siphon’

‘liquefaction of the flesh and bone into urine’

Lavoisier’s legacy Late 18th century

established the concept of the respiratory quotient

Baron Justus von Liebig Identified protein, carbohydrates and fats

Claude Bernard Questioned role of pancreas in diabetes

Apollinaire Bouchardat and E. Lancereaux

Identified two forms of diabetes

1921 Banting and Best worked on ‘isletin’extraction

1922 ‘insulin’ Leonard Thompson first human recipient

1923 Nobel Prize in Medicine awarded for discovery of insulin

Sulfonylurea Introduced in 1955

Biguanide Phenformin, metformin

α – glucosidase inhibitors 1980’s

Thiazolidinediones 1990’s

Nonsulfonylureas

Key hormone involved in storage and controlled release of chemical energy

Coded for on chromosome 11

Synthesized in β – cells of pancreatic islets

Pre - proinsulin Proinsulin Insulin C-peptide

α – subunit

β – subunit

Insulin

Increases glucose uptake into cells and glycogen formation

Decreases glycogenolysis and gluconeogenesis

Increases fat deposition and decreases lipolysis

Increases protein synthesis

Increases potassium (K+) uptake into cells

Decrease [glucose]

Decrease [amino acid]

Decrease [fatty acid]

Decrease [ketoacid]

Hypokalemia

Carbohydrate metabolism

Normal blood glucose = 63 – 144 mg/dL

Liver is principal organ of glucose homeostasis

Glycogenolysis

Gluconeogenesis

Carbohydrate Glycemia

Insulin

Cell

Glucose

Glucose

Glucose – 6 – phosphate

Fructose 6 – P

Fructose 1,6 – P

Pyruvate

Glycogen

Ribose 5 – P

Uric acid

Fructose

Lactate

Mobilization of substrates for gluconeogenesis and ketogenesis

Accelerated production of glucose and ketones

Overwhelmed excretory mechanisms

Impaired removal by insulin responsive tissues

Insulin deficiency

Glucose cannot enter cells

Alternatives for cellular energy

Lipolysis -> glycerol and free fatty acids

Glycerol -> glucose

Free fatty acids -> ketones

Peripheral resistance to insulin

Increased production of glucose by the liver

Altered pancreatic insulin secretion

Secondary Diabetes Genetic defects in β – cell function

Genetic defects in insulin action

Disease of exocrine pancreas

Drug or chemical induced diabetes

Gestational Diabetes

Review

www.thelancet.com Published online December 4, 2013 http://dx.doi.org/10.1016/S0140-6736(13)62154-6 5

obtained through these assessments could provide the

level of detail needed to establish the mediator (or

mediators) of the feedback loop that interconnects β cells

with insulin-sensitive tissues, and help to unravel the

heterogeneity of the disease. Furthermore, these

assessments should complement and advance present

understanding of the best approaches to treat the

dysregulated metabolic milieu in type 2 diabetes, which

includes not only glucose but also fatty acids and

aminoacids.

Treatment of type 2 diabetesOral and injectable drugs: present knowledge, lessons learned, and implications for the futureThe increasing prevalence of type 2 diabetes has

stimulated development of many new approaches to

safely treat hyperglycaemia (fi gure 3). The aim of these

therapies is to reduce and maintain glucose

concentrations as close to normal for as long as possible

after diagnosis (panels 1, 2), and thereby prevent

development of complications. Although some therapies

have been unsuccessful because of adverse eff ects or

negligible therapeutic effi cacy, several are very well

accepted and are used worldwide. The mode of action for

most of these drugs has been reported (fi gure 3).

However, individual responses to these drugs can diff er

greatly, probably as a result of the heterogeneous nature

of the pathophysiology of type 2 diabetes. The

appendix provides further discussion on drugs that have

been widely available for more than a decade (eg,

sulfonylurea antidiabetics, biguanide antidiabetics,

α-glucosidase inhibitors, and peroxisome proliferator-

activated receptor γ agonists).

Drugs with actions dependent on the gastro-intestinal tractDrugs that mediate their eff ect through the gastro-

intestinal tract include α-glucosidase inhibitors that slow

glucose absorption by delaying degradation of complex

carbohydrates in the gastrointestinal tract;87 pramlintide,

which slows gastric emptying and thus delays glucose

absorption;88 and the bile-acid-binding resin colesevelam,

which lowers cholesterol and modifi es release of other

gastrointestinal peptides that can reduce plasma

concentrations of glucose. 89

Incretin-related products are designed to mimic or

augment the action of GLP-1 and GIP, which are released

by the intestine. GLP-1 receptor agonists are peptides

with longer half-lives than GLP-1, whereas dipeptidyl

peptidase 4 (DPP4) inhibitors block the action of DPP4,

which is responsible for rapid degradation of GLP-1 and

GIP.90 Improvement of the pharmacokinetics and

pharmaco dynamics of incretin-based drugs is under

investigation to reduce dosing and to improve glucose

control.91 Although not completely understood, infusion

of large doses of GLP-1 intravenously can normalise

glucose concentrations with less nausea or vomiting—

adverse eff ects that can be dose limiting and prevent

normalisation of glucose concentrations—than for

subcutaneous administration.92,93 Whether new drugs

can further improve glucose lowering and reduce nausea

and vomiting remains unknown. In addition to the clear

eff ect of these drugs on improvement of glycaemia,

incretin-related products might also have benefi cial

eff ects on the cardiovascular system,94,95 although

fi ndings from the fi rst two of a series of intervention

studies showed a neutral eff ect.96,97 Incretin-related

medications have been purported to increase the risk of

acute pancreatitis; this suggestion is based on fi ndings

from studies that used the inherently biased

pharmacovigilance and administrative databases.98–101

More recently, GLP-1 receptor agonists and DPP4

inhibitors have been postulated to cause malignant

transformations in the pancreas. However, this

suggestion was based on histological assessments of a

very small number of samples from brain-dead organ

donors that were inadequately matched with controls for

several crucial variables.102,103 Importantly, despite

Figure 3: Drugs to treat type 2 diabetes

(A) The rate of introduction of new classes of drugs has accelerated during the past 20 years. Two classes (animal

insulin and inhaled insulin; red) are essentially no longer available as therapeutics. (B) Di ff erent classes of drugs act

on diff erent organ systems. Insulin is a replacement for the natural product of islet β cells. Classic organ systems

that have been targeted for decades comprise the pancreatic islet, liver, muscle, and adipose tissue. Non-classic

targets have been focused on recently, and include the intestine, kidneys, and brain. DPP4=dipeptidyl peptidase 4.

SGLT2=sodium–glucose co- transporter 2. GLP-1=glucagon-like peptide 1.

1940 1950 1960 1970 1980 1990 2000 2010

Sulfonylurea antidiabetics

Metformin

Human insulin

α-glucosidase inhibitors

Insulin analogues

Thiazolidinedione antidiabetics

Glinides

GLP-1 receptor agonists

Pramlintide

Inhaled insulin

DPP4 inhibitors

Colesevelam

Bromocriptine

SGLT2 inhibitors

1920 1930

Animal insulin

00

5

10

15

Cla

sses

of glu

cose

-low

erin

g d

rugs

Year

A

Classic Less classicB

Sulfonylurea antidiabetics

Glinides

GLP-1 receptor agonists

DPP4 inhibitors

Insulin

Lifestyle modification

Metformin

Thiazolidinedione antidiabetics

α-glucosidase inhibitors

Pramlintide

Colesevelam

SGLT2 inhibitors

Bromocriptine

See Online for appendix

2002

2008

Primary focus is insulin replacement

Healthy lifestyle

Prevent long term complications

Category Name

Rapid acting Insulin lispro (Humalog)

Insulin aspart (Novolog)

Insulin glulisine (Apidra)

Short acting Regular insulin (Humulin R, Novolin R)

Intermediate acting NPH (Humulin N, Novolin N)

Insulin detemir (Levemir)

Long acting Insulin glargine (Lantus)

Mixtures 70/30 Humulin/Novolin (70% NPH, 30% regular)

50/50 Humulin/Novolin (50% NPH, 50% regular)

75/25 Humalog (75% NPL, 25% lispro)

50/50 Humalog (50% NPL, 50% lispro)

70/30 NovoLog Neutral (70% protamine aspart, 30% aspart)

Intervention at time of diagnosis Metformin

Lifestyle changes

Aim to achieve and maintain recommended levels of glycemic control

Continuing timely augmentation of therapy

Review

www.thelancet.com Published online December 4, 2013 http://dx.doi.org/10.1016/S0140-6736(13)62154-6 5

obtained through these assessments could provide the

level of detail needed to establish the mediator (or

mediators) of the feedback loop that interconnects β cells

with insulin-sensitive tissues, and help to unravel the

heterogeneity of the disease. Furthermore, these

assessments should complement and advance present

understanding of the best approaches to treat the

dysregulated metabolic milieu in type 2 diabetes, which

includes not only glucose but also fatty acids and

aminoacids.

Treatment of type 2 diabetesOral and injectable drugs: present knowledge, lessons learned, and implications for the futureThe increasing prevalence of type 2 diabetes has

stimulated development of many new approaches to

safely treat hyperglycaemia (fi gure 3). The aim of these

therapies is to reduce and maintain glucose

concentrations as close to normal for as long as possible

after diagnosis (panels 1, 2), and thereby prevent

development of complications. Although some therapies

have been unsuccessful because of adverse eff ects or

negligible therapeutic effi cacy, several are very well

accepted and are used worldwide. The mode of action for

most of these drugs has been reported (fi gure 3).

However, individual responses to these drugs can diff er

greatly, probably as a result of the heterogeneous nature

of the pathophysiology of type 2 diabetes. The

appendix provides further discussion on drugs that have

been widely available for more than a decade (eg,

sulfonylurea antidiabetics, biguanide antidiabetics,

α-glucosidase inhibitors, and peroxisome proliferator-

activated receptor γ agonists).

Drugs with actions dependent on the gastro-intestinal tractDrugs that mediate their eff ect through the gastro-

intestinal tract include α-glucosidase inhibitors that slow

glucose absorption by delaying degradation of complex

carbohydrates in the gastrointestinal tract;87 pramlintide,

which slows gastric emptying and thus delays glucose

absorption;88 and the bile-acid-binding resin colesevelam,

which lowers cholesterol and modifi es release of other

gastrointestinal peptides that can reduce plasma

concentrations of glucose. 89

Incretin-related products are designed to mimic or

augment the action of GLP-1 and GIP, which are released

by the intestine. GLP-1 receptor agonists are peptides

with longer half-lives than GLP-1, whereas dipeptidyl

peptidase 4 (DPP4) inhibitors block the action of DPP4,

which is responsible for rapid degradation of GLP-1 and

GIP.90 Improvement of the pharmacokinetics and

pharmaco dynamics of incretin-based drugs is under

investigation to reduce dosing and to improve glucose

control.91 Although not completely understood, infusion

of large doses of GLP-1 intravenously can normalise

glucose concentrations with less nausea or vomiting—

adverse eff ects that can be dose limiting and prevent

normalisation of glucose concentrations—than for

subcutaneous administration.92,93 Whether new drugs

can further improve glucose lowering and reduce nausea

and vomiting remains unknown. In addition to the clear

eff ect of these drugs on improvement of glycaemia,

incretin-related products might also have benefi cial

eff ects on the cardiovascular system,94,95 although

fi ndings from the fi rst two of a series of intervention

studies showed a neutral eff ect.96,97 Incretin-related

medications have been purported to increase the risk of

acute pancreatitis; this suggestion is based on fi ndings

from studies that used the inherently biased

pharmacovigilance and administrative databases.98–101

More recently, GLP-1 receptor agonists and DPP4

inhibitors have been postulated to cause malignant

transformations in the pancreas. However, this

suggestion was based on histological assessments of a

very small number of samples from brain-dead organ

donors that were inadequately matched with controls for

several crucial variables.102,103 Importantly, despite

Figure 3: Drugs to treat type 2 diabetes

(A) The rate of introduction of new classes of drugs has accelerated during the past 20 years. Two classes (animal

insulin and inhaled insulin; red) are essentially no longer available as therapeutics. (B) Di ff erent classes of drugs act

on diff erent organ systems. Insulin is a replacement for the natural product of islet β cells. Classic organ systems

that have been targeted for decades comprise the pancreatic islet, liver, muscle, and adipose tissue. Non-classic

targets have been focused on recently, and include the intestine, kidneys, and brain. DPP4=dipeptidyl peptidase 4.

SGLT2=sodium–glucose co- transporter 2. GLP-1=glucagon-like peptide 1.

1940 1950 1960 1970 1980 1990 2000 2010

Sulfonylurea antidiabetics

Metformin

Human insulin

α-glucosidase inhibitors

Insulin analogues

Thiazolidinedione antidiabetics

Glinides

GLP-1 receptor agonists

Pramlintide

Inhaled insulin

DPP4 inhibitors

Colesevelam

Bromocriptine

SGLT2 inhibitors

1920 1930

Animal insulin

00

5

10

15

Cla

sses

of glu

cose

-low

erin

g d

rugs

Year

A

Classic Less classicB

Sulfonylurea antidiabetics

Glinides

GLP-1 receptor agonists

DPP4 inhibitors

Insulin

Lifestyle modification

Metformin

Thiazolidinedione antidiabetics

α-glucosidase inhibitors

Pramlintide

Colesevelam

SGLT2 inhibitors

Bromocriptine

See Online for appendix

Metformin

Reduces hepatic glucose production

Improves peripheral glucose utilzation

Reduces plasma glucose and insulin levels

Improves lipid profile

Promotes moderate weight loss

Pioglitazone, rosiglitazone

Binds to PPAR – γ

Reduces insulin resistance

Promote redistribution of fat from central to peripheral

Stimulate insulin secretion

Act on ATP – sensitive potassium channel on the β – cell

Most effective in Type II diabetics onset < 5 years

Sulfonylureas

Reduce fasting and post prandial glucose

Increase insulin acutely

Hypoglycemia can be related to delayed meals, increased physical activity, alcohol intake, renal insufficiency

Incretins

Amplify glucose – stimulated insulin secretion

Mimic or augment the action of GLP – 1 and GIP

GLP – 1 analogue or GLP – 1 receptor agonist Exanatide

Gila monster saliva

Liraglutide

DPP – IV inhibitors

Inhibit degradation of native GLP – 1

Promote insulin secretion

Absence of weight gain and hypoglycemia

Have preferential effect on post prandial glucose

α – glucosidase inhibitors Slow glucose absorption

Delay degradation of complex carbohydrates

Pramlintide

Slows gastric emptying

Colesevelam Lowers cholesterols

Modifies release of GI peptides that reduce plasma [glucose]

Inhibitors of Sodium – glucose co transporter 2

Increases urinary glucose excretion

Inhibits SGLT 2 reabsorption of glucose

Dapagliflozin and canagliflozin available

Reduce plasma glucose, body weight and BP

Parameter Normal Target

Pre – prandial plasma glucose (mg/dL) < 100 90 – 130

2 –hr post – prandial plasma glucose (mg/dL)

< 140 < 160 – 180

Bedtime plasma glucose (mg/dL) < 120 110 – 150

Hemoglobin A1c (%) < 6 < 7

LDL cholesterol (mg/dL) < 130 < 100

HDL cholesterol (mg/dL) > 40 (m), > 50 (w) > 45 (m), > 55 (w)

Fasting triglycerides (mg/dL) < 150 < 150

Blood pressure (mmHg) < 140/90 < 130/80

Sugar = 28.8g

Sugar = 14.8g

Sugar = 21.7g

Diabetic Ketoacidosis (DKA)

Hyperosmolar Hyperglycemic state (HHS)

Insulin deficiency

Increased counter – regulatory mechanisms Glucagon

Catecholamines

Cortisol

Growth hormone

Triad of hyperglycemia, ketosis and acidemia

Mortality is < 5% but remains most common cause of death in young people

Blood glucose > 250 mg/dL (13.8 mmol/L)

pH < 7.30

Serum bicarbonate < 18 mmol/L

Anion gap > 10

Ketonemia

DKA forms rapidly Symptoms may be present for several days before

ketoacidosis forms

Presenting symptoms

Polyuria, polydipsia, weight loss

Vomiting and abdominal pain

Physical signs

Increased respiratory rate

Kussmaul breathing

Fruity breath

Evidence of dehydration with hypotension Fluid depletion of 5 – 8 L

Diagnostic criteria [Glucose], pH, [bicarbonate], ketones, osmolality

Electrolyte abnormalities Sodium

Pseudohyponatremia Glucose and triglyceride elevation

Potassium Loss and cellular shifts

Magnesium

Phosphate High levels at presentation with decreases with DKA treatment

Correct fluid depletion

Decrease blood glucose levels

Correct electrolyte imbalance

Treat precipitating causes

Isotonic saline (0.9% normal saline)

First hour aim to restore renal perfusion

Rate of fluid infusion depends on clinical status

Corrects blood glucose and plasma osmolality

Severe hypovolemia Mild dehydration Cardiogenic shock

Administer 0.9% normal saline at

1L/hour

Hemodynamic monitoring/pressorsEvaluate corrected

Sodium (Na+)

Serum Na+ high Sodium Na+ normal Sodium Na+ low

0.45% NaCl (250 – 500 ml/hr) depending on

hydration status

0.9% NaCl (250 – 500 ml/hr) depending on

hydration status

When glucose reaches 200 mg/dL, change to 5% dextrose with 0.45% NaCl at 150 – 250 ml/hr

Lowers blood glucose Increases peripheral glucose utilization

Decreases hepatic glucose production

Lowers ketones

Inhibits release of free fatty acidsCorrects acidosis

Dose of insulin

Intravenous Bolus 0.1 U/kg

Infusion at 0.1 U/kg/hr

Subcutaneous Rapid acting insulin

0.3 U/kg, then 0.2 U/kg one hour later

0.2 U/kg subcutaneous every two hours

If serum glucose does not fall by 50 – 70 mg/dL in first hour, double dose of insulin

Alternatives

Low dose infusions as effective as standard

Randomized controlled trial Compared load with infusion, no load, and no load with twice

the infusion dose

0.14 U/kg/hr

Longer time to reach peak free insulin levels

No differences in times to reach glucose < 250 mg/dL, pH = 7.3, and HCO3 > 15 mmol/L

Aim to correct glucose to 200 mg/dL

Reduce insulin infusion to 0.02 – 0.05 U/kg/hr

Give rapid acting insulin at 0.1 U/kg sc every 2 hours

Keep serum glucose at 150 – 200 mg/dL until DKA resolves

Start after 1st liter of fluid

Aim to maintain concentration at 4 – 5 mmol/L

K+ < 3.3 mmol/L Hold insulin

Give 20 – 30 mEq/hr until K+ > 3.3 mmol/L

K+ > 5.3 mmol/L

Do not give K+, check serum K+ every 2 hours

Rarely need > 20 mEq K+/500 mls of fluid

If serum K+ > 3.3 and < 5.3 Give 20 – 30 mEq K+ in each liter of IV fluid

Replacement remains controversial

RCT’s have not shown clear benefit

Experts advise use if pH < 7

Worsens hypokalemia

NaHCO3 (100 mmol) in 400 ml H2O with 20 mEq KCL over 2 hours

No clear benefit from iv replacement

Can be harmful

If needed replace with oral forms

Caused by an inadequacy of insulin

High mortality As high as 15%

Higher in elderly

Blood glucose > 600 mg/dL (> 33.3 mmol/L)

pH > 7.30

Bicarbonate > 15 mmol/L

Serum osmolality > 320 mOsm/kg

Small amount of ketones may be present

Correct fluid depletion

Decrease blood glucose levels

Correct electrolyte imbalance

Treat precipitating causes

Severe hypovolemia Mild dehydration Cardiogenic shock

Administer 0.9% normal saline at

1L/hour

Hemodynamic monitoring/pressorsEvaluate corrected

Sodium (Na+)

Serum Na+ high Sodium Na+ normal Sodium Na+ low

0.45% NaCl (250 – 500 ml/hr) depending on

hydration status

0.9% NaCl (250 – 500 ml/hr) depending on

hydration status

When glucose reaches 300 mg/dL, change to 5% dextrose with 0.45% NaCl at150 – 250 ml/hr

Regular insulin

Bolus dose of 0.1 U/kg

Intravenous infusion of 0.1 U/kg/hr

If serum glucose does not fall by 50 – 75 mg/dL in the first hour, double the infusion dose

When serum glucose reaches 300 mg/dL, reduce insulin infusion to 0.02 – 0.05 U/kg/hr.

Aim to keep serum glucose 250 – 300 mg/dL until patient is mentally alert

Glucose every hour until stable

Serum electrolytes, BUN, serum creatinine, pH (venous), osmolality every 2 – 4 hours depending on severity of illness

Hypoglycemia

Hypokalemia

Cerebral edema

Non cardiogenic pulmonary edema

Lower limit of normal plasma glucose 70 mg/dL (3.9 mmol/L)

Hypoglycemia occurs at < 50 – 55 mg/dL

Diabetic Hypoglycemia occurs at < 63 mg/dL

Neurogenic Tremor

Palpitations

Anxiety/arousal

Sweating

Hunger

Paresthesias

Neuroglycopenic

Cognitive impairment

Behavioral changes

Psychomotor abnormalities

Seizure

Coma

Pallor

Diaphoresis

Rise in heart rate and systolic blood pressure

Transient neurological deficits

Glucose Oral carbohydrate

Fruit juice, dextrose drink

Simple sugars Buccal absorption from honey, chewable toffees or candy

Complex carbohydrates Meal substitutes, biscuits, bread

Parenteral glucose IV dextrose 50%, 25%, 10%, 5%

Glucagon 1 – 2 mg IM or sc

IV Hydrocortisone

SC adrenaline

SC terbutaline

Primarily disease of children treated for DKA

Associated mortality rate of 20 – 40%

Clinical features

Headache, lethargy, decreased arousal

Rapid neurological deterioration Seizures, incontinence, bradycardia, respiratory arrest

Avoiding cerebral edema Gradual replacement of sodium and water deficits

Addition of glucose to the solution once serum levels reach 200 mg/dL in DKA or 250 – 300 mg/dL in HHS

Maintain serum glucose in HHS at 250 – 300 mg/dL until hyperosmolality and mental status improve

Treatment with mannitol (0.2 – 1.0 g/kg) or 3% hypertonic saline (5 – 10 ml/kg over 30 mins.)

Rare complication of DKA treatment

Hypoxemia Reduced colloid oncotic pressure

Increased lung water content and decreased lung compliance

Pulmonary edema Higher risk if widened alveolar – arterial gradient noted on initial

ABG

DKA resolution Serum glucose < 200 mg/dL

Serum anion gap < 12

Serum bicarbonate > 18 mmol/L

Venous pH > 7.30

HHS

Serum glucose 250 – 300 mg/dL

Mentally alert

Plasma osmolality < 315 mOsm/kg

If known diabetic, give previous insulin dose

Insulin naïve patients

Multi – dose insulin regimen

0.5 – 0.8 U/kg/day

Timing of switch Rapid acting sc insulins 15 – 30 mins

Regular insulin 1 – 2 hours

Intermediate and long acting longer with a gradual taper of infusion

Before breakfast 2/3 of total daily dose

1/3 as rapid acting insulin

2/3 as intermediate acting insulin

Before dinner 1/3 of total daily dose

1/3 as rapid acting insulin

2/3 as intermediate acting insulin

Diabetes Mellitus treatment goal to reduce hyperglycemia and prevent long term complications

Diabetic emergencies: DKA and HHS

Treatment goals in DKA and HHS correct fluid depletion and electrolyte losses, reduce hyperglycemia, treat underlying precipitants

During treatment watch for complications including hypoglycemia

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