13. Type 2 Diabetes

Question 1

Define Type 2 Diabetes.

Describe the aetiology and epidemiology.

Answer 1

End organ insulin resistance leading to metabolic disorder characterized by hyperglycaemia

• Chronically elevated levels of blood glucose
• Most common diabetes (80%)
• Occurs in adult, specifically those with obesity
• Genetic predisposition, strong family history
• Vascular disease —> 60-80% die from stroke / heart attack
• Increases risk for microvascular complications

Question 2

Stage the diagnostic criteria for T2DM.

Answer 2

1. Random glucose ≥ 11.1mmol/l with osmotic symptoms
2. Fasting glucose ≥ 7.0 mmol/l on 2 occasions
3. 2 hour glucose value post 75gm oral glucose tolerance test of ≥ 11.1mmol/l
4. HbA1c ≥ 6.5% (48mmol/mol)

Question 3

What is the pathogenesis of T2DM.

What does histology show?

What is the clinical presentation?

Answer 3

• Earliest detectable lesion = insulin resistance
  1. Increased insulin secretion at early stage of disease
  2. Beta-cell becomes desensitized (exhausted) to the glucose stimulus and insulin levels decrease (deficiency)
  3. Therefore, get hyperglycaemia b/c increase in blood glucose due to inadequate uptake by adipose tissue and skeletal muscle due to lack of insulin (insulin allows glucose to be taken up by tissues)
• Insulin resistance and beta-cell failure are genetically programmed and influenced by environmental factors, such as diet, activity, and aging
• Genetic factors: insulin resistance and secretion genes, B-cell capacity genes, obesity genes
• Environemental factors: obesity, diet, activity, age
• Insulin resistance associated with:
  —> Hypertension, atherosclerosis, dyslipidemia, decreased fibrinolytic activity, impaired glucose tolerance, obesity, polycystic ovary disease, and acanthosis nigricans

CP

• clinically silent
  1. Polyuria
  2. Polydypsia
  3. Hyperglycaemia

HISTOLOGY
- Amyloid deposition in islets

Question 4

What drugs are used to treat T2DM?

3

Answer 4

1. Metformin
2. Sulphonylureas
3. Thiazolidinedions

Question 5

What is the MOA of Metformin?

What are the SE’s?

Answer 5

MOA: reduce glucose released into blood from liver —> helps blood glucose levels

• Inhibition of gluconeogenesis and reduction of glucose output from the liver
• a-cells of the liver contain amino acids, glycerol and lactic acid
• Glucose is produced in the a-cells of the liver by gluconeogenesis; a process in which nutrients such as amino acids, glycerol and lactic acid are converted into glucose
• Reduces hepatic glucose output
• Increases insulin mediated glucose utilisation in peripheral tissues
• Anti-lipolytic effect
• Intestinal glucose utilisation

SE’s:
- GI upset, Lactic Acidosis, Renal Failure, Septic shock, Acute coronary insufficiency, Pulmonary oedema, Acute ischaemic limb, Vitamin B12 deficiency, weight loss

Question 6

What is the MOA of Sulphonylureas?

Answer 6

MOA: stimulate pancreas to produce more insulin

Question 7

What is the MOA of Thaizolidonide?

What are the SE’s of Thaizolidonides?

Answer 7

MOA: promote adipogenesis an fatty acid uptake in peripheral (not visceral) fat

SE’s
o	GI upset
o	Lactic Acidosis
o	Renal Failure 
o	Septic shock
o	Acute coronary insufficiency
o	Pulmonary oedema
o	Acute ischaemic limb
o	Vitamin B12 deficiency

Question 8

What is the Incretin Effect? Describe.
(2)

What are the incretin hormones?
(2)

Answer 8

1. Demonstrates response to oral vs. IV glucose
   - Measured by C-peptide (as a measure of insulin secretion) b/c C-peptide isn’t affected by hepatic insulin extraction
2. Reduced in patients with T2DM
   - B-cell secretory response reduced in patients with T2DM
   - Differences in insulin response to oral and IV glucose administration describes incretin effect

INCRETIN HORMONES

1. GLP-1: reduced
2. Glucose dependent insulinotropic polypeptide (GIP): present but doesn’t bind to its receptor

Question 9

Describe the action of GLP-1 (glucagon-like peptide).

What is DPP-4 and its effect on GLP-1?

Answer 9

• GLP-1 is important regulator of glucose homeostasis
• Released by L cells form SI after food ingestion
• Increases B cell response and response by enhancing glucose-dependent insulin secretion
• ALSO decreases B-cell workload and demand for insulin by:
  1. Regulating the rate of gastric emptying such that meal nutrients are delivered to SI and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (β-cell workload)
  2. Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counterregulatory balance between insulin and glucagon
  3. Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on β-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output
  4. Having effects on CNS, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake
• Therapeutic potential of GLP-1 is limited primarily by its rapid degradation by ubiquitous enzyme dipeptidyl peptidase-IV (DPP-IV)
• Rapid inactivation of GLP-1, in addition to its rapid renal clearance, contributes to a short half-life of less than two minutes
  —> Thus, sustaining plasma concentrations of GLP-1 long enough to produce a therapeutic effect requires continuous administration
• As is typical of other peptides, GLP-1 requires administration by injection
  —> Exenatide (GLP-1 analog) —> NOT metabolized by DPP-IV
  —> Liraglutide, Dulaglutide —> IS metabolized by DPP – IV
• Inhibition of DPP-4 Increases Active GLP-1
  —> Inhibition of DPP-4 by a drug designed to be highly selective and orally active may enable endogenous GLP-1 to avoid inactivation, augment the deficient incretin response seen in T2DM, and improve metabolic control cross the multiple defects associated with the disorder

Question 10

How much glucose is:

1. Stored?
2. Turned over?
3. Required by brain?
4. Rest of body?
5. Eaten in normal diet?
6. Kidneys filter and reabsorb?
7. Produced?

Answer 10

1. 450g
2. 250g /d
3. 125g / d
4. 125g / d
5. 180g / d —> with stored glucose and gluconeogenesis (liver and kidneys)
6. 180g / d —> no glucose (<0.5g in a day) excreted in urine
7. 70g / d

Question 11

What happens to glucose in T2DM with regards to the kidney?

Answer 11

1. Amount of glucose released into circulation by kidney is increased (increase in glucose during fasting state is done by gluconeogensis)
2. Renal glucose uptake increased in post-absorptive and post-prandial states and exceeds increased glucose production
3. Renal glucose reabsorption from glomerular filtrate increased, so that glucosuria doesn’t occur at plasma glucose levels that would normally produce glucosuria in non-diabetic patients
4. Glucosuria occurs in patients with T2M when max reabsorptive capacity of proximal tubule is exceed (hyperglycaemia exacerbated)
   - SGLT2 helps lower blood glucose by acting on kidneys

Question 12

What are the treatment options?
(4)

How is T2DM managed?
(6)

Answer 12

TX

1. Laparoscopic adjustable gastric band: low pre-op risks, high post-op complications (infections)
2. Weight loss procedure: vertical banded gastroplasty: roux-en-Y gastric bypass
3. Biliopancreatic diversion
4. Duodenal switch

MANAGEMENT

1. Education
2. Diet
3. Exercise
4. Glycaemic Control
5. Blood Pressure Control
6. Correct Vascular Risk Factors

Question 13

What is the treatment for BP?

4

Answer 13

1. 1st Line: ACE Inhibitor or ARB
2. 2nd Line: Diuretic, Calcium Channel Blocker
3. 3rd Line: Beta-blocker*
4. 4th Line: Alpha blocker

Question 14

How are lipids controlled?

(2)

Answer 14

1. Vascular event:
   - Every one with diabetes on a statin
   - Aim for a LDL cholesterol < 1.8mmol/l
2. No vascular event
   - Aim for a LDL cholesterol < 2.6mmol/l

Question 15

What is aspirin used for?

2

Answer 15

1. Aspirin for secondary prevention
2. Aspirin in primary prevention
   - Smoker
   - Microalbuminuria
   - Carotid artery disease
   - Peripheral arterial disease
   - Abnormal 12 lead ECG

Question 16

See case study on PowerPoint

Answer 16

Case study