Type II diabetes mellitus

Question 1

Define type II DM

Answer 1

DM is defined as a state of chronic hyperglycaemia sufficient to cause long term damage to specific tissues, notably the retina, kidney, nerves and arteries

Type 2 diabetes is a chronic metabolic condition characterised by insulin resistance and insufficient pancreatic insulin production, resulting in high blood glucose levels.

There is genetic predisposition and environmental precipitant to T2DM

Question 2

What are the defining values?

Answer 2

Diabetes is defined as a fasting blood glucose > 7 mmol/L

The space in between the defining markers for diabetes and being normal is considered: See diagram

• Impaired Fasting Glucose - when measuring fasting blood glucose
• Impaired Glucose Tolerance - when measuring the 2 hour response in a glucose tolerance test

The people in these ranges are on the way to getting diabetes

Question 3

What is MODY

Answer 3

Maturity onset diabetes of the young - single gene defect (mutations of transcription factor genes, glucokinase gene)

• Several hereditary forms (1-8)
• Autosomal dominant
• Causes ineffective pancreatic B cell insulin production
• Positive family history

Question 4

Describe the epidemiology of T2DM

Answer 4

• Most people with diabetes have T2
• Diabetes is prevalent (10% at 60yr) and is increasing
• More common with increasing age, but now in children due to obesity
• Prevalence in different populations varies enormously- Greatest in ethnic groups that move from rural to urban lifestyle

Question 5

What is the aetiology of T2DM?

Answer 5

Genetics: Big factor for T2DM

• Tendency to develop thrombosis (PAI-1 deficiency)
• Autosomal dominant inheritance pattern whereas T1DM less genetic input

Intrauterine environment:

• Epigenetic changes
• IUGR: Intrauterine growth restrictions - being born light maybe altering the risks of genetic mechanisms of T2DM. Your weight can be used as a predictor for diabetes or impaired glucose tolerance

Adult environment:

• Obesity % some Fatty Acids
• High blood pressure
• Disturbed blood lipid levels (dyslipidaemia)

Question 6

What is the pathophysiology of T2DM?

Answer 6

1) Genes causes insulin resistance, modulated by adipocytokines.
2) Other risk factors discussed (obesity - Adipocytokines: cell signalling proteins secreted by adipose tissue - more in obese people - Increased cytokine production which increases insulin resistance)

3) Insulin resistance is present for a long time before glucose gets elevated and it causes:
- Dyslipidaemia *
- Stimulates mitogenic pathway = ↑smooth muscle hypertrophy –> ↑BP
^ both ↑ risk of macrovascular disease and speed up development of diabetes

4) Insulin resistance gets worse and damages beta cells –> gradual beta cell failure so person can’t make enough insulin to cover for their decreased insulin sensitivity –> hyperglycaemia
5) There is a loss of 1st phase insulin (preformed insulin stored in granules in the beta cells). They can still make 2nd phase insulin but it takes them longer and it is immature insulin which doesn’t work properly –> hyperglycaemia. Note you can get around this by eating complex carbohydrates
6) Eventually, absolute insulin deficiency

NOTE:

• The hyperglycaemia causes microvascular disease.
• Like T1 diabetes, there is beta cell failure, in T1 there is autoimmune destruction whereas T2 there is gradual destruction due to the insulin resistance as the beta cells become exhausted and fail
• As we grow older, we all make less insulin and become more insulin resistant so eventually everyone will become diabetic (110 years old for Caucasaians)

See diagram of pathophysiology

Question 7

How do you get hyperglycaemia after a meal?

Answer 7

Normally after we’ve eaten, insulin stops hepatic glucose output and drives glucose into muscle and adipose tissue, but with resistance to insulin and no/ little production (later), the blood glucose increases.

Question 8

Describe the mechanism of dyslipidaemia?

Answer 8

Dyslipidaemia is an effect of insulin resistance

• Insulin normally stops the breakdown of triglycerides and release glycerol and NEFA from adipocytes.
• In T2 diabetes there is less insulin but also the process of fatty acid mobilisation itself becomes insulin resistant.
• TG from more metabolically active omental adipocytes are broken down into NEFAs which go to liver, are chopped up into 2 (not to ketones as still some insulin present) and are used to make VLDL-TG which are ATHEROGENIC.- Normally insulin would stop these from leaving the liver.

Question 9

What are the metabolism and presentations of T2DM?

Answer 9

1) Heterogeneous - range of conditions
2) Obesity - central or omental obesity. 80% with T2DM are obese.
3) Insulin resistance and insulin secretion deficit
4) Hyperglycaemia and dyslipidaemia
5) Acute and chronic complications

Question 10

What is the effect of insulin on adipocytes?

Answer 10

Insulin switches of lipolysis - Triglycerides are no longer broken down in glycerol and fatty acids.

Question 11

Describe the effect of the gut microbiota on the pathophysiology of T2DM

Answer 11

1) Lipopolysaccharides fermented by gut bacteria to short chain FA
2) Enter circulation and modulate bile acids
3) Modulate host metabolism (i.e cause obesity) and are involved in adipocytokine pathways (modulating insulin resistance)

Microbiota transplants can be used for obesity.

Question 12

What are the clinical presentation of T2DM?

Answer 12

• Osmotic symptoms
• Infections

With a complications of diabetes:

• Acute; hyperosmolar coma
• Chronic; ischaemic heart disease

Question 13

Complications of T2DM?

Answer 13

Microvascular

• nephropathy
• retinopathy
• neuropathy

Metaoblic - a lot rare compared to ketoacidosis in T1DM

• Lactic acidosis
• Hypersomolar

Macrovascular

• IHR
• Cerebrovascular disease
• Renal artery stenosis
• PVD

Question 14

What is the basis of management of T2DM?

Answer 14

1) Education - important to educate people about the consequences of poor treatment
2) Diet
3) Pharmacological treatment

Need to manage different aspects of DM - BP, cholesterol (look out for dysplipidaemia), blood glucose (HbA1c) and weight

The aims of treatment:

• ↓long- term complications (micro and macrovascular diseases)
• ↓ acute metabolic complication (unlikely in T2DM)
• ↓ symptoms

Question 15

What diet should people with Type II diabetes eat?

Answer 15

↓ kcal intake/ exercise more
↓ refined carbs (sugar), ↑ complex carbs
↓ fat as proportion of kcal, ↑ unsaturated fats as proportion of fat
↑ soluble fibre (takes longer to absorb carbohydrates)
↓ salt – for BP

Question 16

What are the pharmacological treatment

Answer 16

Metformin – Used in everyone with T2DM. a Biguanide
Reduces insulin resistance –> reduced HGO and increased perhipheral glucose disposal.
Doesn’t cause weight gain
Don’t use in severe liver/ cardiac/ renal failure

Glibenclamide - a Sulphonylurea
Makes pancreas secrete more insulin by blocking ATP sensitive potassium channel –> influx of calcium –> insulin secretion
Causes weight gain and hypoglycaemia

Acrabose - alpha glucosidase inhibitor
Prolongs absorption of carbs to cope with loss of 1st phase insulin
Sugars reach large intestine, are fermented, cause flatus

Glucagon like Peptide-1 (GLP-1) agonist
GLP-1 released in response to nutrients in gut, it stimulates insulin, supresses glucagon, increases satiety.
It has a short half-life; broken down by dipeptidyl peptidase- 4 (DPPIV)
Injected

Gliptins (DPPGIV inhibitors)
Increase half life of GLP-1
Not as effective as GLP-1 agonist

Other Drugs:

Orlistat - pancreatic lipase inhibitor- fat not broken down therefore reabsorption in gut is reduced

Thiazolodinediones – PPAR-γ agonist- peripheral insulin sensitiser
Peripheral weight gain

Empaglifozin- inhibits Na-Glu transporter- reabsorption of glucose in kidney reduced to excreted

See slides for more detail