The Aetiology And Treatment Of Type 2 Diabetes Mellitus

Question 1

What tests are performed to diagnose diabetes and what are the defining values?

Answer 1

Fasting Blood Glucose:
Normal < 6
Impaired Fasting Glucose = 6-7
Diabetes > 7

Glucose Tolerance Test (2 hr measurement):
Normal < 7.8
Impaired Glucose Tolerance = 7.8-11.1
Diabetes > 11.1

Question 2

State three factors that influence the pathophysiology of T2DM.

Answer 2

Genetics
Intrauterine environment
Adult environment (which would accelerate pathogenesis)

Question 3

How is the intrauterine environment important in the pathogenesis of T2DM?

Answer 3

There will be epigenetic changes that take place in utero, which affect blood glucose control in the future

Question 4

What is MODY?

Answer 4

Mature onset diabetes of the young (8 types):

• It is autosomal dominant
• Characterised by ineffective pancreatic beta cell insulin production e.g. caused by mutations of transcription factor genes (glucokinase gene)
• Positive family history with NO obesity

Question 5

How would you describe the pathogenesis of T2DM?

Answer 5

It results from a combination of insulin resistance and a failure of the beta cells to be able to increase insulin secretion sufficiently in order to overcome the resistance.

• Initially as the insulin resistance worsens, the beta cells overcome this and produce more insulin, so that the patient is hyperinsulinaemic and euglycaemic.
• Eventually the pancreas cannot keep up the large insulin production rate and the blood glucose concentration then begins to rise.
• There is, however, enough insulin to prevent ketogenesis, but not enough to prevent the hyperglycaemia.
• There is a gradual and insidious increase in plasma glucose levels over time, and patients present with polyuria and polydipsia without ketoacidosis.

Question 6

What do adipocytes secrete which may be implicated in insulin resistance?

Answer 6

Adipocytokines (e.g. leptin, Adiponectin etc.)

Question 7

In terms of weight, what type of babies are more likely to develop T2DM in later life?

Answer 7

Small babies (low birth weight) 
This is due to intrauterine growth restriction

Question 8

How does insulin resistance lead to hypertension?

Answer 8

The hyyperinsulinaemia stimulates the mitogenic pathway causing smooth muscle hypertrophy => high blood pressure

Question 9

Describe how beta cell reserve and insulin resistance change with age normally

Answer 9

Beta cell reserve decreases with age and insulin resistance increases
(The point at which these lines meet comes at an earlier stage in life for patients pre-disposed to T2DM)

Question 10

Describe the presentation of a typical patient with T2DM.

Answer 10

• Heterogeneous
• Obese (80%)

Insulin resistance and insulin secretion deficit =>

• Hyperglycaemia
• Dyslipidaemia
• Acute complications
• Chronic complications

Question 11

State (and explain) the acute complications of T2DM

Answer 11

• Patients may develop urinary tract infections because the high level of glucose in the urine encourages organisms to grow there
• Severe hyperglycaemia can sometimes cause a hyperosmolar state (of the blood) that can be life threatening, occasionally causing coma = hyperosmolar non-ketotic coma (HONKC).
• Not only is the blood glucose level high, but also because the glycosuria takes water with it, the plasma sodium concentration can rise, causing hypernatraemia which contributes to the hyperosmolar state.
• The very high osmolality can contribute to confusion and loss of consciousness.

Question 12

What are the potential long term complications of T2DM?

Answer 12

Stroke 
Myocardial Infarction 
Neuropathy 
Retinopathy 
Nephropathy 
Hypoglycaemia

Question 13

What happens to fatty acids when they go into the liver?

Answer 13

They cannot be used to make glucose so they are converted to very low-density lipoproteins (VLDLs), which are highly atherogenic

Question 14

Which adipocytes are particularly marked for breakdown of triglycerides?

Answer 14

Omental adipocytes (this is why omental fat correlates with risk of heart disease); have a more direct connection with liver

Question 15

Describe how gut microbiota is implicated in T2DM.

Answer 15

They may be important in host signalling – they ferment various lipopolysaccharides to produce short chain fatty acids, which enter the circulation and modulate bile acids (so they can also affect host metabolism)
They are also important in inflammatory and adipocytokine pathways

Question 16

What is a very common side effect of diabetes treatment?

Answer 16

Weight gain

Question 17

Which diabetes treatment does not cause this problem?

Answer 17

Metformin

Question 18

What dietary measures are recommended for someone with T2DM?

Answer 18

• Decreased fat (particularly saturated fats)
• Decreased refined carbohydrates
• Increased complex carbohydrates to release glucose more slowly (reduces the effect of the missing first phase insulin release)
• Increased soluble fibre
• Control total calories/increase exercise

Question 19

What is orlistat and why is it sometimes used in T2DM?

Answer 19

Pancreatic Lipase Inhibitor

It reduces the break down of fats in the intestines thus reducing the absorption of fats

Question 20

State 5 classes of drugs that are used to treat T2DM and briefly state what they do.

Answer 20

1. Metformin – decreases gluconeogenesis, increases insulin sensitivity, enhances peripheral glucose uptake and decreases intestinal absorption of glucose (drug class = biguanides)
2. Sulphonylureas – makes the existing pancreas produce more insulin
3. Alpha-glucosidase inhibitors – prolongs the absorption of glucose from the intestine
4. Thiazolidinediones – addresses peripheral insulin resistance (muscle and fat)
5. GLP-1 agonists and DPIV inhibitors – increase insulin secretion

Question 21

When should you NOT use metformin?

Answer 21

Severe liver failure
Severe cardiac failure
Mild renal failure

Question 22

Name one sulphonylurea. Who is it given to?

Answer 22

Glibenclamide

Given to lean patients with T2DM

Question 23

Explain how sulphonylureas work.

Answer 23

They bind to receptors and block the ATP-sensitive K+ channels on the pancreatic beta cell membranes
This ultimately leads to Ca2+ influx, which causes insulin release

Question 24

Name one alpha-glucosidase inhibitor. Explain how it works and state some side effects.

Answer 24

Acarbose

• They act as competitive inhibitors of enzymes needed to digest carbohydrates (specifically alpha-glucosidase enzymes in the brush border of the small intestines)
• Therefore, they prolong the absorption of oligosaccharides and allow the body to cope with the loss of first phase insulin

Side effect: it means that some sugars get to the colon and are fermented => flatulence

Question 25

Name one thiazolidinedione. What are they and describe their effects. Side effects?

Answer 25

Pioglitazone

• These are peroxisome proliferator-activated receptor (PPAR-) agonists.
• This activated nuclear receptor increases transcription of a number of specific genes and decreases transcription of others
• These are insulin sensitisers mainly in peripheral tissues
• Increase storage of fatty acids in adipocytes leads to peripheral weight gain, not central
• Main side effect = water retention, leading to oedema
• For older thiazolidinediones, side effects = hepatitis, heart failure

Question 26

What class of drugs prolong the duration of GLP-1? How?

Answer 26

Gliptins

They inhibit Dipeptidyl peptidase-4 (which breaks it down)

Question 27

What does GLP-1 do?

Answer 27

• Responsible for the incretin effect

- Stimulates insulin and suppresses glucagon

Question 28

What effect do long-acting GLP-1 agonists and gliptins have on weight gain?

Answer 28

GLP-1 agonists = weight loss

Gliptins = neutral

Question 29

What other pharmaceutical interventions must be considered with T2DM patients?

Answer 29

Many T2DM patients also have dyslipidaemia (high cholesterol, high triglyceride, low HDL) and hypertension, which need to be dealt with as well

Question 30

What can occur during pregnancy to identify women who are at high risk of getting diabetes in the future?

Answer 30

Gestational diabetes