PBL

Question 1

List clinical features unique to T2DM?

Answer 1

Overweight (BMI >30).
Usually present with a longer history with slowly progressing symptoms.
Hyperglycaemia is less marked than T1DM.
Islet cell antibodies not present (as not autoimmune).
Weight loss is minimal.

Question 2

List clinical features seen in both T1DM and T2DM?

Answer 2

Polyuria: Due to osmotic diuresis.
Thirst: Due to resulting fluid and electrolyte loss. So dehydration, dry mouth. 
Fatigue 
Impaired conciousness
Impaired vision
Muscle weakness and wasting.
Skin more prone to infection.
Tachycardia.

Question 3

What are the risk factors for T2DM?

Answer 3

Older age
Obesity 
Ethnicity (south asian, caribbean, african)
Family history of T2DM.
Inactivity.

Question 4

Describe the pathophysiology of T2DM?

Answer 4

Unknown.

1. In the early stage, response to insulin resistance is to increase insulin secretion in islet Beta cells causing hyperinsulaemia. This may lead to down regulation of insulin receptors.
2. Beta cells are unable to compensate and blood glucose rises to give hyperglycaemia.
3. With more Beta cell failure, glycaemic control deteriorates and treatment requirements increase.

Question 5

Describe metabolic syndrome and how it relates to T2DM?

Answer 5

Is a cluster of conditions occurring together which increase your risk of heart disease, stroke and diabetes.

These include hypertension, duslipiaemia (high LDL’s, triglycerides and low HDL’s), fatty liver and polycystic ovarian syndrome.

Question 6

Describe how obesity and inactivity contribute to T2DM?

Answer 6

Increased sugar uptake leads to hyperinsulaemia, which is though to lead to down regulation of insulin receptors.

Inactivity is also associated with down regulation of insulin-senstive kinases and may promote accumulation of FFA’s in skeletal muscle.

Question 7

List macrovascular complications of DM?

Why do they occur?

Answer 7

Ischeamic heart disease: MI.
Peripheral Vascular Disease: Claudication in limbs, Ischaemia, Ulceration/Gangrene in feet.
Cerebrovascular disease: Stroke, Transient Ischaemic Attack (brief neurological attack).

Due to hyperglycaemia damaging vessels and causing atherosclerosis. High BP and high serum lipid due to metabolic syndrome can also contribute to this.

Question 8

What can prevent macrovascular complication of DM?

Answer 8

Good glycaemic control.
Increase exercise, reduce weight.
Manage hypertension: (ARB’s, ACEi, B-Blockers, Calcium channel blockers, Alpha1-adrenoceptor blockers, diuretics).
Manage dyslipidaemia: Statins.

Question 9

List examples of microvascular complications of T2DM?

Answer 9

Retinopathy
Nephropathy
Neuropathy

Question 10

How do microvascular complications of diabetes occur?

Answer 10

Due to damage to small capillaries.
This is due to thickening of the BM and increased permeability.

When there is excess glucose and it has no where to go, it is converted to sorbitol via the polyol pathway. Sorbitol cant cross membrane so accumulates within cells and causes osmotic stress, drawing water into insulin dependent tissues.
There is also a build up of reactive oxygen species (which causes LDL to be negatively charged and move into foam cells) and also a build up of oxidative stress.
This causes inflammation and cell damage.

Question 11

What did the DCCT snd UKPDS trials prove?

Answer 11

the basal bolus insulin regime (1 injection of long acting and injection of short acting before meals) is better than the conventional regime (2 injections of mixed insulin) for controlling hyperglycaemia.
Controlling hyperglycaemia helps prevent microvascular disease.

Question 12

Why are microvascular complications more common in patients with T1DM?

Answer 12

As T2DM patients often die of CV disease first.

Question 13

List drug treatments (and give examples) for T2DM?

Answer 13

Biguanides (Metformin)
Sulphonylureas (Glipizide) 
Thiazolidinediones (Pioglitazone)
Incretin based therapies (Exenatide - Mimics GLP-1 and Sitagliptin - Inhibits DPP-4). 
SGLT2 Inhibitors (Dapaglifolzin).

Question 14

How do Biguanidides (Metformin) work?

Answer 14

First line therapy in T2DM.
Though to reduce hepatic gluconeogenesis by inhibiting G6Pase and PEPCK.
Side effects include GI problems and more risk of lactic acidosis.

Question 15

How do Sulphonylurea’s (Glipizide) work?

Answer 15

Inhibit ATP-sensitive K+ channels. Closed K+ channels cause a depolarisation and calcium influx causes insulin release.
Side effects: Weight gain and hypoglycaemia. Potentially not good for extrememly obese patients?

Question 16

How do Thiazolidinediones (TZD - Pioglitazone) work?

Answer 16

Ligand for transcription factor PPARy (gamma), which stimulates expression of genes involved in triglyceride storage.
Stops inappropriate deposition of lipid in non-adipose tissue which can lead to insulin resistance. Therefore it improves insulin sensitivity.
Side effects: Weight gain.

Question 17

How do Incretin-based therapies work?

Answer 17

Incretins are peptides hormones released in the GI tract in response to food. The potentiate insulin secretion.
The are Glucagon-like Peptide 1 (GLP-1) and Gastrointestinal Peptide (GIP).
Incretins are rapidly broken down by DPP-4. In T2DM this is diminished so you dont get the desired insulin effect.

DPP-4 Inhibitors prevent breakdown so enhances concentrations of GLP1 and GIP, increasing insulin and decreasing glucagon. E.g. Sitagliptin.

Exenatide mimics GLP-1. This Increases insulin secretion and decreases glucagon section. It also helps slow gastric emptying so there is slower, steadier glucose uptake.

Question 18

How do SGLT2 Inhibitors (Dapagliflozin) work?

Answer 18

They inhibit reuptake fo glucose by blocking the action of the SGLT2 transporters in the PCT of the kidney.
As a result, hyperglycaemia reduces by about 25% of filtered glucose is not reabsorbed.
Side Effects: Glycosuria, which can increase risk of UTI’s.

Question 19

Describe the structure of insulin?

Answer 19

Polypeptide hormone consisting of 2 short chains (A and B) linked by disulphide bonds.

Question 20

How is insulin normally synthesised?

Answer 20

Ribosomes of the beta cells synthesise pre-proinsulin from insulin mRNA.
This is broken down to proinsulin by cleavage in the golgi apparatus.
This is then packaged in secretory granules and converted to active insulin ready for release (C chain cleaved off).

Question 21

How is insulin released from Beta cells?

Answer 21

Glucose enters the Beta cells via the Glut 2 receptor.
Glucose is converted to G6P by Glucokinase. It then undergoes metabolism to be converted to ATP.
The sulphonylurea receptor subunit on the ATP-dependant K+ channel senses the ATP increase and closes K+ channels.
This causes depolarisation of the cell which causes calcium influx via calcium channels.
Increased calcium in the cell causes secretory vesicles to release insulin via exocytosis.

More glucose = more ATP = More Ca2+ influx = more insulin release.

Question 22

How does insulin act on other cells?

Answer 22

Insulin binds to insulin tyrosine kinase receptors on the surface of target tissues.
This causes a conformational change in the receptor, causing autophosphorylation and an intracellular signalling cascade.
This leads to translocation of Glut4 transporter to the membrane, and glucose can move into the cell down its concentration gradient.

Question 23

Outline the role of insulin?

Answer 23

Promotes glucose uptake by tissues.
Promotes glycogen synthesis in the liver and muscle.
Promotes fatty acid synthesis in adipose tissue and liver.
Increases amino acid production and protein synthesis.
Increases rate of glucose utilisation and ATP generation.

Question 24

How is glucagon synthesised?

Answer 24

Produced in alpha cells.
Begins as proglucagon and cleaved to glucagon.
Synthesis is stimulated by low blood glucose.

Question 25

What is the role of glucagon?

Answer 25

Maintain normal glucose levels by promoting hepatic glycogen breakdown.
Glucagon binds to a receptor on the surface of hepatocytes and activates a downstream cascade, which ends with the production of Phosphorylase A, which releases glucose-1-phosphate from glycogen polymers.

Question 26

How does somatostatin act on insulin and glucagon?

Answer 26

Via paracrine effects.