Pancreas and Insulin

Question 1

Provide a general outline of the pancreas.

Answer 1

• Has both exocrine (into ducts) and endocrine (into blood) functions.
• Beta cells produce insulin which has two AA chains (A and B) joined by disulphide bonds. Stored as proinsulin.
• DNA (coded from chromosome 11) in beta cells is encoded into m.RNA then pre-proinsulin which contains a signalling peptide.
• Proinsulin also has a C subunit which is cleaved off to activate it.
• Somatostatin and epinephrine inhibit insulin secretion.
• T1D is the destruction of pancreatic beta cells.

Question 2

Describe the stimulus-secretion coupling concept.

Answer 2

• When beta cells are at rest the K/ATP channel is open and the is at resting membrane potential.
• Closure of K/ATP channel (less K+ efflux) depolarises cell triggering exocytosis of insulin.
• Depolarisation causes Ca2+ channels to open allowing influx to trigger exocytosis.
• Increased ATP will shut off the K/ATP channel causing no efflux thus increasing depolarisation.
• ATP will be produced once glucose binds to Glut 2 initiating glycolysis and the TCA.

Question 3

Explain the function of glycagon.

Answer 3

• A 29 AA long polypeptide produced by alpha cells and work in the liver.
• Promotes glycogenolysis, gluconeogenesis and the release of glucose into the blood. Prolonged hypoglycaemia leads formation of ketones.
• May be inhibited by amylin (produced in beta cells).
• Has no direct effect on skeletal muscles due to lack of proper receptors.

Question 4

What is the mechanism of glycagon action.

Answer 4

• Low glucose detected by Glut 2, ATP causes K/ATPase transporters to remove K+ from the cell.
• The small depolarisation formed causes the influx of Na+ triggering an action potential.
• Causes increased activity of P/Q type Ca2+ channels resulting in a hyperpolarisation (high Ca2+ intracellularly) allowing vesicles containing glucagon to undergo exocytosis.

Question 5

Describe the effects of metformin and sulphonylureas.

Answer 5

1. Metformin (liver): Enters the cells via the OCT1 transporter due to its hydrophilic nature and inhibits complex 1 of the mitochondria. Increases the AMP/ATP ratio.
   - Inhibits hepatic glucose production and gluconeogenesis thus restoring the insulin like repression. Does no need beta cells or insulin.
2. Sulphonylureas: Blocks ATP-sensitive K+ channels thus causes increases release of Ca2+ thus more insulin is released. This only works in T2D as islets are required.

Question 6

Describe the insulin and thiazolidinediones as methods of treatment.

Answer 6

1. Insulin: First choice in type 1 but not 2 due to resistance developing.
2. Thiazolidinediones: Increases glucose uptake into the skeletal muscle while decreasing hepatic glucose release.

Question 7

What is the incretin effect?

Answer 7

• Incretins stand for intestinal secretion of insulin, they are a group of metabolic hormones that stimulate a decrease in blood glucose level.
• Released after eating and augment secretion of insulin from beta cells.
• Glucose like peptide-1 (GLP-1) is secreted from intestinal L cells during ingestion, in beta cells it enhances glucose dependent insulin secretions and in alpha cells it suppresses postprandial glucagon secretion.
• GLP-1 also reduces hepatic glucose output and decreases the rate of gastric emptying while promoting satiety in the brain.
• Agonists of GLP-1 improve glycemic control.

Question 8

Describe the activity of DPP-4 inhibitors.

Answer 8

• Stop the conversion of GIP and GLP-1 to inactive metabolites via DPP-4 which would be cleared by the kidney.
• This increases the duration of effect.