Hypoglycaemic agents Lecture 14

Question 1

How is glucose secreted

Answer 1

• Glucose enters B cells
• Metabolised, increasing ATP levels
• Decreased activity of ATP-sensitive K+ channel
• Decrease K+ efflux causing depolarisation
• Opens C2+ channels => secretion of insulin

Insulin acts to decrease blood glucose. Produced in B cell in pancrease. Made as proinsulin

Question 2

How is insulin release biphasic?

Answer 2

• First phase is a result of Ca2+ entry
• Eventually a slower 2nd phase of release occurs due a to a longer term production of insulin - packaged into vesicles which are released by an enzyme triggered process
• Type 2 diabetes don’t have the first phase
• Type 1 don’t have either

Question 3

Describe the insulin receptor

Answer 3

liver muscle and fat

Multisubunit protein- 2x alpha- extracellular bindng site, 2x beta- transmembrane (tyrosine kinase)

Dimer = 2 insulin moelcules bind to and activate it

Receptor–> phosphorylation of insulin receptor substrate proteins (IRS proteins) –> enzyme activation and gene transcription–> glucose uptake (GLUT4 expression), increase synthesis and decrease breakdown of glycogen

Question 4

What are type I and II diabetes?

Answer 4

Type I:

-Genetic cause -> autoimmune response leads to B cell loss

Treated:

• Pre-diabetic (nicotinamide)
• Controlled diet and insuin

Type II:

• Caused by B cell loss or insulin resistance
• Loss of 1st phase of insulin secretion
• Due to obesity, hypertension, hyperlipidaemia

Treatment - diet/exercise, drugs

Question 5

Describe insulin therapy

Answer 5

Type 1 treatment

Achieve 48mmol/mol

Human recombinant DNA

Short acting- soluble insulin or lispro (faster acting), onset 30mins peak 2-4hrs

Intermediate/long- insulin complexes, insulin glargine

SE- hypoglycaemia, allergy, lipodystrophy

Question 6

Describe biguanide

Answer 6

Metformin - oral hypoglycaemic agent.

Mechanism: Requires insulin

• Liver - decreases gluconeogenesis via activation of AMP activated protein kinase (leads to decreased gene expression)
• Muscle - increases glucose uptake

Side effects:

• Lactic acidosis
• No hypoglycaemia or increased appetite (as it does not affect insulin)

Question 7

What are sulphonylureas?

Answer 7

Hypoglycaemic agent

Mechanism:

• Bind to SU receptor on B cells causing K channels to close
• Causes depolarisation which leds to increased insulin secretion
• Increases sensitivity of tissues to insulin

Duration:

• Long - Glibenclamide
• Short - Tolbutamide

Question 8

What is repaglinide

Answer 8

Repaglinide- no sulphonylurea moiety- more selective for the K(ATP) channels in beta cells, shorter duration

SE- hypoglycaemia (less with repaglinide), stimulate appetite, contraindicated in pregnancy

Question 9

Describe thiazolidinediones

Answer 9

Hypoglycaemic Agent

Mechanism:

-Binds TF => affect gene expression

1st action - adipose tissue: increases FA uptake and increase lipogenesis - weight gain

2nd action - decreased plasma FA causes increased glucose uptake and decreased gluconeogenesis

Used with SU or metformin

Side effects:

-Fluid retention

Question 10

Describe Acarbose

Answer 10

alpha-glucosidase inhibitor–> decrease ketone absorption used for obese diabetics

Alone or with metformation

Question 11

Describe drugs that manipulate incretins

Answer 11

Incretins stimulates insulin secretion

1. Increase endogenous incretin

Sitaglandins- dipeptidyl peptidase-4 inhibitor–> blocks breakdown of incretins

2. Incretin agonist

Exenatide GLP-1 agonist- subcutaneous injection, slow gastric emptying

Combined with metformin