Drug Control of Diabetes

Question 1

Where is insulin released from? What is the stored precursor of insulin?

Answer 1

B cells in the islets of Langerhans

Proinsulin

Question 2

What is the main regulator of insulin secretion?

What else regulates it?

Answer 2

glucose levels

sympathetic/parasympathetic stimulation, somatostatin, glucagon

Question 3

How do increased glucose levels stimulate insulin secretion?

Answer 3

• glucose enters cell
• metabolised –> increases [ATP]i
• decreases activity of ATP sensitive K+ channel
• decreases K+ efflux –> depolarisation
• opens Ca2+ channels, Ca2+ enters
• vesicles containing insulin fuse with membrane
• Ca2+ also stimulated PKC pathway involving DAG

Question 4

Insulin secretion can be described as….

What is the difference between the 2 phases?

Answer 4

biphasic
1st due to exocytosis of insulin
2nd = insulin stores used up so second rise due to enzyme pathways that produce insulin

Question 5

What is the structure of the insulin receptor?
What are the different subunits?
What links them?
How does it work?

Answer 5

Multisubunit protein, x2 extracellular binding sites, x2 transmembrane tyrosine kinases. Disulphide bonds link subunits
Insulin binds, phosphorylation of insulin receptor substrate
Enzyme activation + gene transcription
increases glucose uptake through expression of Glut-4
increases glycogen synthesis

Question 6

What is the difference between short and long acting insulin?
Examples of each
How is this achieved?

Answer 6

Short = quick onset, short duration
- soluble insulin (wild type), lispro (switch 2 AA’s, increases solubility so even faster acting)
Long = slow onset, long duration
- insulin complexes (zinc), insulin glargine (ppt)
Insulin solubility depends on if the insulin proteins can attach to each other

Question 7

3 x complications of insulin injections

Answer 7

• hypoglycaemia
• allergy
• lipodystrophy (abnormal growth/atrophy of adipose tissue) (requires rotation of injection site)

Question 8

Which phases of insulin secretion is often lost in Type 11 diabetes?

Answer 8

1st phase

Question 9

Give 3 examples of sulphonylureas (SU)

What do they do? x2

Answer 9

• tolbutamide, glivenclamide, gliclazide (differ in half-life)
• bind to SU receptor (part of Katp channel)
• causes channel to close (similar to effect of increased ATP) –> depolarisation
• increases insulin secretion
• also increases tissue sensitivity to insulin

Question 10

Give an example of another sulphonylurea receptor modulator. Facts about it

Answer 10

repaglinide
no SU moiety
shorter duration of action
more selective for Katp channels in B cells

Question 11

What are the side effects of SUR drugs? x3

Answer 11

• hypoglycaemia
• stimulate appetite (not for obese!)
• contraindicated in pregnancy/breastfeeding

Question 12

What class is metformin in?
How does it work?
Side effects?

Answer 12

biguanide

• mechanism requires insulin
• decreases gluconeogenesis in liver, via activation of enzymes that decrease gene expression of gluconeogenesis enzymes
• increases glucose uptake in muscle
• Side Effects: NO hypoglycaemia, NO increased appetite, YES lactic acidosis

Question 13

What class is pioglitazone in?
How does it work?

Answer 13

Thiazolidinediones

• increases fatty acid uptake in adipose tissue and increases lipogenesis
• decerases plasma fatty acids which causes increased glucose uptake and decreased gluconeogenesis
• Side Effects: weight gain, fluid retention

Question 14

What does acarbose do?

Answer 14

• works in the gut

- decreases CHO absorption

Question 15

What are incretins?

Answer 15

GI hormones that stimulate insulin secretion

Question 16

Gliptins are a class of drugs? What do they do?

Answer 16

• block breakdown of incretins, therefore increasing insulin secretion

Question 17

What does exanatide do?

Answer 17

• mimics incretins

- slows gastric emptying, fuller for longer