Physiology/Pharmacology of T2DM Drug Targets 1

Question 1

What drugs used to treat T2DM increase insulin secretion

Answer 1

SU’s, incretin mimetics, glinides (aka meglitinides), DPP-4 inhibitors (gliptins) - all increase insulin secretion so are insulin dependent

Question 2

What drugs used to treat T2DM decrease insulin resistance

Answer 2

biguanides, thiazolidinediones (glitazones) - they decrease insulin resistance and reduce hepatic glucose output so are therefore insulin dependent in there mechanism

Question 3

Which drugs used to treat T2DM slow down glucose absorption in the GI tract ?

Answer 3

α-glucosidase inhibitors

Question 4

Which drugs used to treat T2DM enhance glucose excretion by the kidneys ?

Answer 4

SGLT2 inhibitors these are insulin independent

Question 5

Refresh the insulin secretion pathway

Answer 5

Question 6

Describe the structure of K_ATP channels

Answer 6

Octomeric complex of 4 potassium inward rectifier 6.2 subunits (Kir6.2) and four sulphonylurea receptor 1 subunits (SUR1)

Question 7

How does the K_ATP channel normally work in insulin secretion

Answer 7

ATP will bind to Kir 6.2 subunits closing the channel causing deplorisation in the beta cell and insulin release

Question 8

What opens K_ATP channels ?

Answer 8

ADP-Mg2+ binding to the SUR1 subunits opens the channel maintaining the resting potential of the b cell and inhibits insulin secretion

Question 9

Describe the action of SU’s in T2DM treatment

Answer 9

Appear to act by displacing the binding of ADP-Mg2+ from the SUR1 subunit (thus closing the KATP channel and stimulating insulin release)

Question 10

What are potential side effects of sulphonylureas ?

Answer 10

• May cause hypo’s due to excessive insulin secretion
• Tend to cause weight gain

Question 11

Give a couple examples of Glinides (Meglitinides)

Answer 11

Repaglinide and nateglinide (think glinide)

Question 12

What is the action of Glinides (Meglitinides)

Answer 12

Act similarly to the sulfonylureas – bind to SUR1 (at a distinct benzamido site) to close the KATP channel and trigger insulin release

Question 13

Describe the incretin pathway

Answer 13

1. Food ingested
2. Stimulates release of Glucagon Like 1 (GLP-1) and Glucose Dependent Insulinotropic Peptide (GIP) in the intestines
3. GLP-1 and GIP enter portal blood
4. GLP-1 and GIP enhance (increment) insulin release
5. GLP-1 decreases glucagon release
6. This results in enhanced glucose uptake and utilisation
7. Decreased glucose production
8. Hence decreased blood glucose levels

Question 14

Describe the action of GLP1 receptor antagonists = Incretin mimetics/ anagoluges

Answer 14

1. Mimics action of GLP-1
2. Binds to GPCR GLP-1 receptors that increase intracellular cAMP concentration
3. This Increases insulin secretion, suppresses glucagon secretion, slows gastric emptying, decreases appetite

Question 15

Describe the action of DPP-4 Inhibitors (Gliptins)

Answer 15

• Actions of GLP-1 and GIP are very rapidly terminated by the enzyme dipeptidyl peptidase-4 (DPP-4)
• Gliptins competitively inhibit DPP-4, prolonging the actions of GLP-1 and GIP

Question 16

Give an example of an a-Glucosidase Inhibitors

Answer 16

Acarbose

Question 17

Describe the action of alpha-Glucosidase Inhibitors

Answer 17

• Alpha-Glucosidase is a brush border enzyme that breaks down starch and disaccharides to absorbable glucose
• Inhibitors of a-glucosidase (i.e. acarbose) delay absorption of glucose thus reducing postprandial increase in blood glucose

Question 18

Describe the action of biguanides

Answer 18

Reduces hepatic gluoconeogenesis [by stimulating AMP-activated protein kinase (AMPK)]

Question 19

Describe the action of Thiazolidinediones (TZDs, Glitazones)

Answer 19

Exogenous agonists of nuclear receptor PPARY (largely confined to adipocytes) which associates with RXR. The activated PPARY-RXR complex acts as a transcription factors that binds to DNA to promote expression of genes encoding proteins involved in insulin signalling e.g. lipoprotein lipase, fatty acid transport protein, GLUT4

Question 20

Describe the action of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors

Answer 20

Act to selectively block the reabsorption of glucose by SGLT2 in the proximal tubule of the kidney nephron to deliberately cause glucosuria