Treatments of Diabetes

Question 1

Biguanides are a class of treatment for diabetes - give an example.

Answer 1

Metformin.

Question 2

Outline how metformin decreases BGL.

Answer 2

Decreases hepatic glucose production.
Potentiates insulin action on muscle and adipose.
Stimulates glycolysis and glucose uptake.
Decrease CHO absorption.
Stimulates lactate production.
Decrease LDL and VLDL.
Inhibits the expression of genes involved in gluconeogenesis.

Question 3

What doesn’t metformin affect the release of?

Answer 3

insulin, glucagon, GH, cortisol, somatostatin.

Question 4

What are the side effects?

Answer 4

Diarrhoea, nausea

Decreases intestinal absorption of folate and vit B12.

Question 5

What is good about metformin?

Answer 5

Doesn’t causes hypoglycemia, stimulate apetite or cause weight gain!

Good for obese people who fail to control their diabetes by diet alone.

Decreases microvasular complications.

Question 6

What other drugs would you give metformin with?

Answer 6

Sulphonylureas, thiazolindenediones and or insulin.

Question 7

Give 2 examples of sulphonylureas.

Answer 7

Glibenclamide, gliclazide.

Question 8

How to sulphonylureas work?

Answer 8

They bind to the K+ATP channels and affect insulin release. Close the channel therefore they acutely increase insulin release…increasing plasma insulin and decrease the hepatic clearance of insulin.

Chronically - the increase in insulin doesn’t remain but the decrease in glucose does.

Chronic hyperglycemia - decrease insulin release due to a down reg of the sulphonylurea receptor.

Question 9

What drug interactions do sulphonylureas have and why?

Answer 9

Largely protein bound and therefore have drug interactions with NSAIDs, MAOI and some antibiotics.

Question 10

How are sulphonylureas removed from the body?

Answer 10

Excreted in the urine.1st gen have long half lives.

2nd gens are 100x more potent and therefore have less drug interactions.

Question 11

Side effects of sulphonylureas?

Answer 11

Hypoglycemia.
Neuroglycopenia.
Confusion and coma.

take oral glucose.

if these are severe - can take iv glucose, glucagon or adrenaline.

Question 12

Give an example of a thiazolidenedione.

Answer 12

Pioglitazone.

Question 13

How do thiazolidenediones work?

Answer 13

Selective agonist for PPARgamma which combines with RXR to…
…activate insulin responsive genes that control CHO and lipid metabolism. Potentiates insulin, Decrease insulin resistance in peripheral tissues. Decrease glucose production in the liver. Increase glucose uptake into muscle and adipocytes. Increase adipocyte number and lipogenesis.

Question 14

Pharmacokinetics of pioglitazone?

Answer 14

Protein bound, half life of 7 hours but active metabolite has a half life of 24hrs.
Takes 6-12 weeks for max effect.
Give with metformin, insulin or other hypoglycemia drugs,

Question 15

Side effect of pioglitazone?

Answer 15

Weight gain due to increased differentiation of adipocytes and fluid retention by stimulating amiloride sensitive sodium absorption.

Question 16

Give 2 examples of meglitinides.

Answer 16

Repaglinide and nateglinidine.

Question 17

How do meglitinides work?

Answer 17

Close K+ATP channels - share 2 binding sites with sulphonylureas but have their own distinct one too.

Question 18

How are meglitinides better than sulphonylureas?

Answer 18

More rapid and less sustained release. More potent than sulphonylureas.
Less hypoglycemic.
t1/2 is one hour.
More selective for beta cell channels that cardiac/vascular channels.

Question 19

How do incretins work?

Answer 19

Oral glucose causes a larger secretion of insulin due to incretin release.

Question 20

Give 2 naturally occuring incretins.

Answer 20

GIP - glucose independannt insulinotrophic peptide.

GLP-1 : glucagon like peptide 1

Question 21

Where does exenatide come from and how does it work?

Answer 21

Comes from the saliva of the glia monster.
Acts on the GLP-1 incretin receptor - stimulates insulin release, suppresses glucagon secretio, reduceds appetite and body weight. Slows gastric emptying. Stimulates B cell number.

Question 22

What does DPP4 do? How does that relate to the treatment of DM?

Answer 22

breaks down incretins - therefore to treat DM we want to use DPP4 inhibitors. THey would potentiate the action of endogenous GLP and synthetic analogues.

Question 23

Give and example of a DPP4 inhibitor.

Answer 23

Sitagliptin - doesn’t have an effect on body weight and doesn’t cause hypoglycemia.

Question 24

Give an example of an alpha glucosidase inhibitor and how they work.

Answer 24

Acarbose.
Inhibits the intestinal brush border alpha glucosidase.
Inhibits CHO breakdown and decreases the postpyrandial spike in BGL.
BUT poorly absorbed in gut - no hypoglycemia.
BUT flatulence and diarrhoea.

Question 25

Give an example of an amylin analogue and how it works.

Answer 25

Pramlintide.
Related to calcitonin/CGRP
Decreases gastric emptying, inhibiting glucagon release and increase satiety.

Question 26

What are future developments for treatment of DM?

Answer 26

Improved insulin delivery.
Islet transplants.
Sodium glucose transporters (inhibit glucose reuptake in the kidney)
alpha 2 antags - a2 receptors block insulin release.
beta 3 agonists - increase lipolysis and theremogenesis in brown adipose tissue.