Diabetes

Question 1

Type 1 diabetes

Answer 1

Insulin dependent. Autoimmune destruction of beta-cells

Question 2

Type 2 diabetes

Answer 2

Non-insulin dependent. Insulin secretion is unable to match increasing insulin demands due to insulin resistance.

Question 3

What is insulin?

Answer 3

Peptide. T(1/2)=7 mins. Cleaved from pro-insulin in beta-cells. 2 insulin molecules can form a dimer and then a hexadimer around a Zn ion but must dissociate before binding to the insulin receptor.

Question 4

Insulin receptor

Answer 4

Dimer. Receptor tyrosine kinase. Upon binding undergoes mutual phosphorylation that recruits substrate proteins such as insulin receptor substrate.

Question 5

How is insulin secretion controlled?

Answer 5

Local intra-islet regulation. Also interactions between insulin and glucagon. Incretin effect.

Question 6

What is the incretin effect?

Answer 6

Glucose in the gut stimulates release of incretins. Bind to GPCRs on beta-cells and stimulate an increase in cAMP. Cause an increase in the gain of glucose evoked insulin release.

Question 7

How does glucose stimulate insulin release?

Answer 7

Taken up passively by GLUT-2 transporter into beta-cells. Phosphorylated to glucose-6-phosphate by glucokinase. Causes an increase in ATP/ADP ratio. Closes ATP-K+ channel. Causes depolarisation and opening of L-type calcium channels. Stimulates release of insulin containing vesicles

Question 8

2 main treatments for type 1 diabetes?

Answer 8

Insulin replacement therapy and islet transplantation.

Question 9

Islet transplantation.

Answer 9

Follow Edmonton protocol. Require immunosuppression by diclizumab.

Question 10

Insulin replacement therapy

Answer 10

Given subcutaneously to prolong action. Also given with zinc crystals.

Question 11

Factors affecting s/c absorption

Answer 11

Prep of dose. Injection site. Changes at injection site.

Question 12

Humulin S

Answer 12

Short acting insulin replacement therapy. 30 min onset. 2-4 hr peak. 8hr duration

Question 13

Insulatard

Answer 13

Medium acting insulin replacement therapy. 1-2hr onset, 4-12hr peak, 16-24 hr duration.

Question 14

Human ultratard

Answer 14

Long acting insulin replacement therapy. 1-2hr onset. 4-12 hr peak. 20-35 hr duration .

Question 15

Levemir

Answer 15

Insulin analogue. 0-15 min onset, 1-2hr peak, 4-6 hr duration.

Question 16

Diabetes

Answer 16

Defective control of plasma glucose concentration by insulin

Question 17

What can cause type 2 diabetes?

Answer 17

Obesity. Receptor defect. Decrease in number of receptors. Beta-cell burnout - decrease in insulin sensitivity.

Question 18

What are the 5 main treatment options?

Answer 18

Lifestyle (alcohol, smoking). Diet/exercise. Oral monotherapy. Oral combination therapy. Insulin.

Question 19

4 main non-pharmacological treatments?

Answer 19

Statins. Fibrates. Resins. Orlistat.

Question 20

Statins

Answer 20

Inhibit HMG-CoA reductase. The RL enzyme in the melavonate pathway of cholesterol synthesis

Question 21

Fibrates

Answer 21

Fenofibrate. Increase HDL, decrease triglyceride levels and improve insulin resistance

Question 22

Resins

Answer 22

Bind cholesterol

Question 23

Orlistat

Answer 23

Inhibits pancreatic lipase and decreases triglyceride absorption from the gut by 30%.

Question 24

What does GLP-1 do?

Answer 24

Increases glucose evoked insulin secretion from beta-cells. Decreases postprandial glucagon production from alpha cells. Slows gastric emptying. Increases satiety and decreases appetite. Decreases hepatic output from liver.

Question 25

Liraglutide and exanatide

Answer 25

Long lasting GLP-1 analogues

Question 26

Januvia

Answer 26

DPP IV inhibitor, decreases metabolism of GLP-1 but can cause upper respiratory tract infection, sore throat and diarrhoea.

Question 27

Alpha glycosidase inhibitors
Acarbose
Moglitol
Voglibose

Answer 27

Reduce carbohydrate metabolism. Saccharides that act as competitive substrates for alpha-glucosidase enzymes in the brush border of the gut.

Question 28

Acarbose

Answer 28

Oligosaccharide. Alpha glucosidase inhibitor.

Question 29

Moglitol

Answer 29

Alpha glucosidase inhibitor. Monosaccharide.

Question 30

Voglibose

Answer 30

Alpha-glucosidase inhibitor. Fewer side effects but Acarbose has higher efficacy.

Question 31

Thiazolidinediones

Answer 31

Insulin sensitisers.

Question 32

Glitizones

Answer 32

Thiazodolinedione. Binds to PPAR(gamma) receptor that binds to retinoid X receptor and upregulates insulin sensitive genes. GLUT4, lipoprotein lipase, fatty acid transporter protein, fatty acid CoA synthase.

Question 33

Rosaglitizone

Answer 33

In combo with metformin - avandamet. In combo with glimepiride - avandaryl. Decreases excessive lipolysis and free fatty acid output. Decreases excessive hepatic glucose production. Directly decreases insulin resistance.

Question 34

Metformin

Answer 34

Biguanine. T(1/2)= 4-6 hrs. Decreases hepatic gluconeogenesis. Increases insulin sensitivity by increasing peripheral glucose uptake. Stimulates AMPK. Decreases glucose absorption from GI tract.

Question 35

Sulphonylureas

Answer 35

Increase insulin secretion. Bind to SUR1 region on ATP-k+ channels, stimulate depol, opening of L-type ca channels and release of insulin containing vesicles. Eg gliclazide.