Diabetic Drugs

Question 1

Thiazolidinediones (TZDs) (eg, pioglitazone)

Answer 1

• exert their glucose-lowering effect by improving insulin sensitivity.
• bind to peroxisome proliferator-activated receptor-gamma (PPAR-γ), causing it to form a heterodimer complex with the retinoid X receptor.
• This complex then binds to transcriptional regulatory sequences of various genes responsible for glucose and lipid metabolism, altering their expression.
• One of the most important genes regulated by PPAR-γ is one that codes for adiponectin, a cytokine secreted by fat tissue that enhances insulin sensitivity and fatty acid oxidization.
• Adiponectin levels are low in obese patients and those with type 2 diabetes. Treatment with TZDs increases adiponectin levels, improving insulin sensitivity.

Question 2

Metformin

Answer 2

inhibits mitochondrial glycerophosphate dehydrogenase, reducing hepatic gluconeogenesis

Question 3

Alpha-glucosidase inhibitors

Answer 3

decrease the activity of the membrane-bound disaccharidases on the intestinal brush border, reducing carbohydrate absorption

Question 4

Sulfonylureas and meglitinides

Answer 4

• bind to the regulatory subunits of the ATP-dependent potassium channel on pancreatic beta cells, causing membrane depolarization and influx of calcium.
• High intracellular calcium levels within beta cells then trigger insulin release by exocytosis.

Question 5

Insulin

Answer 5

• acts by binding to a cell-surface receptor on target cells.
• The receptor for insulin is a tetrameric structure consisting of 2 alpha and 2 beta subunits.
• The alpha subunits are located extracellularly and provide binding sites for insulin;
• the membrane-spanning beta subunits contain the intracellular tyrosine kinase domains.

Question 6

Long-acting GLP-1 agonists (eg, exenatide, liraglutide)

Answer 6

• Glucagon-like polypeptide-1 (GLP-1) is secreted by intestinal L cells in response to food intake
• decreases blood glucose by inducing satiety, decreasing gastric emptying, and increasing insulin release from pancreatic beta cells
• acts through cell surface receptors coupled with the G protein-adenyl cyclase system.