20, 21 - Diabetes Flashcards
What are the 3 types of diabetes?
- Type 1 – autoimmune destruction of insulin-producing beta cells
- Type 2 – metabolic disorder characterized by hyperglycemia
- Gestational diabetes – development of DM during pregnancy
What are the causes of type 1 DM?
Genetic and environmental (autoimmune, viral, exposure to toxic chemicals)
What is insulin?
- Peptide hormone produced by beta cells in pancreas
- Central for regulating carbohydrate and fat metabolism
- Causes skeletal muscles and fat tissue to absorb glucose from blood, lowering blood glucose levels
- Stops use of fat as an energy source and inhibits release of glucagon
What is glucagon?
Peptide hormone produced by alpha cells in pancreas, raising blood glucose levels
What is the insulin receptor?
- Transmembrane receptor
- Tyrosine kinase mediates activity by phosphorylation of tyrosine that starts many protein activation cascades
What happens when insulin binds to insulin receptor?
1) Protein activation
2) Translocation of glut-4 transporter to plasma membrane and glucose influx
3) Glycogen synthesis
4) Glycolysis
5) Fatty acid synthesis
What are the problems w/ insulin binding in type 1 and type 2 DM?
- Type 1 = ineffective activation of glut-4, resulting in diminished glucose uptake
- Type 2 = defective activation/signaling to glut-4, resulting in diminished glucose uptake
What are the 3 tests for diabetes?
- Fasting plasma glucose (normal = 80-100 mg/dL)
- A1C - reflects average plasma glucose over 3 months (normal = 5%)
- 2h fasting plasma glucose (normal = below 200 mg/dL)
Diabetes is the most common cause of _____
Blindness
What is the target organ of each diabetes drug class?
- Pancreas = sulfonylureas, DPP-4 inhibitors and meglitinides
- Muscle and fat = thiazolidinediones, biguanides, and insulin
- Gut = alpha-glucosidase inhibitors
- Liver = biguanides, thiazolidinediones, DPP-4 inhibitors, GLP-1 inhibitors, and insulin
How is insulin produced (as what)?
- Produced and stored as hexamer
- Inactive, giving long-term stability
- Contains 2 polypeptide chains, A and B linked together by disulfide bonds
What is important about insulin monomer?
Fast-reacting, higher diffusion rate
What happens with lantus (insulin glargine)?
- Precipitation on injection
- Slow release (18-26 h)
What substitutions occur in lantus (insulin glargine)? Why are these beneficial? What is the benefit to the parent compound?
- Substitute glycine for asparagine w/ two arginines added to carboxy terminal B chain
- Arginine shifts isoelectric point from 5.4 to 6.7, making it more soluble at acidic pH
- Glycine substitution avoids deamidization at pH 4
What substitution occurs in NovoRapid (insulin aspart)? What effect does this have on release rate?
- Aspartic acid substituted for proline, which increases charge repulsion and prevents formation of hexamers
- Modification allows quick absorption into bloodstream, onset in 15 min
What modification occurs in Humalog (insulin lispro)? What effect does this have? What is the onset?
- Penultimate lysine and proline residues on C-terminal end of B-chain are reversed
- Blocks formation of insulin dimers and hexamers; doesn’t alter receptor binding
- Faster onset than regular insulin
What is the modification in Levemir (insulin detemir)? What effect does this have?
- Fatty acid (myristic acid) bound to lysine aa at position B29
- Quickly absorbed and binds to albumin in blood
What is the modification in Apidra (insulin glulisine)? What effect does this have? Is this a short or long acting form?
- Asparagine at B3 replaced w/ lysine and lysine at B29 replaced w/ glutamic acid
- Decreases zinc-free self-association (decreased dimers)
- Since it decreases dimers, it is a short acting form (taken before meals)
Which drugs are first gen sulphonylureas?
- Acetohexamide
- Chlopropamide
- Tolbutamide
- Tolazamide
Which drugs are second gen sulphonylureas?
- Glipizide
- Gliclazide
- Glibenclamide
- Gliquidone
- Glyclopyramide
Which drug is a third gen sulphonylurea?
Glimepiride
What is the MOA of sulphonylureas?
- Binds to ATP-dependent K+ channels on cell membranes of pancreatic beta-cells, preventing K+ efflux
- Potential over cell becomes positive and opens voltage gated Ca2+ channels
- Increased Ca2+ causes increased fusion of insulin granulae w/ cell membrane, increasing secretion of insulin
Which 2 sulphonylureas are used most often?
Glibenclamide (glyburide) and glimepiride
What is a severe side effect of sulphonylureas?
Hypoglycemia
What is the MOA of meglitinides?
- Bind to ATP-dependent K+ channel on cell membrane of pancreatic beta cells; have weaker affinity and faster dissociation from SUR1 binding site than sulphonylureas
- Increased intracellular K+ causes positive potential to develop across membrane, depolarizing voltage-gated Ca2+ channels, increasing fusion of insulin
What is the main meglitinide?
Repaglinide
Which drug is a biguanide?
Metformin
What is a difference between metformin and sulphonylureas?
Metformin doesn’t affect ouput of insulin; sulphonylureas do
What is the MOA of metformin?
- Suppresses hepatic gluconeogenesis (generation of glucose from non-carbohydrates)
- Increases insulin sensitivity and fatty acid oxidation
- Decreases absorption of glucose in GI tract