Langerhansel & Gretel Insulin, Sulfonylureas, Meglitinides, GLP-1 Agonists, DPP-4 Inhibitors

2.1 – “Langerhan “Langerhansel sel & Grete Gretel”: l”: Insul Insulin, in, sulfo sulfonylureas, nylureas, meglitinides, GLP -1 agonists, DPP-4 inh inhibitors ibitors • Insulin is a major storage and anabolic hormone of the body, and “invites” fat & carbs into cells (“welcome inside” mat for creepy high carb house). Produced pancreatic β-cells in the islets of Langerhans. Release is stimulated by glucose (most potent), or direct sympathetic activation of β-cells (holding candy; β bugler). o 1) When glucose enters into circulation from GI tract, resultant hyperglycemia increases intracellular ATP levels. ↑ATP stimulates closure of ATP-gated K+ channels (closed garden gate). o 2) Closed K channels → ↓K efflux and increased intracellular K concentration → membrane depolarization (elevated bananas in garden). Membrane depolarization leads to opening of voltage gated calcium channels → Calcium influx, which stimulates insulin release from secretory granules (Gretel riding a calcium ice cream flower to carry the candy out of the cell). o 3) Insulin binds receptor tyrosine kinase insulin receptors (tyrosine tire swing). Downstream has a number of effects: ▪ Increases GLUT4 glucose transporter expression in the cell membrane (#4 door) ▪ Increase hepatic glycogenesis (candies in liver-shaped container) ▪ Increased glycogen storage & protein synthesis in skeletal muscles (ham with glycogen glaze) ▪ ↑storage of triglyceride in adipocytes (jar of donuts) ▪ ↓serum K+ by enhancing Na-K-ATPase in skeletal muscle (witch holding eaten banana candy). • Prior to release from β cells, C-peptide is cleaved from proinsulin in the secretory granule; endogenous insulin release is accompanied by equimolar release of C-peptide (Candy wrappers on the ground). • Note that insulin is cleared by both kidneys and liver. Injectable ins insulin ulin prepara preparation tion & analo analogs gs • Used in Type 1 Diabetes mellitus (T1DM). May be used in the case of severe insulin resistance or severe pancreatic insufficiency in late stages of T2DM. • Long acting for basal control, short acting for control of post-prandial glucose spike. Intermediate acting formulations were the earliest produced, less used now. (note the shape of the house mimics the graph of insulin onset & duration) • Rapid acting, short duration o Include insulin glulisine, insulin aspart, & insulin lispro formulations (Girls & lads sign on tower). “Do not LAG” o Amino acid modifications → slower onset o Rapid onset & short duration of action (onset of 15 minutes, peak 45-75 minutes) (high peaked tower). Used for postprandial spike; mimics endogenous postprandial insulin (Birds pecking away). • Intermediate acting o Regular & neutral protamine Hagedorn (NPH) (Rest Now sign) o Delayed onset & intermediate duration of acting d/t formation of dimers & hexamers, which take time to break down, similar to endogenous insulin (low-peaked gable). NPH is somewhat slower onset. o Regular insulin can be administered IV (ivy). ▪ Particularly useful in DKA (diabetic key). Administer in conjunction with glucose & K. ▪ Monitor potassium, as insulin in the setting of DKA can precipitate hypokalemia. ▪ Should never use subcutaneous insulin in DKA. o IV regular insulin also useful in hyperkalemia. o NPH is less predictable with delayed onset within 2 hours. Not used as much clinically nowadays. • Long acting o Insulin detemir & glargine (“Don’t Go”) o Long duration with steady basal level of insulin (flat roof). Glargine is longest acting, 24h activity with no distinct peak • Adverse effects o Hypoglycemia risk with tachycardia palpitations, sweating, nausea, hunger (ANS hyperactivity, both SNS &PNS). May progress to convulsions & coma if untreated. Falling candies = falling glucose levels ▪ Treat with IM glucagon (glucagon when glucose is gone), or glucose by PO or IM Other agent agentss All of the following function of endogenous β cells or external insulin sensitivity. Note that is only works with T2DM. Will see increase C-peptide levels with increases endogenous production. • Sulfonylureas (swan/Mother goose) o Upregulate endogenous insulin release. Binds ATP dependent K+ channel in β cells → release of endogenous insulin by the mechanisms described above (geese in intracellular garden). o First generation: ▪ Include tolbutamide, chlorpropamide, others (mother Goose in maid outfit = -amide) ▪ Longer acting, rarely used nowadays ▪ Some, including chlorpropamide, may cause disulfiram-like reaction when combined with alcohol (“Do not drink” sign) o 2nd generation: ▪ Include glyburide, glipizide, glimepiride (gosling riding on mother’s back for -ride) ▪ Smaller dosing, longer duration of action (goslings are smaller) • Glipizide has shortest duration of action (Z’s in water). So has a lower risk of hypoglycemia o Adverse effects ▪ Is a sulfa drug (sulfa eggs). ▪ Risk of hypoglycemia (falling candies). Increased risk with renal failure. ▪ Weight gain (lady under tree) • Meglitinides o Include repaglinide, nateglinide (Gliding goose for -glinide) o Similar MOA to sulfonylureas. Bind ATP dependent K+ channel in β cells (geese in intracellular garden) o Non-sulfa drugs so can be used in allergy to sulfa drugs. o Adverse effects ▪ Risk of hypoglycemia (falling candies). Increased risk with renal failure. ▪ Weight gain (lady under tree) • GLP analogs o endogenous glucagon-like peptide (GLP) (old lady eliciting gulp from tuba player). GLP is secreted from intestinal L-cells in response to food intake. Acts in opposition to glucagon; binds GLP-1 receptor ▪ Induces satiety ▪ ↓gastric emptying (full stomach shaped water container) ▪ ↓glucagon release (empty glucagon packets) ▪ ↑insulin release from β cells ▪ Combine to decrease serum glucose levels o GLP effects are glucose dependent, so agonists do not cause hypoglycemia (candies not falling from tree) o GLP-1 Agonists ▪ Include exenatide, liraglutide (TIDE detergent) ▪ GLP-1 agonists function as exogenous agonists of the GLP-1 receptor ▪ May increase risk of pancreatitis (pancreas sponge). o DPP-4 inhibitors (gliptins) (dripping laundry) ▪ Include sitagliptin, saxagliptin, linagliptin (clipped in laundry for -gliptin) ▪ Dipeptidyl peptidase-4 (DPP-4) breaks down GLP. Inhibition increases endogenous GLP availability (witch gulping) ▪ Can cause increased risk of nasopharyngitis & URIs (witch with clothespin on her nose)