Overview Goals of diabetes treatment lower serum glucose to physiologic range keep insulin levels in physiologic range eliminate insulin resistance best initial step in management: weight loss, contractile-based exercise weight loss is more important for insulin sensitivity than is a low-carb diet Modalities of diabetes treatment type I DM insulin low-sugar diet type II DM exercise diet insulin 6 classes of drugs shown below Diabetic Drugs Class Example ↑ Insulin secretion ↑ Insulin sensitivity ↓ Glucose production ↓ Glucose absorption Weight Hypoglycemia Insulin Insulin ↑ ++ Sulfonylureas Glyburide ++ + + ↑ ++ Meglitinides Nateglinide ++ + + ↑ ++ Biguanides Metformin + ++ None Glitazones (thiazolidinediones) Pioglitazone ++ +/- ↑↓ + α-glucosidase inhibitors Acarbose ++ None GLP-1 mimetics (incretin mimetics) Exenatide ++ + ↓ + Amylin analog Pramlintide + + + Insulin Insulin is only given parenterally (subcutaneous or IV) Various preparations have different durations of action Other preparations include aspart (rapid), detemir (long) Preparation Onset (hrs) Peak (hrs) Duration (hrs) Lispro (rapid-acting) 15 min 0.5-1.5 3-4 Regular (short-acting) 0.5-1 2-4 5-7 NPH (intermediate) 1-2 6-12 18-24 Glargine (long-acting) 1 None >24 Mechanism bind transmembrane insulin receptor activate tyrosine kinase phosphorylate specific substrates in each tissue type liver ↑ glycogenesis store glucose as glycogen muscle ↑ glycogen and protein synthesis ↑ K+ uptake fat increase triglyceride storage Clinical use type I DM type II DM life-threatening hyperkalemia increases intracellular K+ stress-induced hyperglycemia Toxicity hypoglycemia hypersensitivity reaction (very rare) Insulin Synthesis first generated as preproinsulin with an A chain and B chain connected by a C peptide. c-peptide is cleaved from proinsulin after packaging into vesicles leaving behind the A and B chains Sulfonylureas Drugs first generation tolbutamide chlorpropamide second generation glyburide glimepiride glipizide Mechanism glucose normally triggers insulin release from pancreatic β cells by increasing intracellular ATP → closes K+ channels → depolarization → ↑ Ca2+ influx → insulin release sulfonylureas mimic action of glucose by closing K+ channels in pancreatic β cells → depolarization → ↑ Ca2+ influx → insulin release continued use results in ↓ glucagon release ↑ insulin sensitivity in muscle and liver Clinical use type II DM stimulates release of endogenous insulin cannot be used in type I DM due to complete lack of islet function Toxicity first generation disulfiram-like effects especially chlorpropamide second generation hypoglycemia weight gain Megltinides Drugs nateglinide repaglinide Mechanism binds to K+ channels on β-cells → postprandial insulin release different site than sulfonylureas Clinical use type 2 diabetes mellitus may be used as monotherapy, or in combination with metformin Toxicity ↑ risk of hypoglycemia at even greater risk in those with renal failure weight gain Biguanides Drugs metformin Mechanism ↓ hepatic gluconeogenesis exact mechanism unknown appears to inhibit complex 1 of respiratory chain may also ↑ insulin sensitivity ↑ glycolysis ↓ serum glucose levels ↓ postprandial glucose levels Clinical use first-line therapy in type II DM Toxicity no hypoglycemia no weight gain lactic acidosis is most serious side effect contraindicated in renal failure Glitazones (thiazolidinediones) Thiazolidinediones, also known as the "-glitazones" Drugs pioglitazone rosiglitazone Mechanism bind to nuclear receptors involved in transcription of genes mediating insulin sensitivity peroxisome proliferator-activating receptors (PPARs) ↑ insulin sensitivity in peripheral tissue ↓ gluconeogenesis ↑ insulin receptor numbers ↓ triglycerides Clinical use type II DM as monotherapy or in combination with other agents contraindicated in CHF associated with increased risk of MI (in particular rosiglitazone) Toxicity weight gain edema peripheral edema pulmonary edema hepatotoxicity CV toxicity less risk of hypoglycemia vs. sulfonylureas α-glucosidase inhibitors Drugs acarbose miglitol Mechanism inhibit α-glucosidases in intestinal brush border delayed sugar hydrolysis delayed glucose absorption ↓ postprandial hyperglycemia ↓ insulin demand Clinical use type II DM as monotherapy or in combination with other agents Toxicity no hypoglycemia GI upset Amylin mimetics Drugs pramlintide Mechanism synthetic analogue of human amylin that acts in conjunction with insulin ↓ release of glucagon delays gastric emptying Clinical use type I and II DM Toxicity hypoglycemia if given with insulin nausea diarrhea GLP-1 analogs Drugs exenatide Mechanism GLP-1 is an incretin released from the small intestine that aids glucose-dependent insulin secretion basis for drug mechanism is the observation that more insulin secreted with oral glucose load compared to IV exenatide is a GLP-1 agonist ↑ insulin ↓ glucagon release the class of dipeptidyl peptidase inhibitors ↓ degradation of endogenous GLP-1 e.g.) sitagliptin, -gliptins Clinical use type II DM Toxicity nausea, vomiting pancreatitis hypoglycemia if given with sulfonylureas DPP-4 inhibitors Drugs sitagliptin linagliptin Mechanism prevents the peripheral degradation of GLP-1, thereby potentiating glucose-dependent insulin release Clinical use type II DM Toxicity arthralgias heart failure exacerbation SGLT-2 Inhibitors Drugs canagliflozin empagliflozin Mechanism glucose is reabsorbed in the proximal tubule of the nephron by the sodium-glucose cotransporter 2 (SGLT2) SGLT2-inhibitors lower serum glucose by increasing urinary glucose excretion the mechanism of action is independent of insulin secretion or action Clinical use type II DM Toxicity dehydration urinary and genital infections