Diabetes Treatment: Amylin, GLP-1, and Sulfonylureas PDF

## II. Synthetic Amylin Analog * Amylin is a hormone that is cosecreted with insulin from beta cells following food intake. * The effect of amylin in the **fed state** is: * Increased amylin. * Increased insulin. * Decreased glucagon * Sends signal from the bet...

## II. Synthetic Amylin Analog * Amylin is a hormone that is cosecreted with insulin from beta cells following food intake. * The effect of amylin in the **fed state** is: * Increased amylin. * Increased insulin. * Decreased glucagon * Sends signal from the beta cell to the liver. * Decreases glucose production in the liver. * Decreased glucose from the liver. * It delays gastric emptying, decreases postprandial glucagon secretion, and improves satiety. * **Pramlintide** is a synthetic amylin analog that is indicated as an adjunct to mealtime insulin therapy in patients with type 1 and type 2 diabetes. ## III. Glucagon-like Peptide Receptor Agonists * Oral intake of glucose results in a higher secretion of insulin than occurs when an equal load of glucose is given intravenously. * This effect is referred to as the "incretin effect" and is markedly reduced in type 2 diabetes. * The incretin effect occurs because the gut releases incretin hormones, notably glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), in response to a meal. * Incretin hormones are responsible for 60% to 70% of postprandial insulin secretion. ## IV. Oral Agents * Oral agents are useful in the treatment of patients who have type 2 diabetes that is not controlled with diet. * Patients with long-standing disease may require a combination of oral agents with or without insulin to control hyperglycemia. ## 1. Sulfonylureas * These agents are classified as insulin secretagogues, because they promote insulin release from the beta cells of the pancreas. * The sulfonylureas most used in clinical practice are the second-generation drugs: glyburide, glipizide, and glimepiride. ### Mechanism of action * These agents stimulate insulin release from the beta cells of the pancreas. In addition, sulfonylureas may reduce hepatic glucose production and increase peripheral insulin sensitivity. ### Pharmacokinetics * Given orally, these drugs bind to serum proteins, are metabolized by the liver, and are excreted in the urine and feces. * The duration of action ranges from 12 to 24 hours. ### Adverse effects * Adverse effects of the sulfonylureas include hypoglycemia, hyperinsulinemia, and weight gain. * They should be used with caution in hepatic or renal insufficiency, since accumulation of sulfonylureas may cause hypoglycemia. * Renal impairment is a particular problem for glyburide, as it may increase the duration of action and increase the risk of hypoglycemia significantly. * Glipizide or glimepiride are safer options in renal dysfunction and in elderly patients. ## Glucagon-like Peptide Receptor Agonists * Albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide are injectable GLP-1 receptor agonists used for the treatment of type 2 diabetes. * Two premixed preparations of long-acting insulins and GLP-1 receptor agonists are available: For example: * Insulin glargine plus lixisenatide and * Insulin degludec plus liraglutide. * Use of these combinations may decrease daily insulin requirements and the number of daily injections. ### Mechanism of action * These agents are analogs of GLP-1 that exert their activity by: * Improving glucose-dependent insulin secretion. * Slowing gastric emptying time. * Reducing food intake by enhancing satiety (a feeling of fullness). * Decreasing postprandial glucagon secretion. * Consequently, postprandial hyperglycemia is reduced, HbA1c levels decline, and weight loss may occur. ### Pharmacokinetics * GLP-1 receptor agonists are administered subcutaneously. * Albiglutide, dulaglutide, and semaglutide are dosed once weekly. * Liraglutide is available as a once-daily injection. * Lixisenatide is a short-acting GLP-1 receptor agonist that is dosed once daily. * Exenatide is available as both a short-acting (dosed twice daily) and extended-release preparation (dosed once weekly). Exenatide should be avoided in patients with severe renal impairment. ### Adverse effects * The main adverse effects of the incretin mimetics consist of nausea, vomiting, diarrhea, and constipation. * GLP-1 receptor agonists have been associated with pancreatitis and should be avoided in patients with chronic pancreatitis. Longer-acting agents have been associated with thyroid C-cell tumors in rodents. * It is unknown if GLP-1 receptor agonists cause these tumors or thyroid carcinoma in humans, although they are contraindicated in patients with a history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2.