A 46-year-old woman comes to the office due to episodes of headaches, nausea, sweating, and feeling like she is going to pass out. The patient has had 3 such episodes in the past 2 weeks, with symptoms occurring when she skips a meal. During the most recent episode, her fingerstick glucose was 50 mg/dL. She was diagnosed with type 2 diabetes mellitus 3 years ago and was initially treated with metformin monotherapy; glyburide was added to her regimen 3 months ago due to inadequate glycemic control. The patient has no other medical conditions. Vital signs are within normal limits, and physical examination shows no abnormalities. Laboratory results show hemoglobin A1c is 6.7%. The medication most likely causing this patient's current symptoms works by targeting which of the following?

Question

A 46-year-old woman comes to the office due to episodes of headaches, nausea, sweating, and feeling like she is going to pass out.  The patient has had 3 such episodes in the past 2 weeks, with symptoms occurring when she skips a meal.  During the most recent episode, her fingerstick glucose was 50 mg/dL.  She was diagnosed with type 2 diabetes mellitus 3 years ago and was initially treated with metformin monotherapy; glyburide was added to her regimen 3 months ago due to inadequate glycemic control.  The patient has no other medical conditions.  Vital signs are within normal limits, and physical examination shows no abnormalities.  Laboratory results show hemoglobin A1c is 6.7%.  The medication most likely causing this patient's current symptoms works by targeting which of the following?

Quizplus · Accepted Answer

11ec160b_3bae_42d5_9249_51a38fc0e444_MD0001_00 This patient has symptomatic hypoglycemia following initiation of a sulfonylurea medication (ie, glyburide) for diabetes mellitus. Sulfonylureas inhibit the ATP-sensitive potassium channel on the pancreatic beta cell membrane, inducing depolarization and L-type calcium channel opening. The increased Ca²⁺ influx stimulates beta cell insulin release independent of blood glucose concentrations. Sulfonylureas continue to stimulate insulin secretion even when blood glucose levels are normal, which can lead to hypoglycemia. The longer-acting sulfonylureas (eg, glyburide) are more prone to causing hypoglycemia than shorter-acting drugs (eg, glipizide). Meglitinides (eg, repaglinide, nateglinide) are short-acting drugs that are functionally similar to sulfonylureas. (Choice A) Metformin inhibits the mitochondrial enzymes required for gluconeogenesis, leading to decreased hepatic glucose production and lower circulating glucose levels. It also increases peripheral glucose uptake and improves insulin sensitivity by activating AMP-activated protein kinase. Metformin does not increase endogenous insulin secretion and is therefore less likely to cause hypoglycemia than sulfonylureas. (Choice B) Thiazolidinediones (eg, pioglitazone) decrease insulin resistance by binding to peroxisome proliferator-activated receptor gamma, a transcriptional regulator of genes involved in glucose and lipid metabolism. (Choice D) Glucagon-like polypeptide-1 (GLP-1) is secreted by intestinal L cells in response to food intake, and regulates glucose by slowing gastric emptying and increasing insulin release. GLP-1 (and pharmacologic GLP-1 agonists such as exenatide) acts through cell surface receptors that are coupled with a G protein-adenylyl cyclase system. (Choice E) Alpha-glucosidase inhibitors (eg, acarbose, miglitol) decrease the activity of disaccharidases on the intestinal brush border. Because carbohydrates are absorbed as monosaccharides, the inhibition of disaccharide breakdown delays carbohydrate absorption. (Choice F) Insulin acts by binding to a cell surface receptor 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. Educational objective: Sulfonylureas inhibit the ATP-sensitive potassium channel on the pancreatic beta cell membrane, inducing depolarization and L-type calcium channel opening. The increased Ca²⁺ influx stimulates beta cell insulin release independent of blood glucose concentrations. Sulfonylureas can induce hypoglycemia because they stimulate insulin secretion even when blood glucose levels are normal. __________ References: The role of nateglinide and repaglinide, derivatives of meglitinide, in the treatment of type 2 diabetes mellitus. (http://www.ncbi.nlm.nih.gov/pubmed/24273582)

A 46-Year-Old Woman Comes to the Office Due to Episodes