A 4-week-old infant is evaluated for frequent episodes of hypoglycemia. The patient is found to have elevated insulin levels during periods of fasting. Several members of his family have a similar condition. Genetic testing reveals a mutation involving potassium channels expressed in pancreatic beta cells. The mutated channels have a higher sensitivity to the substance that normally modulates their activity, causing increased beta cell secretory activity. Which of the following substances normally binds to and regulates the ion channels that are responsible for this patient's hypoglycemia?

Question

A 4-week-old infant is evaluated for frequent episodes of hypoglycemia.  The patient is found to have elevated insulin levels during periods of fasting.  Several members of his family have a similar condition.  Genetic testing reveals a mutation involving potassium channels expressed in pancreatic beta cells.  The mutated channels have a higher sensitivity to the substance that normally modulates their activity, causing increased beta cell secretory activity.  Which of the following substances normally binds to and regulates the ion channels that are responsible for this patient's hypoglycemia?

Quizplus · Accepted Answer

11ec160b_3caf_fb58_9249_05b894495ce7_MD0001_00 Pancreatic beta cells secrete insulin in response to elevated glucose levels. Glucose enters beta cells via glucose transporter 2 (GLUT-2) and is metabolized via glycolysis and the citric acid cycle to generate ATP. ATP then binds to the regulatory subunit of the ATP-sensitive potassium channel (K_ATP channel). K_ATP channels are normally open at rest and maintain membrane polarization by allowing outward movement of potassium from the beta cells; however, on binding ATP, the K_ATP channels close. Increased intracellular ATP therefore leads to decreased potassium efflux and membrane depolarization. This triggers opening of voltage-dependent calcium channels, increased intracellular calcium levels, and subsequent insulin release. Mutations in the K_ATP channel causing increased affinity for ATP result in fewer open channels and depolarization at lower glucose concentrations. This causes continued secretion of insulin despite falling blood glucose levels, leading to congenital hypoglycemia. Conversely, mutations of the K_ATP channels that decrease ATP affinity prevent appropriate depolarization in response to rising glucose levels, causing a familial form of neonatal diabetes mellitus. These patients can be treated successfully with sulfonylureas, which bind to K_ATP channels and cause closure independent of ATP. (Choices B, D, and G) Citrate, fumarate, and malate are intermediate products in the citric acid cycle. During this process, energy is stored as NADH and FADH₂. ATP is then produced when NADH and FADH₂ enter oxidative phosphorylation. However, these intermediates do not directly interact with K_ATP channels. (Choices C, F, and H) Fructose-6-phosphate and pyruvate are products of the glycolytic pathway. Lactate is produced from pyruvate during anaerobic glycolysis. Glycolysis raises intracellular ATP levels, but these glycolytic intermediates do not act on K_ATP channels directly. (Choice E) Glucose induces insulin release from beta cells via ATP formation but does not interact with K_ATP channels directly. Educational objective: Oxidative metabolism of glucose in pancreatic beta cells generates ATP. ATP-induced closure of the ATP-sensitive potassium channels leads to membrane depolarization and subsequent insulin release. __________ References: Hyperinsulinemic hypoglycemia. (http://www.ncbi.nlm.nih.gov/pubmed/26210630)

A 4-Week-Old Infant Is Evaluated for Frequent Episodes of Hypoglycemia