Role of K _ATP Channels in Glucose-Regulated Glucagon Secretion and Impaired Counterregulation in Type 2 Diabetes

Summary

Glucagon, secreted by pancreatic islet α cells, is the principal hyperglycemic hormone. In diabetes, glucagon secretion is not suppressed at high glucose, exacerbating the consequences of insufficient insulin secretion, and is inadequate at low glucose, potentially leading to fatal hypoglycemia. The causal mechanisms remain unknown. Here we show that α cell K _ATP-channel activity is very low under hypoglycemic conditions and that hyperglycemia, via elevated intracellular ATP/ADP, leads to complete inhibition. This produces membrane depolarization and voltage-dependent inactivation of the Na ⁺ channels involved in action potential firing that, via reduced action potential height and Ca ²⁺ entry, suppresses glucagon secretion. Maneuvers that increase K _ATP channel activity, such as metabolic inhibition, mimic the glucagon secretory defects associated with diabetes. Low concentrations of the K _ATP channel blocker tolbutamide partially restore glucose-regulated glucagon secretion in islets from type 2 diabetic organ donors. These data suggest that impaired metabolic control of the K _ATP channels underlies the defective glucose regulation of glucagon secretion in type 2 diabetes.

Graphical Abstract

Highlights

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  K _ATP channel closure stimulates insulin secretion but inhibits glucagon release

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  α cell depolarization reduces voltage-gated Ca ²⁺ entry and glucagon release

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  An activating K _ATP channel mutation impairs glucagon release in mice

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  K _ATP channel closure corrects glucagon secretion defect in type 2 diabetic islets