KATP Channels and the Metabolic Regulation of Insulin Secretion in Health and Disease: The 2022 Banting Medal for Scientific Achievement Award Lecture

Abstract

Diabetes is characterized by elevation of plasma glucose due to an insufficiency of the hormone insulin and is associated with both inadequate insulin secretion and impaired insulin action. The Banting Medal for Scientific Achievement Commemorates the work of Sir Frederick Banting, a member of the team that first used insulin to treat a patient with diabetes almost exactly one hundred years ago on 11 January 1922. This article is based on my Banting lecture of 2022 and concerns the mechanism of glucose-stimulated insulin secretion from pancreatic β-cells, with an emphasis on the metabolic regulation of the KATP channel. This channel plays a central role in insulin release. Its closure in response to metabolically generated changes in the intracellular concentrations of ATP and MgADP stimulates β-cell electrical activity and insulin granule exocytosis. Activating mutations in KATP channel genes that impair the ability of the channel to respond to ATP give rise to neonatal diabetes. Impaired KATP channel regulation may also play a role in type 2 diabetes. I conjecture that KATP channel closure in response to glucose is reduced because of impaired glucose metabolism, which fails to generate a sufficient increase in ATP. Consequently, glucose-stimulated β-cell electrical activity is less. As ATP is also required for insulin granule exocytosis, both reduced exocytosis and less β-cell electrical activity may contribute to the reduction in insulin secretion. I emphasize that what follows is not a definitive review of the topic but a personal account of the contribution of my team to the field that is based on my Banting lecture.

Unique features of β‐cell metabolism are lost in type 2 diabetes

“…48 The complete oxidation of glucose is consequently translated into an increase in cytosolic ATP/ADP ratio, which serves to inhibit K ATP channel and consequently, block the polarizing efflux of K + . [52][53][54] This leads to a depolarization of the plasma membrane, triggering the opening of voltage-gated calcium channels and influx of the cation. This rise in intracellular free calcium activates the exocytotic machinery, leading to the initial or triggering phase of insulin secretion.…”