Diabetes and Insulin Secretion

Abstract

The ATP-sensitive K+ channel (KATP channel) senses metabolic changes in the pancreatic β-cell, thereby coupling metabolism to electrical activity and ultimately to insulin secretion. When KATP channels open, β-cells hyperpolarize and insulin secretion is suppressed. The prediction that KATP channel “overactivity” should cause a diabetic state due to undersecretion of insulin has been dramatically borne out by recent genetic studies implicating “activating” mutations in the Kir6.2 subunit of KATP channel as causal in human diabetes. This article summarizes the emerging picture of KATP channel as a major cause of neonatal diabetes and of a polymorphism in KATP channel (E23K) as a type 2 diabetes risk factor. The degree of KATP channel “overactivity” correlates with the severity of the diabetic phenotype. At one end of the spectrum, polymorphisms that result in a modest increase in KATP channel activity represent a risk factor for development of late-onset diabetes. At the other end, severe “activating” mutations underlie syndromic neonatal diabetes, with multiple organ involvement and complete failure of glucose-dependent insulin secretion, reflecting KATP channel “overactivity” in both pancreatic and extrapancreatic tissues.