Diabetes and insulin secretion -: The ATP-sensitive K+ channel (KATP) connection

The ATP-sensitive K+ channel (K-ATP channel) senses metabolic changes in the pancreatic P-cell, thereby coupling metabolism to electrical activity and ultimately to insulin secretion. When K-ATP channels open, P-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 KAT, channel as a major cause of neonatal diabetes and of a polymorphism in K-ATP 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 K-ATP 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 K-ATP channel overactivity in both pancreatic and extrapancreatic tissues.