Chapter 12 - The role of ATP-sensitive K+ channels in familial hyperinsulinism

Abstract

Familial hyperinsulinism, also known as persistent hyperinsulinemic hypoglycemia of infancy (HI or PHHI), is a very heterogeneous disease characterized by the coexistence of severe hypoglycemia and inappropriately elevated serum insulin levels. The most common form of this disease is caused by mutations in the two subunits that form β-cells ATP-sensitive K+ channels (KATP). The chapter illustrates the basic mechanism by which β-cell regulates insulin secretion. This channel regulates insulin secretion in pancreatic β-cells by linking glucose metabolism with the electrical activity of the cell. This chapter describes clinical features, histological findings, diagnostic criteria, genetics, chromosomal linkage, molecular etiology, incidence and mode of transmission, and therapy of HI. The HI is caused by mutations within sulfonylurea receptor gene (SUR1) in KATP channel. The biochemical diagnosis of HI is based on the finding of elevated insulin levels that increase glucose uptake in muscle and fat, and hepatic glycogen storage; and decrease lipolysis and hepatic glucose production. The net result is low plasma glucose levels, inappropriately low plasma levels of ketone bodies, high hepatic glucose response to glucagon stimulation, and very high glucose requirements needed to overcome the massive glucose uptake by muscle and fat. Drugs that inhibit insulin secretion are frequently used, either alone or in combination. Diazoxide, commonly used for K+ channel openers, binds to the sulfonylurea subunit of the β-cell KATP channel.