K_ATP channels and insulin secretion disorders

Abstract

ATP-sensitive potassium (K(ATP)) channels are inhibited by intracellular ATP and activated by ADP. Nutrient oxidation in beta-cells leads to a rise in [ATP]-to-[ADP] ratios, which in turn leads to reduced K(ATP) channel activity, depolarization, voltage-dependent Ca(2+) channel activation, Ca(2+) entry, and exocytosis. Persistent hyperinsulinemic hypoglycemia of infancy (HI) is a genetic disorder characterized by dysregulated insulin secretion and, although rare, causes severe mental retardation and epilepsy if left untreated. The last five or six years have seen rapid advance in understanding the molecular basis of K(ATP) channel activity and the molecular genetics of HI. In the majority of cases for which a genotype has been uncovered, causal HI mutations are found in one or the other of the two genes, SUR1 and Kir6.2, that encode the K(ATP) channel. This article will review studies that have defined the link between channel activity and defective insulin release and will consider implications for future understanding of the mechanisms of control of insulin secretion in normal and diseased states.

Hyperinsulinism in mice with heterozygous loss of KATP channels

“…Although only limited data are available, there are reports that some CHI patients, even those non-surgically treated, can spontaneously progress to diabetes [7,48,49]. In addition, we have shown that normally hypersecreting Kir6.2[AAA] transgenic mice on a Kir6.2 +/− background (which, although untested, presumably have a greater reduction in K ATP channel activity than each genotype alone), but not Kir6.2 +/− mice, can progress from a hypersecreting phenotype to an undersecreting diabetic phenotype, when challenged by a highfat diet [18].…”

“…Naively, reduced or absent K ATP channel activity is expected to result in constitutive membrane depolarisation, elevated [Ca 2+ ] i and hypersecretion of insulin. In humans, heterozygous loss-of-function mutations of beta cell K ATP subunits (SUR1, encoded by the gene ABCC8, and Kir6.2, encoded by the gene KCNJ11) underlie congenital hyperinsulinaemia (CHI) [1][2][3][4][5][6][7], a rare genetic disease characterised by relative hyperinsulinaemia, which generally presents with high insulin levels in parallel with low blood glucose [8].…”

SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator

“…Huopio et al 2002). Consequently, K ATP channels are always closed, independent of the metabolic state of the cell.…”

Hyperinsulinism induced by targeted suppression of beta cell K ATP channels

“…A rise in circulating insulin, in turn, leads to an increased peripheral glucose uptake and compensatory drop in blood glucose. Conversely, a falling intracellular [ATP]͞ [ADP] ratio during the fasting state is presumed to relieve inhibition of K ATP channels, resulting in membrane hyperpolarization and cessation of Ca 2ϩ -induced insulin release (3).…”

“…Profound neonatal diabetes due to permanent suppression of insulin release is observed in transgenic mice expressing overactive beta cell K ATP channels, dramatically illustrating the ability of K ATP channels to inhibit secretion (8). Conversely, the recent discovery of numerous mutations in pancreatic K ATP channel subunits (both the poreforming Kir6.2 and SUR1) in human patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) (3) establishes a causative link between suppressed K ATP activity, and the corollary metabolic disorder of hyperinsulinism (3). PHHIassociated K ATP mutations can be classified into two major categories: those that suppress channel activity without altering cell-surface expression, and biosynthetic or trafficking defects that reduce or abolish surface expression.…”