The role of the KATP channel in glucose homeostasis in health and disease: more than meets the islet

Abstract

ATP-sensitive potassium (K(ATP)) channels are critical for the maintenance of glucose homeostasis. They are essential for glucose-stimulated insulin secretion from pancreatic beta-cells, contribute to the mechanisms by which hypoglycaemia stimulates glucagon release from pancreatic alpha-cells, and are involved in glucose uptake into skeletal muscle, glucose production and release from the liver, and feeding behaviour. Not surprisingly, loss- or gain-of-function mutations in K(ATP) channel genes have profound effects, giving rise to congenital hyperinsulinaemia and neonatal diabetes respectively. This symposium review focuses on our current understanding of the role of the K(ATP) channel in glucose homeostasis in health and disease.

Figure 1. K_ATP channels couple metabolism to electrical activity

A, K_ATP channels are open when metabolism is low, due to low ATP and elevated MgADP concentrations. Their activity generates a hyperpolarised membrane potential that prevents electrical activity. B, When metabolism increases, ATP rises and MgADP falls, closing K_ATP channels. This triggers membrane depolarization and electrical activity, which in turn stimulates cell functions such as contraction, transmitter release and hormone secretion.

Figure 2. Role of K_ATP channels in insulin secretory disorders

A, Loss-of-function mutations in Kir6.2 or SUR1 lead to permanent K_ATP channel closure independent of cell metabolism. Consequently, the β-cell membrane is always depolarised, producing continuous calcium influx and insulin secretion. B, Gain-of-function mutations in Kir6.2 or SUR1 prevent K_ATP channel closure when adenine nucleotide levels rise in response to metabolism. Consequently, the β-cell membrane remains hyperpolarised even when blood glucose levels are high, preventing insulin secretion.

Figure 3. ATP sensitivity correlates with disease severity

Correlation between disease severity and the extent of unblocked K_ATP current measured in inside-out patches at 3 mm MgATP for the wild-type channel (WT) and the indicated Kir6.2 (A) and SUR1 (B) mutations. Mean (±s.e.m.) is shown. Blue bars: neonatal diabetes alone. Green bars: diabetes with muscle hypotonia and developmental delay. Red bars: DEND syndrome (diabetes with muscle hypotonia, developmental delay and epilepsy).

Figure 4. Tolbutamide sensitivity correlates with clinical response

Correlation between the tolbutamide sensitivity of recombinant K_ATP channels carrying the indicated mutations and the ability of at least some patients with the same mutation to transfer to sulphonylurea therapy. Mean (±s.e.m.) percentage K_ATP current inhibition by 0.5 mm tolbutamide for the wild-type channel (WT) and the indicated Kir6.2 mutations, measured in the presence of 3 mm azide. Transparent grey bar indicates the threshold level for transfer (65–72% block). Blue bars: neonatal diabetes alone. Green bars: diabetes with muscle hypotonia and developmental delay. Red bars: DEND syndrome (diabetes with muscle hypotonia, developmental delay and epilepsy).