Nucleotide Sensitivity of Pancreatic ATP-Sensitive Potassium Channels and Type 2 Diabetes

Abstract

Type 2 diabetes is generally perceived as a polygenic disorder, with disease development being influenced by both hereditary and environmental factors. However, despite intensive investigations, little progress has been made in identifying the genes that impart susceptibility to the common late-onset forms of the disease. E23K, a common single nucleotide polymorphism in K IR 6.2, the pore-forming subunit of pancreatic ␤-cell ATP-sensitive K ؉ (K ATP ) channels, significantly enhances the spontaneous open probability of these channels, and thus modulates sensitivities toward inhibitory and activatory adenine nucleotides. Based on previous association studies, we present evidence that with an estimated attributable proportion of 15% in Caucasians, E23K in K IR 6.2 appears to be the most important genetic risk factor for type 2 diabetes yet identified. Diabetes 51 (Suppl. 3):S358 -S362, 2002 ROLE OF K ATP CHANNELS IN INSULIN SECRETIONPlasma insulin concentrations are normally determined by a feedback system that is controlled mainly by the level of plasma glucose (1). The overall activity of the pancreatic ␤-cell is set by the sensitivity of peripheral tissues to the action of insulin, with insulin-resistant subjects having increased plasma insulin levels and secretion rates. Insulin secretion is also elicited in response to amino and fatty acids; the extent of this response is modified by neural (e.g., autonomic tone) and hormonal (e.g., glucagon, glucagon-like peptide) factors. Glucose, however, is the dominating factor in controlling insulin secretion.Glucose enters the ␤-cell by facilitated diffusion, and its phosphorylation by glucokinase to glucose-6-phosphate determines the rate of glycolysis and the rate of pyruvate generation ( Fig. 1) (2,3). Thus the rate of glycolysis will increase with blood glucose. In ␤-cells, pyruvate is the main product of glycolysis (4) and, compared to other cell types, an unusually high proportion of glucose-derived pyruvate enters the mitochondrial tricarboxylic acid (TCA) cycle (2).Subsequent oxidative metabolism generates the trigger for insulin secretion (5). Electron transfer from the TCA cycle to the respiratory chain by NADH and reduced flavin adenine dinucleotide (FADH 2 ) initiates the production of ATP, which is delivered to the cytosol. Here the rise of the ATP-to-ADP ratio causes a reduction in plasma membrane K ϩ conductance, resulting in depolarization of the membrane (6). Hence voltage-sensitive Ca 2ϩ channels are opened that are similar to those expressed in other excitable cells. This is the critical step by which glucose stimulates insulin secretion, as the increase in cytosolic Ca 2ϩ is the main trigger for exocytosis (6,7). The decrease in K ϩ conductance results from closure of the ATP-sensitive potassium (K ATP ) channels (6). These channels dominate the resting membrane potential in ␤-cells and act as transducers of glucose-induced metabolic changes into electrical activity. Their central role in the stimulation of insulin secretion can easily be demonstrat...

Kir6.2 Polymorphisms Sensitize β-Cell ATP-Sensitive Potassium Channels to Activation by Acyl CoAs

“…1C). These results, together with the observation that sulfonylurea sensitivity is unaffected in the presence of the E23K polymorphism (23), suggest that the principal mechanism by which the E23K/I337V polymorphism alters LC-CoA sensitivity lies primarily within the Kir6.2 subunit.…”

“…The E23K and I337V mutations were introduced into the Kir6.2 gene using the protocol outlined in the QuikChange site-directed mutagenesis kit (Stratagene) and the generation of the mutations confirmed through sequence analysis. The ⌬C26Kir6.2 truncation mutant was constructed as previously described (23). Warner Instrument, Hamden, CT) to yield pipettes with a resistance of 2-6 M⍀.…”

Relationship between E23K (an established type II diabetes-susceptibility variant within KCNJ11), polycystic ovary syndrome and androgen levels

“…The E23K variant is established as one of the few polymorphisms with a convincingly replicated impact on T2D susceptibility. In vitro 19 and in vivo 30 functional studies indicate that the K allele at E23K is associated with an increased open probability of the beta-cell K ATP channel and reduced insulin secretion. 19 In this respect, the strong clinical, phenotypic and epidemiological overlap between T2D and PCOS promotes a powerful argument for overlapping genetic influences.…”

Diabetes and Insulin Secretion

“…Although results from initial studies are conflicting (45,46), large-scale association studies and meta-analyses have now identified the E23K polymorphism in KCNJ11 as a slight, but significant, risk factor in the complex development of type 2 diabetes (42,44,(47)(48)(49)(50). However, given the high allelic frequency of E23K in the general population (frequency of heterozygous EK genotype ϭ 47%; homozygous KK genotype ϭ 12%), the polymorphism is likely to represent a large population-attributable risk (41,48,51,52 (27,38,39,51,53) (see below). At the cellular level, an important question is: Just how much change in ATP sensitivity is necessary to cause significant impairment of insulin secretion?…”

“…Transgenic F1 mice from four of five founder lines expressing the truncated channels were severely hyperglycemic, and hypoinsulinemic, and died as neonates by day 5, most likely from acute ketoacidosis ( Fig. 2A) (51)(52)(53)(54). E23K is in linkage disequilibrium with another Kir6.2 polymorphism, I337V, which itself has no reported effect on channel activity (51,53).…”