Diazoxide‐sensitivity of the adenosine 5′‐triphosphate‐dependent K<sup>+</sup> channel in mouse pancreatic β‐cells

Schwanstecher, Christina; Dickel, Corinna; Ebers, Imke; Lins, Sabine; Zünkler, Bernd J.; Panten, U.

doi:10.1111/j.1476-5381.1992.tb14467.x

Cited by 32 publications

(45 citation statements)

References 33 publications

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“…It has also been suggested that GTP is partially degraded into GDP by membrane patches (41). Degradation of ATP into ADP by membrane patches has been demonstrated directly (43,44). Finally, and most importantly, GDP, like ADP, opens K ϩ -ATP channels in the presence of ATP, whereas GTP is ineffective under these conditions (40,42,45).…”

Section: Discussionmentioning

confidence: 96%

Concentration Dependence and Time Course of the Effects of Glucose on Adenine and Guanine Nucleotides in Mouse Pancreatic Islets

Detimary¹,

Berghe

Henquin³

1996

Journal of Biological Chemistry

129

110

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Changes in the ATP:ADP ratio in pancreatic B cells may participate in the regulation of insulin secretion by glucose. Here, we have investigated the possible role of guanine nucleotides. Mouse islets were incubated in a control medium (when K ؉ -ATP channels are the major site of regulation) or in a high K ؉ medium (when glucose modulates the effectiveness of cytosolic Ca 2؉ on exocytosis). Glucose induced a concentration-dependent (0 -20 mM) increase in GTP and a decrease in GDP in both types of medium, thus causing a progressive rise of the GTP:GDP ratio. ATP and ADP levels were 4 -5-fold higher but varied in a similar way as those of guanine nucleotides. Insulin secretion was inversely correlated with ADP and GDP levels and positively correlated with the ATP:ADP and GTP:GDP ratios between 6 and 20 mM glucose in control medium and between 0 and 20 mM glucose in high K ؉ medium. The increases in the GTP: GDP and ATP:ADP ratios induced by a rise of glucose were faster than the decreases induced by a fall in glucose, but the changes of both ratios were again parallel. In conclusion, glucose causes large, concentration-dependent changes in guanine as well as in adenine nucleotides in islet cells. This raises the possibility that both participate in the regulation of nutrient-induced insulin secretion.The regulation of pancreatic B cell function differs from that of other secretory cells in that the control of insulin secretion does not depend on the binding of the major physiological stimulator, glucose, to a receptor, but on its metabolism within B cells (reviewed in Refs. 1-5). It is now widely accepted that this metabolism generates several signals that close ATP-sensitive K ϩ channels (K ϩ -ATP channels) 1 in the plasma membrane. This closure (hereafter referred to as the "primary mechanism" of control) leads to membrane depolarization with subsequent opening of voltage-dependent Ca 2ϩ channels, Ca 2ϩ influx, rise in cytoplasmic free Ca 2ϩ concentration ([Ca 2ϩ ] i ), and eventual triggering of insulin secretion (4 -9). A "second mechanism" of control by glucose exists, which also depends on changes in metabolism (10 -12). It does not involve a further change in [Ca 2ϩ ] i but an increase in the effectiveness of Ca 2ϩ on its intracellular targets (12). Despite numerous studies, the nature of the signals that link the acceleration of metabolism to the closure of K ϩ -ATP channels and to the increase in Ca 2ϩ action has only partially been elucidated. Purine nucleotides clearly stand out as potential candidates.The popular hypothesis that variations in the cytosolic concentrations or ratio of adenine nucleotides are involved in the primary mechanism of control by glucose rests primarily on the fact that K ϩ channels, which control the B cell membrane potential, are regulated by intracellular ATP and ADP (6,8,9,13). Although this hypothesis has long been disputed (reviewed in Ref. 14), our demonstration of a correlation between insulin release and the ATP:ADP ratio in islets incubated in the presence of...

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Section: Discussionmentioning

confidence: 96%

Concentration Dependence and Time Course of the Effects of Glucose on Adenine and Guanine Nucleotides in Mouse Pancreatic Islets

Detimary¹,

Berghe

Henquin³

1996

Journal of Biological Chemistry

129

110

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“…Stimulation of insulin secretion requires reduction of the P O of pancreatic ␤-cell K ATP channels to values Ͻ0.02 (12). Both increased spontaneous P O values (Fig.…”

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confidence: 95%

KIR6.2 Polymorphism Predisposes to Type 2 Diabetes by Inducing Overactivity of Pancreatic β-Cell ATP-Sensitive K+ Channels

2002

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E23K, a common single nucleotide polymorphism in K IR 6.2, the pore-forming subunit of pancreatic ␤-cell ATP-sensitive K ؉ channels, significantly enhanced open probability of these channels, thus reducing their sensitivity toward inhibitory ATP 4؊ and increasing the threshold concentration for insulin release. Previous association studies and high allelic frequency suggest this effect to critically inhibit secretion and play a major role in pathogenesis of common type 2 diabetes. Based on evidence for functional relevance of E23K in both the heterozygous (E/K; with E in position 23 of K IR 6.2 in one allele and K in the other) and homozygous (K/K; with K in position 23 of K IR 6.2 in both alleles) genotype, we propose a model in which enhanced susceptibility to type 2 diabetes is associated with evolutionary advantage of the E/K state. Diabetes 51:875-879, 2002 T ype 2 diabetes is generally perceived as a polygenic disorder, with disease development being influenced by both hereditary and environmental factors (1). Genes encoding for key components of insulin secretion and glucose metabolism pathways have been widely considered as targets for defects in type 2 diabetes. 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 (2).In pancreatic ␤-cells, ATP-sensitive K ϩ (K ATP ) channels critically control insulin secretion by coupling metabolism to electrical activity (3). Recent advances resulted in cloning of these channels and elucidation of their subunit composition (4). The ␤-cell channels are assembled, with tetradimeric stoichiometry, from two structurally distinct subunits: an inwardly rectifying K ϩ channel subunit (K IR 6.2), forming the pore, and the regulatory sulfonylurea receptor subunit-1 (SUR1). While hypoglycemic sulfonylureas (e.g., glibenclamide) exert their effects on channel activity by interaction with SUR1, there is strong evidence that the receptor site for inhibitory ATP 4Ϫ is formed by K IR 6.2.Three common missense single nucleotide polymorphisms (SNPs) have been observed in K IR 6.2 (E23K, L270V, and I337V) (5-9), and their potential impact in type 2 diabetes led us to analyze their functional relevance. Whereas L270V and I337V were without effect on the properties of reconstituted human SUR1/K IR 6.2 channels (including expression rate, single channel conductance, spontaneous open probability [P O ], and nucleotide and drug sensitivities [results not shown]), E23K markedly affected channel gating, significantly reducing the time spent in long interburst closed states (17 Ϯ 3% for SUR1/ the mutant isoform of K IR 6.2 with K instead of E in position 23 [K IR 6.2 E23K ] vs. 54 Ϯ 6% for wild-type channels, n ϭ 10 each, P Ͻ 0.001) (Fig. 1A and B), thus producing a 1.6-fold increase of P O (P O ϭ 0.66 Ϯ 0.05 for SUR1/ K IR 6.2 E23K vs. 0.41 Ϯ 0.04 for wild-type channels, n ϭ 10 each, P Ͻ 0.001). The increase of P O was confirmed by noise analysis (patches with 100 -500 chann...

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“…Consistent with the idea that nucleotide-induced channel inhibition results from interaction with the interburst closed states (39,40), E23K decreased sensitivity toward inhibitory ATP 4Ϫ in the models for the heterozygous and homozygous genotypes (K/K, with K in position 23 of K IR 6.2 in both alleles). Stimulation of insulin secretion requires reduction of the P O of pancreatic ␤-cell K ATP channels to values Ͻ0.02 (25,41). Both the increased spontaneous P O values and the reduced ATP sensitivity contributed to a rightward shift of the corresponding ATP concentration (IC R2 value) through E23K (38).…”

Section: Effect Of E23k a Common Polymorphism In K Ir 62 On Nucleomentioning

confidence: 99%

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

Schwanstecher

2002

Diabetes

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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...

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Diazoxide‐sensitivity of the adenosine 5′‐triphosphate‐dependent K⁺ channel in mouse pancreatic β‐cells

Cited by 32 publications

References 33 publications

Concentration Dependence and Time Course of the Effects of Glucose on Adenine and Guanine Nucleotides in Mouse Pancreatic Islets

Concentration Dependence and Time Course of the Effects of Glucose on Adenine and Guanine Nucleotides in Mouse Pancreatic Islets

KIR6.2 Polymorphism Predisposes to Type 2 Diabetes by Inducing Overactivity of Pancreatic β-Cell ATP-Sensitive K+ Channels

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

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Diazoxide‐sensitivity of the adenosine 5′‐triphosphate‐dependent K+ channel in mouse pancreatic β‐cells

Cited by 32 publications

References 33 publications

Concentration Dependence and Time Course of the Effects of Glucose on Adenine and Guanine Nucleotides in Mouse Pancreatic Islets

Concentration Dependence and Time Course of the Effects of Glucose on Adenine and Guanine Nucleotides in Mouse Pancreatic Islets

KIR6.2 Polymorphism Predisposes to Type 2 Diabetes by Inducing Overactivity of Pancreatic β-Cell ATP-Sensitive K+ Channels

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

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Diazoxide‐sensitivity of the adenosine 5′‐triphosphate‐dependent K⁺ channel in mouse pancreatic β‐cells