Kir6.2 polymorphisms sensitize β-cell ATP-sensitive potassium channels to activation by acyl CoAs:: a possible cellular mechanism for increased susceptibility to type 2 diabetes?
Kir6.2 polymorphisms sensitize β-cell ATP-sensitive potassium channels to activation by acyl CoAs:: a possible cellular mechanism for increased susceptibility to type 2 diabetes?
复制标题
DOI：
10.2337/diabetes.52.10.2630
复制
发表时间：
2003-10-01
期刊：
影响因子：
7.7
通讯作者：
Light, PE
中科院分区：
文献类型：
--
作者：
Riedel, MJ;Boora, P;Light, PE
常见的E23 K和I337 V Kir6.2多态性在ATP敏感性钾（K-ATP）通道中更常见于高加索2型糖尿病人群。然而，导致2型糖尿病发病机制的潜在细胞机制仍不清楚。在肥胖和2型糖尿病受试者中观察到的血浆游离脂肪酸的慢性升高导致胰腺P细胞中长链酰基CoA（LC-CoA）的胞质蓄积。我们推测LC-CoA对K-ATP通道的刺激作用可能在多态性K-ATP通道中增强。膜片钳实验在含有重组KATP通道（Kir6.2/SUR 1）的由内而外的膜片上进行以记录宏观电流。与野生型KATP通道相比，含有Kir6.2（E23 K/I337 V）的KATP通道显示出响应生理棕榈酰辅酶A浓度（100- 1，000 nmol/l）的显著增加的活性。在生理细胞内ATP浓度（mmol/l）下，E23 K/I337 V多态性KATP通道对棕榈酰辅酶A的反应表现出显著增强的活性。观察到的KATP通道活性增加可能导致葡萄糖稳态的多种缺陷，包括胰岛素和胰高血糖素样肽-1分泌受损和胰高血糖素释放增加。总之，这些结果表明，E23 K/I337 V多态性可能通过增加KATP通道活性，对参与维持葡萄糖稳态的组织中内源性LC-CoA水平作出反应，从而产生致糖尿病效应。
The commonly occurring E23K and I337V Kir6.2 polymorphisms in the ATP-sensitive potassium (K-ATP) channel are more frequent in Caucasian type 2 diabetic populations. However, the underlying cellular mechanisms contributing to the pathogenesis of type 2 diabetes remain uncharacterized. Chronic elevation of plasma free fatty acids observed in obese and type 2 diabetic subjects leads to cytosolic accumulation of long-chain acyl CoAs (LC-CoAs) in pancreatic P-cells. We postulated that the documented stimulatory effects of LC-CoAs on K-ATP channels might be enhanced in polymorphic K-ATP channels. Patch-clamp experiments were performed on inside-out patches containing recombinant KATP channels (Kir6.2/SUR1) to record macroscopic currents. KATP channels containing Kir6.2 (E23K/I337V) showed significantly increased activity in response to physiological palmitoyl-CoA concentrations (100-1,000 nmol/l) compared with wild-type KATP channels. At physiological intracellular ATP concentrations (mmol/l), E23K/I337V polymorphic KATP channels demonstrated significantly enhanced activity in response to palmitoyl-CoA. The observed increase in KATP channel activity may result in multiple defects in glucose homeostasis, including impaired insulin and glucagon-like peptide-1 secretion and increased glucagon release. In summary, these results suggest that the E23K/I337V polymorphism may have a diabetogenic effect via increased KATP channel activity in response to endogenous levels of LC-CoAs in tissues involved in the maintenance of glucose homeostasis.