Defective pancreatic β-cell glycolytic signaling in hepatocyte nuclear factor-1α-deficient mice
Defective pancreatic β-cell glycolytic signaling in hepatocyte nuclear factor-1α-deficient mice
复制标题
DOI：
10.1074/jbc.273.38.24457
复制
发表时间：
1998-09-18
影响因子：
4.8
通讯作者：
Polonsky, KS
中科院分区：
文献类型：
--
作者：
Dukes, ID;Sreenan, S;Polonsky, KS
肝细胞核因子-1 α的突变在缺乏HNF-1 α基因的小鼠中，胰岛素分泌和细胞内钙（[Ca 2 +]（i））反应在营养促分泌素如葡萄糖和甘油醛刺激后受损，但在非营养刺激如氯化钾刺激下正常。膜片钳记录显示，β细胞中ATP敏感性K+电流（KATP）对葡萄糖抑制不敏感，但通常对ATP敏感。暴露于线粒体底物抑制KATP，升高[Ca 2 +]（i），并纠正胰岛素分泌缺陷。NAD（P）H对葡萄糖的反应显著降低，糖酵解NADH生成的抑制剂在正常胰岛中再现了突变表型。通过糖酵解的葡萄糖通量从突变小鼠的胰岛减少，其结果是响应于葡萄糖的ATP生成受损。我们的结论是，肝细胞核因子-1 α糖尿病的结果从缺陷的β细胞糖酵解信号，这是潜在的纠正使用基板，绕过缺陷。
Mutations in the hepatocyte nuclear factor-1 alpha (HNF-1 alpha) gene cause maturity onset diabetes of the young type 3, a form of type 2 diabetes mellitus, In mice lacking the HNF-1 alpha gene, insulin secretion and intracellular calcium ([Ca2+](i)) responses were impaired following stimulation with nutrient secretagogues such as glucose and glyceraldehyde but normal with non-nutrient stimuli such as potassium chloride. Patch clamp recordings revealed ATP-sensitive K+ currents (KATP) in beta-cells that were insensitive to suppression by glucose but normally sensitive to ATP, Exposure to mitochondrial substrates suppressed KATP, elevated [Ca2+](i), and corrected the insulin secretion defect. NAD(P)H responses to glucose were substantially reduced, and inhibitors of glycolytic NADH generation reproduced the mutant phenotype in normal islets. Flux of glucose through glycolysis in islets from mutant mice was reduced, as a result of which ATP generation in response to glucose was impaired. We conclude that hepatocyte nuclear factor-1 alpha diabetes results from defective beta-cell glycolytic signaling, which is potentially correctable using substrates that bypass the defect.