A pyruvate cycling pathway involving cytosolic NADP-dependent isocitrate dehydrogenase regulates glucose-stimulated insulin secretion.
作者： Sarah M. Ronnebaum , Olga Ilkayeva , Shawn C. Burgess , Jamie W. Joseph , Danhong Lu
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摘要: Glucose-stimulated insulin secretion (GSIS) from pancreatic islet beta-cells is central to control of mammalian fuel homeostasis. Glucose metabolism mediates GSIS in part via ATP-regulated K+ (KATP) channels, but multiple lines evidence suggest participation other signals. Here we investigated the role cytosolic NADP-dependent isocitrate dehydrogenase (ICDc) beta-cells. Delivery small interfering RNAs specific for ICDc caused impairment two independent robustly glucose-responsive rat insulinoma (INS-1-derived) cell and primary islets. Suppression also attenuated glucose-induced increments pyruvate cycling activity NADPH levels, a predicted by-product pathways, as well total cellular NADP(H) content. Metabolic profiling eight organic acids extracts revealed that suppression increases lactate production both INS-1-derived islets, consistent with attenuation cycling, no significant changes intermediates. Based on these studies, propose pathway involving plays an important GSIS.
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