期刊
BIOCHEMICAL JOURNAL
卷 435, 期 -, 页码 277-284出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20100655
关键词
hypoxia-inducible factor (HIF); mitochondria; pancreatic islet; insulin; Type 2 diabetes (T2D)
资金
- Swedish Research Council [14196-06-3]
- Crafoord Foundation
- European Foundation for the Study of Diabetes
- Lars Hierta Foundation
- Fredrik and Ingrid Thuring Foundation
- Ake Wiberg Foundation
- Albert Pahlsson Foundation
- O.E. and Edla Johansson Foundation
- Knut and Alice Wallenberg Foundation
- Royal Physiographic Society
- Lund University Diabetes Centre
- Faculty of Medicine at Lund University
- Inga and John Hain Foundation
Insulin secretion from pancreatic beta-cells is controlled by complex metabolic and energetic changes provoked by exposure to metabolic fuels. Perturbations in these processes lead to impaired insulin secretion, the ultimate cause of T2D (Type 2 diabetes). To increase our understanding of stimulus secretion coupling and metabolic processes potentially involved in the pathogenesis of T2D, a comprehensive investigation of the metabolic response in the glucose-responsive INS-1 832/13 and glucose-unresponsive INS-1 832/2 beta-cell lines was performed. For this metabolomics analysis, we used GC/MS (gas chromatography/mass spectrometry) combined with multivariate statistics. We found that perturbed secretion in the 832/2 line was characterized by disturbed coupling of glycolytic and TCA (tricarboxylic acid)-cycle metabolism. The importance of this metabolic coupling was reinforced by our observation that insulin secretion partially could be reinstated by stimulation of the cells with mitochondrial fuels which bypass glycolytic metabolism. Furthermore, metabolic and functional profiling of additional beta-cell lines (INS-1, INS-1 832/1) confirmed the important role of coupled glycolytic and TCA-cycle metabolism in stimulus-secretion coupling. Dependence of the unresponsive clones on glycolytic metabolism was paralleled by increased stabilization of HIF-1 alpha (hypoxia-inducible factor 1 alpha). The relevance of a similar perturbation for human T2D was suggested by increased expression of HIF-1 alpha target genes in islets from T2D patients.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据