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Pancreatic beta cells lack a low glucose and O2-inducible mitochondrial protein that augments cell survival.

ABSTRACT: beta cell failure is a common denominator of diabetes. Susceptibility to stress-induced apoptosis may underlie beta cell failure and/or hamper islet transplantation therapy. The causal basis is not well understood. In efforts to identify important differences in gene expression in alpha vs. beta cells, a gene termed HIMP1 (Hypoglycemia/hypoxia Inducible Mitochondrial Protein, or HIG1) has been cloned from an alpha cell cDNA library. It is a member of a well conserved eukaryote protein family. In mice, its two alternatively spliced products each form a transmembrane loop, having an N(outside)-C(outside) orientation and are expressed highly in the mitochondrial inner membrane in several tissues including heart and pancreatic alpha cells, but not in beta cells. Ectopic expression of HIMP1 in MIN6 beta cells protects the cells from apoptosis induced by several stimuli and prolongs their survival. These results suggest an important role for HIMP1 in stress protective programs in mitochondria.

SUBMITTER: Wang J

PROVIDER: S-EPMC1502284 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Pancreatic beta cells lack a low glucose and O2-inducible mitochondrial protein that augments cell survival.

Wang Jie J Cao Yun Y Chen Ying Y Chen Yimei Y Gardner Paul P Steiner Donald F DF

Proceedings of the National Academy of Sciences of the United States of America 20060630 28

beta cell failure is a common denominator of diabetes. Susceptibility to stress-induced apoptosis may underlie beta cell failure and/or hamper islet transplantation therapy. The causal basis is not well understood. In efforts to identify important differences in gene expression in alpha vs. beta cells, a gene termed HIMP1 (Hypoglycemia/hypoxia Inducible Mitochondrial Protein, or HIG1) has been cloned from an alpha cell cDNA library. It is a member of a well conserved eukaryote protein family. In ...[more]

PMID: 16815968

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Project description:Aims/hypothesisIn islets from individuals with type 2 diabetes and in islets exposed to chronic elevated glucose, mitochondrial energy metabolism is impaired. Here, we studied early metabolic changes and mitochondrial adaptations in human beta cells during chronic glucose stress.MethodsRespiration and cytosolic ATP changes were measured in human islet cell clusters after culture for 4 days in 11.1 mmol/l glucose. Metabolomics was applied to analyse intracellular metabolite changes as a result of glucose stress conditions. Alterations in beta cell function were followed using insulin secretion assays or cytosolic calcium signalling after expression of the calcium probe YC3.6 specifically in beta cells of islet clusters.ResultsAt early stages of glucose stress, mitochondrial energy metabolism was augmented in contrast to the previously described mitochondrial dysfunction in beta cells from islets of diabetic donors. Following chronic glucose stress, mitochondrial respiration increased (by 52.4%, p < 0.001) and, as a consequence, the cytosolic ATP/ADP ratio in resting human pancreatic islet cells was elevated (by 27.8%, p < 0.05). Because of mitochondrial overactivation in the resting state, nutrient-induced beta cell activation was reduced. In addition, chronic glucose stress caused metabolic adaptations that resulted in the accumulation of intermediates of the glycolytic pathway, the pentose phosphate pathway and the TCA cycle; the most strongly augmented metabolite was glycerol 3-phosphate. The changes in metabolites observed are likely to be due to the inability of mitochondria to cope with continuous nutrient oversupply. To protect beta cells from chronic glucose stress, we inhibited mitochondrial pyruvate transport. Metabolite concentrations were partially normalised and the mitochondrial respiratory response to nutrients was markedly improved. Furthermore, stimulus-secretion coupling as assessed by cytosolic calcium signalling, was restored.Conclusion/interpretationWe propose that metabolic changes and associated mitochondrial overactivation are early adaptations to glucose stress, and may reflect what happens as a result of poor blood glucose control. Inhibition of mitochondrial pyruvate transport reduces mitochondrial nutrient overload and allows beta cells to recover from chronic glucose stress. Graphical abstract.

Dataset Information

Pancreatic beta cells lack a low glucose and O2-inducible mitochondrial protein that augments cell survival.

Publications

Pancreatic beta cells lack a low glucose and O2-inducible mitochondrial protein that augments cell survival.

Similar Datasets

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