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Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic ?-cells.

ABSTRACT: Diabetes is a global health problem caused primarily by the inability of pancreatic ?-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of ?-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic ?V59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 ?-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in ?-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of ?-cells in diabetes.

SUBMITTER: Haythorne E

PROVIDER: S-EPMC6554411 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells.

Haythorne Elizabeth E Rohm Maria M van de Bunt Martijn M Brereton Melissa F MF Tarasov Andrei I AI Blacker Thomas S TS Sachse Gregor G Silva Dos Santos Mariana M Terron Exposito Raul R Davis Simon S Baba Otto O Fischer Roman R Duchen Michael R MR Rorsman Patrik P MacRae James I JI Ashcroft Frances M FM

Nature communications 20190606 1

Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysi ...[more]

PMID: 31171772

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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.

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Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic ?-cells.

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Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells.

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