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Hyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic ?-cells.

ABSTRACT: Insulin secretion from pancreatic ?-cells is impaired in all forms of diabetes. The resultant hyperglycaemia has deleterious effects on many tissues, including ?-cells. Here we show that chronic hyperglycaemia impairs glucose metabolism and alters expression of metabolic genes in pancreatic islets. In a mouse model of human neonatal diabetes, hyperglycaemia results in marked glycogen accumulation, and increased apoptosis in ?-cells. Sulphonylurea therapy rapidly normalizes blood glucose levels, dissipates glycogen stores, increases autophagy and restores ?-cell metabolism. Insulin therapy has the same effect but with slower kinetics. Similar changes are observed in mice expressing an activating glucokinase mutation, in in vitro models of hyperglycaemia, and in islets from type-2 diabetic patients. Altered ?-cell metabolism may underlie both the progressive impairment of insulin secretion and reduced ?-cell mass in diabetes.

SUBMITTER: Brereton MF

PROVIDER: S-EPMC5123088 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Hyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic β-cells.

Brereton Melissa F MF Rohm Maria M Shimomura Kenju K Holland Christian C Tornovsky-Babeay Sharona S Dadon Daniela D Iberl Michaela M Chibalina Margarita V MV Lee Sheena S Glaser Benjamin B Dor Yuval Y Rorsman Patrik P Clark Anne A Ashcroft Frances M FM

Nature communications 20161124

Insulin secretion from pancreatic β-cells is impaired in all forms of diabetes. The resultant hyperglycaemia has deleterious effects on many tissues, including β-cells. Here we show that chronic hyperglycaemia impairs glucose metabolism and alters expression of metabolic genes in pancreatic islets. In a mouse model of human neonatal diabetes, hyperglycaemia results in marked glycogen accumulation, and increased apoptosis in β-cells. Sulphonylurea therapy rapidly normalizes blood glucose levels, ...[more]

PMID: 27882918

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Project description:Mitochondria are best known as the essential intracellular organelles that host the homeostasis required for cellular survival, but they also have relevance in diverse disease-related conditions, including Alzheimer's disease (AD). Amyloid β (Aβ) peptide is the key molecule in AD pathogenesis, and has been highlighted in the implication of mitochondrial abnormality during the disease progress. Neuronal exposure to Aβ impairs mitochondrial dynamics and function. Furthermore, mitochondrial Aβ accumulation has been detected in the AD brain. However, the underlying mechanism of how Aβ affects mitochondrial function remains uncertain, and it is questionable whether mitochondrial Aβ accumulation followed by mitochondrial dysfunction leads directly to neuronal toxicity. This study demonstrated that an exogenous Aβ(1-42) treatment, when applied to the hippocampal cell line of mice (specifically HT22 cells), caused a deleterious alteration in mitochondria in both morphology and function. A clathrin-mediated endocytosis blocker rescued the exogenous Aβ(1-42)-mediated mitochondrial dysfunction. Furthermore, the mitochondria-targeted accumulation of Aβ(1-42) in HT22 cells using Aβ(1-42) with a mitochondria-targeting sequence induced the identical morphological alteration of mitochondria as that observed in the APP/PS AD mouse model and exogenous Aβ(1-42)-treated HT22 cells. In addition, subsequent mitochondrial dysfunctions were demonstrated in the mitochondria-specific Aβ(1-42) accumulation model, which proved indistinguishable from the mitochondrial impairment induced by exogenous Aβ(1-42)-treated HT22 cells. Finally, cellular toxicity was directly induced by mitochondria-targeted Aβ(1-42) accumulation, which mimics the apoptosis process in exogenous Aβ(1-42)-treated HT22 cells. Taken together, these results indicate that mitochondria-targeted Aβ(1-42) accumulation is the necessary and sufficient condition for Aβ-mediated mitochondria impairments, and leads directly to cellular death rather than along with other Aβ-mediated signaling alterations.

Dataset Information

Hyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic ?-cells.

Publications

Hyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic β-cells.

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