Abstract
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 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 β-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 β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.
Highlights
Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin
After 2 weeks of diabetes, blood glucose remained elevated and plasma lipid levels were not significantly altered[26]: the changes we observe are due to hyperglycaemia/hypoinsulinaemia and not a secondary consequence of altered lipid metabolism
The βV59M mouse carries a KATP channel mutation found in patients with neonatal diabetes[22] and is a good model both for this disease and for the effects of chronic hyperglycaemia seen in other types of diabetes
Summary
Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. Multiple contributors have been proposed, including impaired glucose metabolism itself, oxidative stress, endoplasmic reticulum stress, impaired exocytosis and β-cell dedifferentiation[12,18] While all of these may be contributory factors, a crucial question is which is the initial key event that drives diabetes progression. Accumulating evidence suggests this may be impaired β-cell metabolism, as changes in metabolic genes, or in metabolism, have been identified in islets isolated from T2D donors[19,20], control human islets cultured at 25 mM glucose[3], diabetic GK rat islets[21], mouse models of diabetes[22,23,24] and insulin-secreting cell lines exposed to high glucose[4,5]. These findings add strength to the idea that impaired β-cell metabolism has a pathogenic role in the development of human T2D
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