Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells.
Elizabeth HaythorneMaria RohmMartijn van de BuntMelissa F BreretonAndrei I TarasovThomas S BlackerGregor SachseMariana Silva Dos SantosRaul Terron ExpositoSimon DavisOtto BabaRoman FischerMichael R DuchenPatrik RorsmanJames I MacRaeFrances M AshcroftPublished in: Nature communications (2019)
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.
Keyphrases
- type diabetes
- induced apoptosis
- cell cycle arrest
- cardiovascular disease
- glycemic control
- high glucose
- oxidative stress
- global health
- endoplasmic reticulum stress
- public health
- signaling pathway
- multiple sclerosis
- cell death
- metabolic syndrome
- drug delivery
- weight loss
- dna methylation
- skeletal muscle
- cell proliferation
- machine learning
- deep learning
- transcription factor
- obese patients
- cancer therapy
- diabetic rats