Increased glycolysis affects β-cell function and identity in aging and diabetes

Age is a risk factor for type 2 diabetes (T2D). We aimed to elucidate whether β-cell glucose metabolism is altered with aging and contributes to T2D. We used senescence-accelerated mice (SAM), C57BL/6J (B6) mice, and ob / ob mice as aging models. As a diabetes model, we used db / db mice. The glucose responsiveness of insulin secretion and the [U- 13 C]-glucose metabolic flux were examined in isolated islets. We analyzed the expression of β-cell-specific genes in isolated islets and pancreatic sections as molecular signatures of β-cell identity. β cells defective in the malate-aspartate (MA) shuttle were previously generated from MIN6-K8 cells by the knockout of Got1, a component of the shuttle. We analyzed Got1 KO β cells as a model of increased glycolysis. We identified hyperresponsiveness to glucose and compromised cellular identity as dysfunctional phenotypes shared in common between aged and diabetic mouse β cells. We also observed a metabolic commonality between aged and diabetic β cells: hyperactive glycolysis through the increased expression of nicotinamide mononucleotide adenylyl transferase 2 ( Nmnat2 ), a cytosolic nicotinamide adenine dinucleotide (NAD)-synthesizing enzyme. Got1 KO β cells showed increased glycolysis, β-cell dysfunction, and impaired cellular identity, phenocopying aging and diabetes. Using Got1 KO β cells, we show that attenuation of glycolysis or Nmnat2 activity can restore β-cell function and identity. Our study demonstrates that hyperactive glycolysis is a metabolic signature of aged and diabetic β cells, which may underlie age-related β-cell dysfunction and loss of cellular identity. We suggest Nmnat2 suppression as an approach to counteract age-related T2D.