Pancreatic β-Cells From Mice Offset Age-Associated Mitochondrial Deficiency With Reduced KATP Channel Activity

Aging is accompanied by impaired glucose homeostasis and an increased risk of type 2 diabetes, culminating in the failure of insulin secretion from pancreatic beta-cells. To investigate the effects of age on beta-cell metabolism, we established a novel assay to directly image islet metabolism with NAD(P)H fluorescence lifetime imaging (FLIM). We determined that impaired mitochondrial activity underlies an age-dependent loss of insulin secretion in human islets. NAD(P)H FLIM revealed a comparable decline in mitochondrial function in the pancreatic islets of aged mice (W24 months), the result of 52% and 57% defects in flux through complex I and II, respectively, of the electron transport chain. However, insulin secretion and glucose tolerance are preserved in aged mouse islets by the heightened metabolic sensitivity of the beta-cell triggering pathway, an adaptation clearly encoded in the metabolic and Ca2+ oscillations that trigger insulin release (Ca2+ plateau fraction: young 0.211 +/- 0.006, aged 0.380 +/- 0.007, P < 0.0001). This enhanced sensitivity is driven by a reduction in K-ATP channel conductance (diazoxide: young 5.1 +/- 0.2 nS; aged 3.5 +/- 0.5 nS, P < 0.01), resulting in an similar to 2.8 mmol/L left shift in the beta-cell glucose threshold. The results demonstrate how mice but not humans are able to successfully compensate for age-associated metabolic dysfunction by adjusting beta-cell glucose sensitivity and highlight an essential mechanism for ensuring the maintenance of insulin secretion.