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Authors Gregg T, Poudel C, Schmidt BA, Dhillon RS, Sdao SM, Truchan NA, Baar EL, Fernandez LA, Denu JM, Eliceiri KW, Rogers JD, Kimple ME, Lamming DW, Merrins MJ
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Journal Diabetes Volume: 65 Issue: 9 Pages: 2700-10
Publish Date 2016 Sep
PubMed ID 27284112
PMC ID 5001174

Aging is accompanied by impaired glucose homeostasis and an increased risk of type 2 diabetes, culminating in the failure of insulin secretion from pancreatic β-cells. To investigate the effects of age on β-cell metabolism, we established a novel assay to directly image islet metabolism with NADH fluorescence lifetime imaging (FLIM). We determined that impaired mitochondrial activity underlies an age-dependent loss of insulin secretion in human islets. NADH FLIM revealed a comparable decline in mitochondrial function in the pancreatic islets of aged mice (≥24 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 β-cell triggering pathway, an adaptation clearly encoded in the metabolic and Ca(2+) oscillations that trigger insulin release (Ca(2+) plateau fraction: young 0.211 ± 0.006, aged 0.380 ± 0.007, P < 0.0001). This enhanced sensitivity is driven by a reduction in KATP channel conductance (diazoxide: young 5.1 ± 0.2 nS; aged 3.5 ± 0.5 nS, P < 0.01), resulting in an ∼2.8 mmol/L left shift in the β-cell glucose threshold. The results demonstrate how mice but not humans are able to successfully compensate for age-associated metabolic dysfunction by adjusting β-cell glucose sensitivity and highlight an essential mechanism for ensuring the maintenance of insulin secretion.

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