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

Diabetes. 2016 Sep;65(9):2700-10. doi: 10.2337/db16-0432. Epub 2016 Jun 9.


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 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 (≥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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Aging / metabolism*
  • Animals
  • Calcium / metabolism
  • Electrophysiology
  • Glucose / metabolism
  • Humans
  • In Vitro Techniques
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • NAD / metabolism
  • NADP / metabolism
  • Potassium Channels / metabolism*


  • Insulin
  • Potassium Channels
  • mitochondrial K(ATP) channel
  • NAD
  • NADP
  • Adenosine Triphosphate
  • Glucose
  • Calcium