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

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

Author information

1
Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI Biophysics Graduate Training Program, University of Wisconsin-Madison, Madison, WI Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, WI.
2
Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, WI.
3
Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI.
4
Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI.
5
Integrated Program in Biochemistry, University of Wisconsin-Madison, Madison, WI.
6
Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, Madison, WI.
7
Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, WI Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI.
8
Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI William S. Middleton Memorial Veterans Hospital, Madison, WI.
9
Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI William S. Middleton Memorial Veterans Hospital, Madison, WI merrins@wisc.edu dlamming@medicine.wisc.edu.
10
Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, WI Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI William S. Middleton Memorial Veterans Hospital, Madison, WI merrins@wisc.edu dlamming@medicine.wisc.edu.

Abstract

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.

PMID:
27284112
PMCID:
PMC5001174
DOI:
10.2337/db16-0432
[Indexed for MEDLINE]
Free PMC Article

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