Pancreatic β-Cells From Mice Offset Age-Associated Mitochondrial Deficiency With Reduced KATP Channel Activity
Open Access
- 9 June 2016
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 65 (9), 2700-2710
- https://doi.org/10.2337/db16-0432
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 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 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.Keywords
Funding Information
- National Institutes of Health (T32-GM-08293)
- American Diabetes Association (1-14-BS-115)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-102598)
- NIA (R00-AG-041765)
- NIDDK (K01-DK-101683)
- American Diabetes Association (1-16-IBS-212)
This publication has 53 references indexed in Scilit:
- Oscillations of sub-membrane ATP in glucose-stimulated beta cells depend on negative feedback from Ca2+Diabetologia, 2013
- A Novel High-Throughput Assay for Islet Respiration Reveals Uncoupling of Rodent and Human IsletsPLOS ONE, 2012
- Physical Fitness and Mitochondrial Respiratory Capacity in Horse Skeletal MusclePLOS ONE, 2012
- Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in MiceCell Metabolism, 2011
- Metabolic Oscillations in Pancreatic Islets Depend on the Intracellular Ca2+ Level but Not Ca2+ OscillationsBiophysical Journal, 2010
- The CDK4–pRB–E2F1 pathway controls insulin secretionNature, 2009
- Mitochondrial DNA mutations and aging: devils in the details?Trends in Genetics, 2008
- Mitochondrial NADH Fluorescence Is Enhanced by Complex I BindingBiochemistry, 2008
- The Phasor Approach to Fluorescence Lifetime Imaging AnalysisBiophysical Journal, 2008
- Glucose Modulates [Ca2+]i Oscillations in Pancreatic Islets via Ionic and Glycolytic MechanismsBiophysical Journal, 2006