Gregg 2016 Diabetes
|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 (2016) Pancreatic β cells from mice offset age-associated mitochondrial deficiency with reduced KATP channel activity. Diabetes 65:2700-10.|
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 using 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), resulting from 52% and 57% defects in flux through complex I and II 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 a ∼2.8 mM left shift in the β cell glucose threshold. Our results demonstrate how mice, but not humans, are able to successfully compensate for age-associated metabolic dysfunction by adjusting their β cell glucose sensitivity, and highlight an essential mechanism for ensuring the maintenance of insulin secretion.
© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
• O2k-Network Lab: US WI Madison Denu JM
Labels: MiParea: Respiration, Comparative MiP;environmental MiP Pathology: Aging;senescence
Organism: Human, Mouse Tissue;cell: Islet cell;pancreas;thymus, Other cell lines Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS, ET Pathway: N, S, NS, ROX HRR: Oxygraph-2k