Pancreatic β-Cells From Mice Offset Age-Associated Mitochondrial Deficiency With Reduced KATP Channel Activity. Diabetes 2016 Sep;65(9):2700-10
Date
06/11/2016Pubmed ID
27284112Pubmed Central ID
PMC5001174DOI
10.2337/db16-0432Scopus ID
2-s2.0-84987608759 (requires institutional sign-in at Scopus site) 51 CitationsAbstract
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.
Author List
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 MJAuthor
Nathan A. Truchan PhD Research Scientist I in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adenosine TriphosphateAging
Animals
Calcium
Electrophysiology
Glucose
Humans
In Vitro Techniques
Insulin
Insulin-Secreting Cells
Islets of Langerhans
Male
Mice
Mice, Inbred C57BL
Mitochondria
NAD
NADP
Potassium Channels
