Pancreatic β-Cells From Mice Offset Age-Associated Mitochondrial Deficiency With Reduced KATP Channel Activity
| Autor: | Rashpal S. Dhillon, Luis A. Fernandez, Sophia M. Sdao, Emma L. Baar, Jeremy D. Rogers, Dudley W. Lamming, Brian A. Schmidt, Kevin W. Eliceiri, Nathan A. Truchan, Chetan Poudel, Matthew J. Merrins, Trillian Gregg, John M. Denu, Michelle E. Kimple |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Aging medicine.medical_specialty Potassium Channels Endocrinology Diabetes and Metabolism medicine.medical_treatment Type 2 diabetes In Vitro Techniques Carbohydrate metabolism Biology Islets of Langerhans Mice 03 medical and health sciences Adenosine Triphosphate Insulin-Secreting Cells Internal medicine Internal Medicine medicine Diazoxide Animals Humans Insulin Glucose homeostasis Pancreatic islets NAD medicine.disease Mitochondria Insulin oscillation Electrophysiology Mice Inbred C57BL Glucose 030104 developmental biology Endocrinology medicine.anatomical_structure Islet Studies Calcium NAD+ kinase NADP medicine.drug |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db16-0432 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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