Pancreatic β-Cells From Mice Offset Age-Associated Mitochondrial Deficiency With Reduced KATP Channel Activity.
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.
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.
Trillian
T
Gregg
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.
Chetan
C
Poudel
Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI.
Brian A
BA
Schmidt
Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI.
Rashpal S
RS
Dhillon
Integrated Program in Biochemistry, University of Wisconsin-Madison, Madison, WI.
Sophia M
SM
Sdao
Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI.
Nathan A
NA
Truchan
Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI.
Emma L
EL
Baar
Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, Madison, WI.
Luis A
LA
Fernandez
Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI.
John M
JM
Denu
Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, WI Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI.
Kevin W
KW
Eliceiri
Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, WI Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI.
Jeremy D
JD
Rogers
Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI William S. Middleton Memorial Veterans Hospital, Madison, WI.
Michelle E
ME
Kimple
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.
Dudley W
DW
Lamming
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.
Matthew J
0000-0003-1599-9227
MJ
Merrins
D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004594:Electrophysiology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*
D007328:Insulin; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D009243:NAD; D009249:NADP; D000255:Adenosine Triphosphate; D005947:Glucose; D002118:Calcium