Pancreatic β-Cells From Mice Offset Age-Associated Mitochondrial Deficiency With Reduced KATP Channel Activity.
Pancreatic β-Cells From Mice Offset Age-Associated Mitochondrial Deficiency With Reduced KATP Channel Activity.
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DOI：
10.2337/db16-0432
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发表时间：
2016-09
期刊：
影响因子：
7.7
通讯作者：
Merrins MJ
中科院分区：
文献类型：
--
作者：
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
衰老伴随着葡萄糖稳态受损和2型糖尿病风险增加，最终导致胰腺β细胞分泌胰岛素失败。为了研究年龄对β细胞代谢的影响，我们建立了一种新的方法，用NAD（P）H荧光寿命成像（FLIM）直接成像胰岛代谢。我们确定线粒体活性受损是人类胰岛中胰岛素分泌随年龄增长而减少的基础。NAD（P）H FLIM显示老年小鼠（≥24个月）胰岛中线粒体功能的相当下降，这是电子传递链通过复合物I和II的通量分别有52%和57%缺陷的结果。然而，老年小鼠胰岛中的胰岛素分泌和葡萄糖耐量通过β细胞触发途径的代谢敏感性提高而得以保留，这是一种在触发胰岛素释放的代谢和Ca 2+振荡中明确编码的适应（Ca 2+平台分数：年轻0.211 ± 0.006，老年0.380 ± 0.007，P < 0.0001）。这种增强的敏感性是由KATP通道电导的降低驱动的（二氮嗪：年轻时为5.1 ± 0.2 nS;老年时为3.5 ± 0.5 nS，P < 0.01），导致β细胞葡萄糖阈值左移约2.8 mmol/L。结果表明，小鼠而不是人类能够通过调节β细胞葡萄糖敏感性成功地补偿与年龄相关的代谢功能障碍，并强调了确保维持胰岛素分泌的重要机制。
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.
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线粒体DNA突变和衰老：细节中的魔鬼？
影响因子：
11.4
作者：
Khrapko, Konstantin;Vijg, Jan
通讯作者：
Vijg, Jan
DOI：
10.18632/aging.100350
发表时间：
2011-06
期刊：
Aging
影响因子：
--
作者：
Gunasekaran U;Gannon M
通讯作者：
Gannon M
影响因子：
2.9
作者：
Blinova, Ksenia;Levine, Rodney L.;Boja, Emily S.;Griffiths, Gary L.;Shi, Zhen-Dan;Ruddy, Brian;Balaban, Robert S.
通讯作者：
Balaban, Robert S.
影响因子：
5.5
作者：
Luciani, DS;Misler, S;Polonsky, KS
通讯作者：
Polonsky, KS
影响因子：
7.7
作者：
Li, Luosheng;Trifunovic, Aleksandra;Berggren, Per-Olof
通讯作者：
Berggren, Per-Olof