Adaptive β-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet cyclin D2 expression
Adaptive β-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet cyclin D2 expression
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DOI：
10.1152/ajpendo.00040.2013
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发表时间：
2013-07-01
影响因子：
5.1
通讯作者：
Alonso, Laura C.
中科院分区：
文献类型：
--
作者：
Stamateris, Rachel E.;Sharma, Rohit B.;Alonso, Laura C.
2型糖尿病（T2 D）是由相对胰岛素缺乏引起的，部分原因是β细胞质量减少（11，62）。旨在扩大β细胞群的疗法可能有助于治疗T2 D（14）。虽然长时间（3-6个月）喂食啮齿动物高脂饮食（HFD）可通过诱导β细胞增殖增加β细胞质量（16，20，53，54），但有证据表明成年人β细胞可能不会因肥胖而有意义地增殖。啮齿类动物代偿性生长反应的最早启动者的时间和身份（驱动难治性人β细胞增殖的可能治疗靶点）尚不清楚。为了开发一种模型来识别β细胞增殖的早期驱动因素，我们在HFD暴露的第一周期间研究了小鼠，确定了在饮食相关生理变化的背景下增殖的开始。在HFD的第一周内，小鼠消耗了更多的千卡，体重和脂肪量增加，并由于胰岛素分泌受损而出现高血糖症、高胰岛素血症和葡萄糖耐受不良。β细胞增殖反应也在HFD喂养的第一周内开始。有趣的是，在检测到胰岛素抵抗之前，β细胞增殖增加。细胞周期蛋白D2蛋白表达在第7天在胰岛中增加，表明它可能是小鼠中驱动代偿性β细胞增殖的早期效应子。本研究定义了时间框架和生理学，以识别驱动小鼠β细胞群扩增的新型上游调控信号，以探索其在启动人β细胞增殖中的功效或无效原因。
Type 2 diabetes (T2D) is caused by relative insulin deficiency, due in part to reduced beta-cell mass (11, 62). Therapies aimed at expanding beta-cell mass may be useful to treat T2D (14). Although feeding rodents a high-fat diet (HFD) for an extended period (3-6 mo) increases beta-cell mass by inducing beta-cell proliferation (16, 20, 53, 54), evidence suggests that adult human beta-cells may not meaningfully proliferate in response to obesity. The timing and identity of the earliest initiators of the rodent compensatory growth response, possible therapeutic targets to drive proliferation in refractory human beta-cells, are not known. To develop a model to identify early drivers of beta-cell proliferation, we studied mice during the first week of HFD exposure, determining the onset of proliferation in the context of diet-related physiological changes. Within the first week of HFD, mice consumed more kilocalories, gained weight and fat mass, and developed hyperglycemia, hyperinsulinemia, and glucose intolerance due to impaired insulin secretion. The beta-cell proliferative response also began within the first week of HFD feeding. Intriguingly, beta-cell proliferation increased before insulin resistance was detected. Cyclin D2 protein expression was increased in islets by day 7, suggesting it may be an early effector driving compensatory beta-cell proliferation in mice. This study defines the time frame and physiology to identify novel upstream regulatory signals driving mouse beta-cell mass expansion, in order to explore their efficacy, or reasons for inefficacy, in initiating human beta-cell proliferation.