Adaptive beta-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet cyclin D2 expression

作者：Stamateris Rachel E; Sharma Rohit B; Hollern Douglas A; Alonso Laura C^*

来源：American Journal of Physiology - Endocrinology And Metabolism, 2013, 305(1): E149-E159.

DOI：10.1152/ajpendo.00040.2013

• overnutrition
• short-term high-fat diet
• diet-induced obesity
• islet replication
• pancreatic beta-cell mitosis

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.

• 出版日期2013-7