In the setting of obesity and insulin resistance, glycemia is controlled in part by beta cell compensation and subsequent hyperinsulinemia. Weight loss improves glycemia and decreases hyperinsulinemia, whereas weight cycling worsens glycemic control. The mechanisms responsible for weight cycling-induced deterioration in glucose homeostasis are poorly understood. Thus, we aimed to pinpoint the main regulatory junctions at which weight cycling alters glucose homeostasis in mice. Using in vivo and ex vivo procedures we show that despite having worsened glucose tolerance, weight-cycled mice do not manifest impaired whole-body insulin action. Instead, weight cycling reduces insulin secretory capacity in vivo during clamped hyperglycemia and ex vivo in perifused islets. Islets from weight-cycled mice have reduced expression of factors essential for β-cell function (Mafa, Pdx1, Nkx6.1, Ucn3) and lower islet insulin content, compared to those from obese mice, suggesting inadequate transcriptional and posttranscriptional response to repeated nutrient overload. Collectively, these data support a model in which pancreatic plasticity is challenged in the face of large fluctuations in body weight resulting in a mismatch between glycemia and insulin secretion in mice.

中文翻译：

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体重循环会损害胰腺胰岛素分泌，但不会干扰饮食诱导的肥胖小鼠的全身胰岛素作用

在肥胖和胰岛素抵抗的情况下，血糖部分受β细胞代偿和随后的高胰岛素血症控制。减肥可改善血糖并降低高胰岛素血症，而体重循环会恶化血糖控制。对体重循环引起的葡萄糖稳态恶化的机制知之甚少。因此，我们旨在确定体重循环改变小鼠葡萄糖稳态的主要调节点。我们使用体内和体外程序表明，尽管葡萄糖耐量恶化，但体重循环的小鼠并没有表现出全身胰岛素作用受损。相反，体重循环降低了钳位高血糖期间体内胰岛素分泌能力和灌注胰岛离体胰岛素分泌能力。与肥胖小鼠相比，体重循环小鼠的胰岛对 β 细胞功能至关重要的因子（Mafa、Pdx1、Nkx6.1、Ucn3）的表达降低，胰岛胰岛素含量降低，这表明对重复营养的转录和转录后反应不足超载。总的来说，这些数据支持了一个模型，在该模型中，面对体重的大幅波动，导致小鼠血糖和胰岛素分泌不匹配，胰腺可塑性受到挑战。