Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
VA Tennessee Valley Healthcare System, Nashville, TN.
Diabetes. 2022 Nov 1;71(11):2313-2330. doi: 10.2337/db22-0161.
In the setting of obesity and insulin resistance, glycemia is controlled in part by β-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 with 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.
在肥胖和胰岛素抵抗的情况下，血糖部分通过β细胞代偿和随后的高胰岛素血症来控制。体重减轻可以改善血糖控制并降低高胰岛素血症，而体重波动则会使血糖控制恶化。导致体重波动引起的葡萄糖稳态恶化的机制尚未完全清楚。因此，我们旨在确定体重波动改变小鼠葡萄糖稳态的主要调节节点。通过体内和体外程序，我们表明，尽管体重波动会使葡萄糖耐量恶化，但体重波动的小鼠并没有表现出全身胰岛素作用受损。相反，体重波动会在夹闭高血糖期间体内降低胰岛素分泌能力，并在灌注分离胰岛时体外降低胰岛素分泌能力。与肥胖小鼠相比，体重波动小鼠的胰岛中表达对β细胞功能至关重要的因子（Mafa、Pdx1、Nkx6.1、Ucn3）减少，胰岛胰岛素含量降低，这表明其对反复营养超负荷的转录和转录后反应不足。总的来说，这些数据支持这样一种模型，即面对体重的大幅波动，胰腺的可塑性受到挑战，导致小鼠的血糖和胰岛素分泌之间不匹配。
