Maternal low-protein diet (LP) throughout gestation affects pancreatic β-cell fraction of the offspring at birth, thus increasing their susceptibility to type 2 diabetes in adulthood. The present study sought to strictly examine the effects of LP during the last week of gestation (LP12.5) as a developmental window for β-cell programming and metabolic dysfunction in adulthood. Islet morphology analysis revealed normal β-cell fraction in LP12.5 newborns. Normal glucose tolerance was observed in 6-8 weeks old male and female LP12.5 offspring. However, male LP12.5 offspring displayed glucose intolerance and reduced insulin sensitivity associated with β-cell dysfunction with aging. High-fat diet exposure of metabolically normal 12-week-old male LP12.5 induced glucose intolerance due to increased body weight, insulin resistance and insufficient β-cell mass adaptation despite higher insulin secretion. Assessment of epigenetic mechanisms through MicroRNAs (miRs) by a real-time PCR-based microarray in islets revealed elevation in miRs that regulate insulin secretion (miRs 342, 143), insulin resistance (miR 143), and obesity (miR 219). In the islets, overexpression of miR 143 reduced insulin secretion in response to glucose. In contrast to the model of LP exposure throughout pregnancy, islet protein levels of mTOR and Pdx1 were normal in LP12.5 islets. Collectively, these data suggest that LP diet during the last week of pregnancy is critical and sufficient to induce specific and distinct developmental programming effects of tissues that control glucose homeostasis, causing permanent changes in specific set of microRNAs that may contribute to the overall vulnerability of the offspring to obesity, insulin resistance and type 2 diabetes.

中文翻译：

---

妊娠最后一周的母体低蛋白饮食会导致小鼠后代的胰岛素抵抗和 β 细胞功能障碍。

母体整个妊娠期的低蛋白饮食 (LP) 会影响出生时后代的胰腺 β 细胞分数，从而增加其成年后对 2 型糖尿病的易感性。本研究试图严格检查 LP 在妊娠最后一周 (LP12.5) 作为成年期 β 细胞编程和代谢功能障碍的发育窗口的影响。胰岛形态分析显示 LP12.5 新生儿的 β 细胞分数正常。在 6-8 周龄的雄性和雌性 LP12.5 后代中观察到正常的葡萄糖耐量。然而，雄性 LP12.5 后代表现出葡萄糖不耐受和胰岛素敏感性降低与 β 细胞功能障碍相关的衰老。代谢正常的 12 周龄雄性 LP12.5 暴露于高脂肪饮食会导致体重增加导致葡萄糖不耐受，尽管胰岛素分泌较高，但胰岛素抵抗和 β 细胞质量适应不足。通过基于实时 PCR 的胰岛微阵列通过微RNA (miRs) 评估表观遗传机制揭示了调节胰岛素分泌 (miRs 342, 143)、胰岛素抵抗 (miRs 143) 和肥胖 (miRs 219) 的 miRs 升高。在胰岛中，miR 143 的过表达减少了响应葡萄糖的胰岛素分泌。与整个怀孕期间的 LP 暴露模型相比，mTOR 和 Pdx1 的胰岛蛋白水平在 LP12.5 胰岛中是正常的。总的来说，这些数据表明，怀孕最后一周的 LP 饮食对于诱导控制葡萄糖稳态的组织的特定和独特的发育编程效应是至关重要的，