Investigating the Downstream Mechanisms Contributing to Beta Cell Failure in Offspring Exposed to Maternal Obesity

项目摘要/摘要 在美国，每年有100多万肥胖母亲所生的新生儿有更高的患病风险。 在更年轻的时候患上2型糖尿病。2型糖尿病(T2D)的发病情况 肥胖母亲的后代继发于胰岛素抵抗、肥胖增加、 炎症加重，β细胞功能下降。使用母体肥胖的临床前模型， 我们和其他人已经表明，雄性后代更有可能产生胰岛胰岛素分泌 与雌性后代相比，有功能障碍。然而，潜在的分子过程仍然 不清楚。我们的初步数据还显示，葡萄糖耐量和胰岛的性别差异 功能障碍与再生胰岛衍生蛋白3-Gamma的差异表达 (Reg3g)。Reg3g是启动肝素的Exostosin样糖基转移酶3(EXTL3)的配体 硫酸糖胺聚糖(HSG)聚合。具体来说，我们发现雌性后代 暴露于母亲肥胖的人表现出较高的胰岛Reg3g HSG，并受到葡萄糖的保护 不耐受和胰岛功能障碍。在Reg3g单倍体不足的雌性中，保护作用减弱 后代。相比之下，肥胖水母所生的雄性后代的胰岛Reg3g和HSG没有变化， 表现出明显更差的葡萄糖耐量和体外胰岛素分泌减少。最后， 重组Reg3g和硫酸肝素类似物可改善小鼠的糖耐量 肥胖小鼠的雄性后代。我们的初步数据也表明ERK1/2信号是 下游通路由Reg3g和HSG激活，维持β细胞胰岛素的分泌。vt.给出 这些发现，我们假设Reg3g的上调诱导HSG的形成并保护 肥胖小鼠的后代通过维持ERK1/2的磷酸化而导致β细胞功能障碍。我们也 假设Reg3g保留肥胖小鼠和人类后代的胰岛胰岛素分泌 胰岛通过HSG聚合。在本提案中，我们将1)定义Reg3g-HSG-ERK1/2的角色 信号调节肥胖小鼠后代胰岛胰岛素分泌的性别差异，以及2) 确定Reg3g介导的HSG聚合在挽救胰腺中的治疗潜力 肥胖小鼠后代和人类胰岛的胰岛功能障碍。这项研究计划将为小说 以及调节后代胰岛功能障碍的性别差异的顺从分子途径 肥胖的母亲。这一职业发展奖还允许首席调查员获得 对最新的胰岛生物学概念和实验室技能进行培训，以成为 独立的内科科学家。

Project Summary/Abstract Annually, over one million newborns are born to obese mothers in the US and suffer a higher risk of developing type 2 diabetes at a younger age. The development of type 2 diabetes (T2D) in the offspring of obese mothers is secondary to a combination of insulin resistance, increased adiposity, increased inflammation, and decreased β cell function. Using preclinical models of maternal obesity, we and others have shown that male offspring are more likely to develop islet insulin secretory dysfunction compared to female offspring. However, the underlying molecular processes remain unclear. Our preliminary data also showed that the sex-differences in glucose intolerance and islet dysfunction correlated with differential expression of Regenerating islet derived protein 3-Gamma (Reg3g). Reg3g is a ligand to Exostosin-Like Glycosyltransferase 3 (EXTL3) that initiates heparan sulfate glycosaminoglycan (HSG) polymerization. Specifically, we found that female offspring exposed to maternal obesity exhibited higher islet Reg3g HSG, and were protected from glucose intolerance and islet dysfunction. The protection was diminished in Reg3g haploinsufficient female offspring. In contrast, male offspring born to obese dams had unchanged islet Reg3g and HSG, and exhibited significantly worse glucose tolerance and a decrease in ex-vivo insulin secretion. Finally, treatment with recombinant Reg3g and a heparan sulfate analogue improved glucose tolerance in male offspring of obese mice. Our preliminary data also implicated ERK1/2 signaling as the downstream pathway activated by Reg3g and HSG that maintains β cell insulin secretion. Given these findings, we hypothesize that the upregulation of Reg3g induces HSG formation and protects offspring of obese mice from β cell dysfunction by maintaining ERK1/2 phosphorylation. We also hypothesize that Reg3g preserves islet insulin secretion in offspring of obese mice and in human islets through HSG polymerization. In this proposal, we will 1) define the role of Reg3g-HSG-ERK1/2 signaling in mediating sex-differences in islet insulin secretion in the offspring of obese mice, and 2) determine the therapeutic potential of Reg3g-mediated HSG polymerization in rescuing pancreatic islet dysfunction in offspring of obese mice and in human islets. This research plan will inform novel and amenable molecular pathways that regulate sex-differences in islet dysfunction in offspring of obese mothers. This career development award also allows the principal investigator to receive training in the state-of-the-art concepts of islet biology and laboratory skills necessary to become an independent physician scientist.