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

项目概要/摘要 在美国，每年有超过一百万的新生儿出生于肥胖的母亲， 2型糖尿病的发病率2型糖尿病（T2 D）的发展 肥胖母亲的后代是继发于胰岛素抵抗，肥胖增加， 炎症增加和β细胞功能降低。使用母体肥胖的临床前模型， 我们和其他人已经表明，男性后代更有可能发展为胰岛胰岛素分泌型， 与雌性后代相比，然而，潜在的分子过程仍然存在， 不清楚我们的初步数据还表明，糖耐量和胰岛功能的性别差异， 再生胰岛衍生蛋白3-γ差异表达相关的功能障碍 （Reg3g）。Reg 3g是外生肌肽样糖基转移酶3（EXTL 3）的配体，其启动乙酰肝素 硫酸化糖胺聚糖（HSG）聚合。具体来说，我们发现雌性后代 暴露于母体肥胖的小鼠表现出更高的胰岛Reg 3g HSG，并保护其不受葡萄糖的影响 不耐受和胰岛功能障碍。在Reg 3g单倍不足雌性中，保护作用减弱 后代相比之下，肥胖母鼠所生的雄性后代的胰岛Reg 3g和HSG没有变化， 表现出显著更差的葡萄糖耐量和离体胰岛素分泌的减少。最后， 用重组Reg 3g和硫酸乙酰肝素类似物治疗改善了 肥胖小鼠的雄性后代。我们的初步数据还表明ERK 1/2信号转导是 由Reg 3g和HSG激活的下游途径，其维持β细胞胰岛素分泌。给定 根据这些发现，我们推测Reg 3g的上调诱导了HSG的形成并保护了HSG的表达。 通过维持ERK 1/2磷酸化，肥胖小鼠的后代免于β细胞功能障碍。我们也 假设Reg 3g在肥胖小鼠后代和人类中保持胰岛胰岛素分泌 胰岛通过HSG聚合。在本提案中，我们将1）定义Reg 3g-HSG-ERK 1/2的作用 在肥胖小鼠后代中介导胰岛胰岛素分泌性别差异的信号传导，和2） 确定Reg 3g介导的HSG聚合在拯救胰腺癌中的治疗潜力 肥胖小鼠后代和人类胰岛中的胰岛功能障碍。这项研究计划将告知小说 以及调节胰岛功能障碍的性别差异的顺从分子途径， 肥胖的母亲该职业发展奖还允许主要研究者获得 培养胰岛生物学和实验室技能的最新概念， 独立的医学科学家。

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.