Type 2 diabetes (T2D) is a major health problem worldwide. Identifying modifiable risk factors is key in decreasing the incidence and associated economic burden of T2D. Both genetic and environmental factors contribute to the development of T2D. The fetal nutrient environment during pregnancy is as a major factor that modifies the risk for developing T2D. Studies from humans and animal models show robust associations between poor fetal growth and the development of T2D due to maternal malnutrition during pregnancy, which results from permanent changes in pancreatic ?-cell function and increases susceptibility to T2D. The overall research objective of this K01 proposal is to understand how maternal low-protein-diet during pregnancy (LP0.5) alters the offspring's ?-cell function and susceptibility to T2D and to identify the mechanistic link between LP0.5 and sensitivity to cellula stress dysregulation in chronic hyperglycemia and hyperlipidemia conditions (glucolipotoxicity). The roles of O-GlcNAc transferase (OGT), a nutrient-sensing protein and a key regulator of cellular stress responses, in LP0.5 ?-cell susceptibility to T2D will also be identified. Thus, th central hypothesis to be tested is that LP0.5 predisposes offspring to T2D by regulating OGT levels, which enhances the susceptibility of ?-cells to glucolipotoxicity-induced ER stress and cell death.
Three specific aims will be carried out to test this hypothesis: 1) Identify the mechanisms of how LP0.5 ?-cell susceptibility to glucolipotoxicity; 2) Identify how OGT activity (enhanced O-GlcNAcylation) modulates ?-cell susceptibility to glucolipotoxicity-induced ER stress; and 3) Determine the extent to which gain of O-GlcNAcylation during pregnancy rescues the abnormalities induced by LP0.5. Based on preliminary data, the working hypothesis of these specific aims is that LP0.5 predisposes ?-cells to increased sensitivity to glucolipotoxicity by enhancing ER stress and cell death responses by regulating OGT activity. This hypothesis will be tested in vivo by subjecting LP0.5 mice to in vivo infusion of glucose and lipid. ?-cell functin, molecular markers of ER stress and cell death, and morphology of the ER will be assessed. The working hypothesis that enhancing O- GlcNAcylation during pregnancy will protect the offspring against T2D by inducing long-term gains in ?-cell mass and function will further show the importance of OGT in -cell development and function. Thus, the metabolic profile and ?-cell phenotype of LP0.5 offspring exposed to a drug that enhances O-GlcNAcylation during gestation will be assessed in normal and diabetogenic conditions. These studies will fill significant gaps on the roles of OGT in ?-cell development and function and the pathogenesis of T2D and the results will have a significant impact on multiple levels. In the short-term, the generated data will identify the molecular mechanisms by which LP0.5 alters ?-cell development, impacting sensitivity to cellular stress and the susceptibility to T2D. The long-term objective is that these studies will aid in the development of drugs targeting OGT and dietary approaches to prevent T2D and other chronic diseases.
The mechanisms by which adverse intrauterine environments increase the susceptibility to developing glucose intolerance and type 2 diabetes are not well understood, but a primary developmental insult to the pancreatic ?-cell, causing permanent changes in both insulin secretion capacity and sensitivity to cellular stress, has been described as an important contributing factor. The goal of this application is to identify the molecular mechanisms by which maternal malnutrition during pregnancy impacts ?-cell sensitivity to cellular stress dysregulation and susceptibility to type 2 diabetes. This proposal will fill significant gaps in our understanding of the pathogenesis of type 2 diabetes and provide a framework for developing strategies for preventing diabetes in growth-retarded fetuses and identifying pharmacological targets to improve ?-cell mass and function.
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