Extensive epidemiological evidence in humans and animal models suggests that poor maternal nutrition increases the susceptibility of the offspring to develop type-2 diabetes (T2D). The mechanisms by which adverse intrauterine environment increases the susceptibility to develop glucose intolerance and T2D are not well understood. However, current evidence supports the idea that a fetal nutrient environment induces long- term defects in -cell mass and function. How the fetal nutrient environment induces permanent changes in - cells and alters susceptibility to T2D is unknown. In the previous cycle, we discovered that protein restriction during pregnancy (LP) induces alterations in insulin secretion,increased susceptibility to glucolipotoxicity induced ER stress and impaired glucose tolerance by inducing the expression of a subset of microRNAs in islets from adult animals (mir-199 and mir-7). We also identified that these functional changes in -cells were associated to microRNA-mediated permanent reduction in mTOR and O-GlcNAc transferase (OGT) protein levels. The objective of this application is to build on these observations and assess how LP induces permanent changes in microRNA expression to regulate mTOR and OGT levels and susceptibility to diabetes. The central hypothesis to be tested is that protein insufficiency durin pregnancy alters insulin secretion and susceptibility to glucolipotoxicity-induced ER stress by regulating expression of mir-199 and mir-7 and their target genes mTOR and OGT respectively. These studies will determine first how LP acts on mir-199 and mir- 7 expression to regulate mTOR and OGT. Second, we will delineate how LP0.5 alters insulin secretion and - cell susceptibility to glucolipotoxicity. Finally, we will determine the extent to which different interventions during pregnancy rescue the metabolic and molecular abnormalities induced by LP0.5. These studies will enhance our understanding of the molecular mechanisms that govern the long-term consequences of the fetal environment on -cell mass and function. This information can be used to design novel therapeutic approaches to improve -cell mass and function in diabetics. Finally, understanding the pathophysiology of glucose intolerance observed in individuals with intrauterine growth retardation is important for both prevention and therapy.
The mechanisms by which adverse intrauterine environment increases the susceptibility to develop glucose intolerance and type 2 diabetes are not well understood but a primary developmental insult to the -cell has been described. The goal of this application is to elucidate the how adverse nutrient environment during pregnancy induces permanent alterations in -cells in an effort to develop strategies to prevent diabetes in growth retarded fetuses and to identify pharmacological targets to improve -cell mass and function.
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