Risk of insulin resistance and diabetes due to deleterious in utero conditions: role of microRNAs – DiamiRs

The world epidemic of type 2 diabetes (T2D) is a major public health problem due to its high human and economical burden. Both environmental/lifestyle and genetic factors contribute to the pathogenesis of T2D which is characterized by insulin resistance coupled to pancreatic beta cell failure leading to chronic hyperglycemia. The risk of developing chronic diseases is partly dependent on environmental factors acting early in life. Indeed, intrauterine growth-retardation (IUGR) is associated to increased risk for T2D in adult progeny probably due to epigenetic modifications. Such modifications have been shown to lead to stable propagation of gene activity from one cell generation to the following one. As microRNAs (miRNAs) are related to epigenetic mechanisms we hypothesize that, under deleterious in utero conditions, alterations occur in miRNA control of gene regulation. The overall aim of our proposal is to identify and characterize miRNAs with modified expression in the fetal liver and pancreas of offspring of rat dams exposed during pregnancy to unfavorable environmental/dietary conditions that lead to increased risk of insulin resistance and T2D.
The proposal is comprised of the four following tasks. In task 1, using “small RNA deep sequencing” we will explore differential miRNA expression in fetal pancreas and liver of three rat models of IUGR leading to development of insulin resistance/T2D. In task 2, we will identify and validate the miRNA targets. We will focus on proteins involved in beta cell mass determination, glucose and lipid metabolism, insulin secretion and action, and the epigenetic machinery. In task 3, we will examine whether changes in miRNA patterns persist until T2D appearance. If they perdure, we will address the transgenerational transmission issue. If they do not persist, we will first determine whether the miRNA changes are mitotically inheritable, and if this is the case, whether the diabetic environment may have blurred the miRNA profile. In task 4, we will examine the causal role of our miRNAs of interest in insulin resistance/T2D. This will be explored by viral expression of miRNAs or their specific antisense oligonucleotides in cultured cells and in intact animals.
Our preliminary data on two models of IUGR show that approximately 30 known miRNAs have a similarly altered expression in the fetal liver, and hence they could be linked to the development of insulin resistance/T2D. Thus, we genuinely believe that our multipronged approach using powerful cutting edge technologies mastered by our research team and partners will allow us to develop our project with success, and to significantly advance the understanding of the mechanisms leading to increased diabetes risk. Therefore, our project will have important medical implications by fostering the development of prevention strategies for T2D, and may in the future harness the epidemic. Hence the impact of our endeavor is likely to lead to health promotion.