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Content archived on 2024-05-27

The role of microRNAs in pancreatic islet dysfunction in type 2 diabetes mellitus

Final Report Summary - MIRT2DM (The role of microRNAs in pancreatic islet dysfunction in type 2 diabetes mellitus)

Type 2 diabetes mellitus (T2DM) is caused by a relative inability of the endocrine pancreas to meet the increasing metabolic demands of insulin resistance associated with obesity and ageing. Impaired insulin secretion is an early and critical step in the pathogenesis of type 2 diabetes, but the underlying mechanism of beta-cell loss and dysfunction in T2DM are incompletely understood. Recent studies have indicated a role for several microRNAs (miRNAs), a recently discovered class of evolutionarily conserved small noncoding RNAs that regulate gene expression at a posttranscriptional level. Specific expression of miRNAs in beta-cells has been reported. However, little is known about the role of miRNAs in the pathogenesis of T2DM. Therefore, the overall objective of this grant proposal was to understand the role of miRNAs in beta-cell function, glucose and lipid metabolism and etiology of T2DM. We aimed to determine whether miRNAs are involved in the loss of beta-cell function and beta-cell mass in T2DM. Using several mouse models of obesity and aging, we have identified several microRNAs, which are differently expressed in islets during obesity and ageing. In order to determine whether the changes in these microRNAs impact beta-cell function, we investigated the impact of changed microRNA expression on insulin secretion both in vitro and in vivo. Overexpression of several microRNAs in INS1E cells stimulated glucose stimulated insulin secretion. In order to determine whether increased microRNA expression would improve beta-cell function in vivo, we employed AAV8-mediated gene transfer using the rat insulin promoter in a double-stranded, self-complementary AAV vector to overexpress microRNAs specifically in the beta-cells. Gene transfer in C57Bl6 mice resulted in increased microRNA expression. Overexpression of specific microRNAs did not impact glucose homeostasis in chow fed animals. However, improved insulin secretion and glucose homeostasis was noticed after high-fat feeding. Furthermore, beta-cell proliferation in mice fed a high-fat diet was increased after gene transfer. Our data show that AAV8-mediated gene transfer of specific microRNAs to beta-cells improves beta-cell function in mice in response to a high fat diet.
Currently, Janine Kruit continues her research into the role of microRNAs in beta-cell dysfunction as an assistant professor at the department of Paediatrics at the University Medical Center Groningen, the Netherlands. Using the Marie Curie reintegration grant, she was able to set up the AAV8-mediated gene therapy to target beta-cells in vivo. The established fully functional core facility can design and produce AAV vectors to be used to study biological processes related to metabolic diseases in vivo in mice.