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 ß-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 β-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 is to understand the role of miRNAs in ß-cell function, glucose and lipid metabolism and etiology of T2DM. We aim to determine whether miRNAs are involved in the loss of ß-cell function and ß-cell mass in T2DM and will investigate the potential of miRNAs as a therapeutic target in T2DM.First we will identify miRNAs that are differentially expressed in β-cells of normoglycemic, hyperglycemic and T2DM mice. We will next examine these differentially expressed miRNAs on their potential to dysregulate β-cell physiology in vitro. The impact of the promising miRNAs on β-cell function and β-cell mass will be assessed in C57Bl6 mice by overexpressing or silencing miRNA specifically in β-cells using AAV vectors. To determine the potential of miRNAs that affect β-cell development or function as therapeutic targets for T2DM, we will study these miRNAs in diabetic mice.This work will generate new knowledge about the role of miRNAs in ß-cell function, glucose metabolism and T2DM. This may point to new therapeutic approaches focusing on restoring or silencing of specific miRNAs in pancreatic β-cells.