MIRT2DM

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

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

Identifying the mechanisms underlying the pathogenesis of diabetes should help treat this modern epidemic.

Descrizione progetto (Article)

Type 2 diabetes mellitus (T2DM) is a metabolic disorder associated with impaired insulin secretion. Obesity and ageing are known to contribute to disease pathogenesis by rendering the pancreas unable to meet the metabolic demands of the associated insulin resistance. However, the underlying mechanism of beta cell loss and dysfunction in T2DM are incompletely understood.

Accumulating evidence underscores the role of various microRNAs (miRNAs) in T2DM pathogenesis. miRNAs are a recently discovered class of small non-coding RNAs that regulate gene expression at the post-transcriptional level.

As a result, scientists on the EU-funded project 'The role of microRNAs in pancreatic islet dysfunction in type 2 diabetes mellitus' (MIRT2DM) decided to study the role of specific miRNAs in beta cell function, glucose and lipid metabolism, and overall aetiology of T2DM. For this purpose, they used several mouse models of obesity and ageing to identify miRNAs, which are differentially expressed in islets during obesity and ageing.

To understand the impact of these miRNAs on physiological pancreatic function, researchers overexpressed them in islets to identify that certain miRNAs stimulated insulin secretion. When beta cells overexpressing these miRNAs were transplanted into mice, improved glucose homeostasis and insulin secretion were observed when these animals switched to a high-fat diet.

Collectively, these observations clearly demonstrate the molecular nature of pancreatic cell function regulation. It remains to be determined how expression of these miRNAs gets altered during diabetes and how they induce beta cell function and mass in T2DM. Nonetheless, the concept of miRNAs as therapeutic targets for T2DM is novel and opens up new avenues for future research studies.