microRNA-483 regulation of pancreatic beta-cell function and identity

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Abstract: Type 2 diabetes is a metabolic disorder that causes hyperglycemia in patients. Loss of functional beta-cell mass is a hallmark of progression from insulin resistance to overt diabetes. New evidence indicated altered identity of β-cells due to beta-cell dedifferentiation is believed to be a new mechanism of β-cell loss in diabetes. However, the mechanism of β-cell dedifferentiation remains to be investigated. microRNAs (miRNAs) are small non-coding RNAs that regulate β- cell function and survival by inhibiting specific target gene expression. We discovered that miR- 483 is highly expressed in β-cells, but much less in α-cells. Mice with β-cell specific deletion of miR-483 exhibited diet-induced hyperglycemia and reduced glucose tolerance without changing in β-cell mass. RNA-seq analysis revealed that miR-483 inactivation resulted in a marked increase in oxidative stress markers including gamma-glutamyltransferase (Ggt1), suggesting that miR- 483 deficiency activates oxidation stress, which causes mitochondrial dysfunction and simultaneously triggers an adaptive antioxidant stress response. Notably, miR-483 deletion increases expression of a β-cell disallowed gene Aldh1a3, pointing to a direction linking dysregulation of microRNAs with β-cell dedifferentiation. The objective of this project is to identity new factors/pathways initiating beta-cell dedifferentiation. We hypothesize that miR-483 maintains β-cell identity by preventing beta-cell dedifferentiation, and miR-483 inactivation induces alteration of antioxidant defense that in turn leads to mitochondrial dysfunction. We will test this hypothesis with the following Aims: Aim 1. Determine the β-cell identity in miR-483 deficient mice after HFD feeding. Aim 2. Elucidate mechanism(s) by which miR-483 maintains β- cell identity. Moreover, the therapeutic potential of miR-483 in preventing β-cell dedifferentiation in human islets will be examined. The results obtained from this project will help understand the underlying mechanisms of β-cell dedifferentiation and guide therapeutical treatments for diabetes. This project will also provide research opportunities for both undergraduate and graduate students.