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 ß-cells due to beta-cell dedifferentiation is believed to be a
new mechanism of ß-cell loss in diabetes. However, the mechanism of ß-cell dedifferentiation
remains to be investigated. microRNAs (miRNAs) are small non-coding RNAs that regulate ß-
cell function and survival by inhibiting specific target gene expression. We discovered that miR-
483 is highly expressed in ß-cells, but much less in a-cells. Mice with ß-cell specific deletion of
miR-483 exhibited diet-induced hyperglycemia and reduced glucose tolerance without changing
in ß-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 ß-cell disallowed gene Aldh1a3, pointing to a direction linking
dysregulation of microRNAs with ß-cell dedifferentiation. The objective of this project is to identity
new factors/pathways initiating beta-cell dedifferentiation. We hypothesize that miR-483
maintains ß-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 ß-cell identity in miR-483
deficient mice after HFD feeding. Aim 2. Elucidate mechanism(s) by which miR-483 maintains ß-
cell identity. Moreover, the therapeutic potential of miR-483 in preventing ß-cell dedifferentiation
in human islets will be examined. The results obtained from this project will help understand the
underlying mechanisms of ß-cell dedifferentiation and guide therapeutical treatments for diabetes.
This project will also provide research opportunities for both undergraduate and graduate
students.