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Date of Award


Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy in Biological Sciences (PhD)

Administrative Home Department

Department of Biological Sciences

Advisor 1

Xiaoqing Tang

Committee Member 1

Ebenezer Tumban

Committee Member 2

Xiaohu Tang

Committee Member 3

Qinghui Chen


Type 2 diabetes is a metabolic disorder that causes hyperglycemia in patients. Pancreatic β-cell dysfunction is central to the development and progression of type 2 diabetes. New evidence indicated that altered β-cell identity due to β-cell dedifferentiation is believed to be a new mechanism for β-cell dysfunction and loss during the development of T2D. However, the precise mechanisms involved in β-cell dedifferentiation are still under investigation. MicroRNAs (miRNA) are a group of small non-coding RNAs known to negatively regulate target gene expression in response to metabolic changes in pancreatic islets. Dysregulation of miRNAs has been associated with pancreatic islet dysfunction in type 2 diabetes. Our previous studies have shown that miR-483 expression is much higher in β-cells than α-cells. Elevated miR-483 is also observed in the islets of prediabetic db/db mice, indicating that miR-483 plays important function in β-cells.

In chapter 1 of this dissertation, we generated a βcell specific knockout mouse model of miR-483 in order to explore the physiological function of miR-483. We found that loss of miR-483 induced hyperglycemia and glucose intolerance through reduction of insulin secretion in miR-483 knockout mice (miR483-/-) fed high-fat-diet (HFD). miR-483 deficiency also induced alteration in blood lipid profile with increased low-density lipoproteins (LDL) and decreased high-density lipoprotein (HDL). RNA sequencing analysis of isolated islets indicated that miR-483 inactivation significantly increased multiple pathways involved in metabolic pathway and mitochondria function.

In chapter 2 of this dissertation, we validated that aldehyde dehydrogenase family 1, subfamily A3 (Aldh1a3) was a direct target of miR-483. ALDH1A3 is a recognized biomarker of β-cell dedifferentiation. miR-483 deficiency significantly increased ALDH1A3 expression in the islets of HFD-fed miR483-/- mice, whereas overexpression of miR-483 repressed ALDH1A3 expression. These data suggest that miR-483 is critical in protecting β-cell function by preventing β-cell dedifferentiation.

In chapter 3 of this dissertation, we further investigated the identity of dedifferentiated β-cells in miR483-/- mice. When mice fed HFD or injected with streptozotocin (STZ), a drug widely used to induce diabetes, a higher percentage of ALDH1A3-positive cells was colocalized with glucagon in miR483-/- mice compared to the control mice. Increased glucagon contents were further confirmed in miR483-/- islets and miR483-deleted MIN6 cells when treated with STZ. In addition, miR-483 inactivation significantly increases multiple enzymes involved in adaptive oxidative stress response including gamma-glutamyl transferase (GGT1). In summary, our data indicated that miR-483 is important for maintaining β-cell identity, and miR-483 deficiency induces oxidation stress and β-cell dedifferentiation.