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Leslie Sedgeman, Ph.D.

Department: Molecular Physiology & Biophysics, 2018

Faculty Mentor: Kasey Vickers, Ph.D.

Dissertation Title: The pathophysiology and functionality of metabolic microRNAs in Type 2 Diabetes Mellitus

Dissertation Abstract: MicroRNAs (miRNA) have been shown to be critical players in metabolism. While most miRNAs studies have focused on their functional role within cells, miRNAs are also found extracellularly and have been proposed to participate in cell-to-cell communication. Our group has uncovered that high-density lipoproteins carry miRNAs in circulation and protect them from degradation by RNases. However, there are considerable gaps in our understanding of the networks of tissues/cells that export miRNAs to HDL and the cells that take up HDL-miRNAs, as well as how these processes are regulated. One of the most abundant miRNAs on HDL is miR-375-3p, an islet-enriched miRNA. To determine if β cells export miR-375-3p to HDL, we developed an assay to quantify miR-375-3p export to HDL, by measuring miRNAs on HDL before and after interaction with islets or INS-1 cells. miRNA export to HDL was found to be specific for miR-375-3p. We next investigated the mechanisms of miR-375-3p export to HDL, and found that this process is independent of cholesterol transporters, and occurs during cellular conditions of low insulin secretion from the β cell. Extracellular miRNAs have also been proposed as biomarkers of disease, and plasma/serum miR-375-3p has been investigated as a biomarker of β cell death in Type I Diabetes (T1D). In line with this, our work found that miR-375-3p was increased in streptozotocin-treated mice (a model of T1D). However, there was no difference in miR-375-3p levels in human subjects with Type 2 Diabetes (T2D) or two rodent models of T2D. Despite these results, studies in other rodent models and humans have found changes suggesting miR-375-3p may have potential as a biomarker for T2D. Furthermore, we also investigated hepatic miRNAs changes in response to the bile acid sequestrant, colesevelam. Colesevelam is a lipid and glucose lowering drug, and we found that the cholesterol regulated miRNA cluster, miR-96/182/183, was upregulated in response to colesevelam. Inhibition of miR-182 in vivo partially reversed the glucose lowering effects of colesevelam, suggesting that miR-182 confers some of the effects of colesevelam on glucose control. Together this work provides novel mechanistic insights into the release of miRNAs to HDL and the role of miR-182 in the liver.