Thesis

MicroRNA-375 has opposing effects on cell proliferation in pancreatic α- and β-cells

Diabetes is a disease in which patients exhibit deficiencies in their ability to secrete or respond to insulin and is affecting both national and worldwide populations. There are two types of diabetes, type I and type II. In type II diabetes patients, tissues become insulin resistant, requiring pancreatic β-cells to produce more insulin. MicroRNAs (miRNAs) are small 21-23 nucleotide non-coding RNAs that target the 3’ untranslated region (UTR) of gene transcripts, inhibiting their expression. One miRNA, miR-375, appears in diabetic’s serum more than non-diabetic patients. In diabetic patients with elevated miR-375, β-cell numbers were reduced while pancreatic α-cells increased. In this thesis, I focus on the effects that miR-375 has on β-cell and α-cell proliferation. When inhibiting miR-375 I discovered that α-cells in culture proliferated about 20% less, as one might see in diabetics. Conversely, β-cells in culture proliferated about 20% more, again, as one might see in diabetics. I also focus on target genes of the miR-375: Rasd1 and Pdk1. Rasd1 is a negative regulator of cell proliferation in G coupled protein receptor signaling. Pdk1 is involved in the PI3/Akt pathway for promoting cell proliferation. I predicted that the negative regulator Rasd1 would be less abundant in α-cells compared to β-cells, and in fact this is what I discovered. Though inconclusive, knock down of miR-375 suggests Rasd1 is targeted in α-cells but not in β-cells. The results suggest that miR-375 is important for cell proliferation within α-cells but is inhibitory to β-cell.

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