Manipulation of Endogenous and Exogenous Sources of Cholesterol and its Effects on Beta Cell Function.
Bacani, Joseph Gerard
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Type 2 diabetes mellitus (T2DM) prevalence continues to increase worldwide. Changes in β-cell function and mechanisms behind the aberrant insulin secretion found in T2DM patients are still poorly understood. Cholesterol is a vital molecule to all cellular systems, being an important factor regulating membrane fluidity and a number of signalling pathways. In this study, a series of experiments are conducted on the mouse insulinoma cell line, MIN6, limiting exogenous cholesterol through use of lipid free serum, as well as limiting endogenous cholesterol sources through the use of 3-hydroxy-3-methyl-glutaryl-CoA reductase and 7-dehydrocholesteral reductase inhibitors. The results show a marked decrease in both cholesterol content as well glucose stimulated insulin secretion in the drug-treated groups. A series of promoter assays, RT-PCR experiments and western blot analysis determined disruption in site-directed surface expression of important channel proteins involved in insulin secretion, and potentially a change in insulin degradation enzyme activity.