Investigation into the mechanisms of beta-cell specific overexpression of peroxisome proliferator activated receptors in obesity-induced type 2 diabetes.

In obesity, adipose tissue expandability and triglyceride storage is challenged resulting in lipid accumulation in ectopic tissues, including pancreatic β-cells. It is hypothesized that accumulation of toxic lipid derivatives induces β-cell failure, causing dysregulated glucose homeostasis in obesity. I am interested in understanding if manipulating expression of peroxisome proliferator activated receptors (PPARs), mediators of lipid sensing and metabolism, in β-cells during development of obesity will affect lipotoxic β-cell failure. Activation of endogenous PPARδ in vitro has been shown to protect against lipotoxic β-cell failure. I report that PPARδ overexpression in β-cells under lipotoxic conditions diminishes this protective effect. Furthermore, in vivo models of β-cell specific PPARγ2 overexpression exhibit impaired carbohydrate metabolism. I report that islets from these obese mice demonstrate reductions in lipids promoting signalling of insulin release and upregulation of genes regulating recruitment of fatty acids and lipid oxidation, which may explain carbohydrate metabolism impairments in these mice.