Research Projects

Chronic inflammation caused by excess Free fatty acids (FFA) due to metabolic overload leads to lipotoxicity and beta cell dysfunction. The most studied mechanism of islet inflammation is through TLR4 activation by FFA, but the underlying mechanism remains unknown. FFAs form complex with fetuin-A, a liver secreted glycoprotein, which binds to TLR4 and activates inflammatory processes in beta cells. Excess accumulation of fetuin-A in the islet microenvironment promotes beta cell dysfunction and death. During obesity, excess lipid storage is deposited to non-adipose tissues like liver and pancreas via Fatty acid translocase or CD36. CD36 expression in islets of diabetic obese subjects is significantly higher than in non-diabetic individuals. Inhibition of TLR4 helps reduce lipid droplets inside cells and triggers assembly of CD36-TLR4-TLR6 heterotrimeric complex in macrophages to promote sterile inflammation. Preliminary results suggest that MIN6 beta cells when incubated with fetuin-A and palmitate show increased accumulation of lipid droplets, leading to questions about the involvement of CD36 in fetuin-A-TLR4 mediated inflammation and its impact on beta cell dysfunction and death. specific objectives and experiments are planned to address these queries, including beta cell specific protein markers, CD36-TLR4 expressions and interaction studies, lipidomics study, lipid droplet marker analysis, and fatty acid uptake assays using specific inhibitors/siRNAs. This proposal aims to provide a fundamental understanding of lipid accumulation and inflammation in beta cells contributing to functional defects and identify CD36 as a potential target for future drug development in the context of lipid-induced type 2 diabetes.