Islet Dysfunction In Diabetes

Type 2 Diabetes [T2DM] is a chronic condition resulting from gradual failure of pancreatic beta cells to synthesize and secrete sufficient insulin to meet the metabolic demands and the inability of tissues [muscle, adipose and liver] to efficiently utilize the secreted insulin leading to an overall increase in blood glucose levels [hyperglycemia]. As indicated by recent estimates from the International Diabetes Federation, the prevalence of the disease in the year 2014 has risen to a record 387 million worldwide. The main objective of my project was to study the mechanisms involved in pancreatic beta cell dysfunction in diabetes, specifically in elucidating the role of endoplasmic reticulum [ER] - mitochondria axis, executioner caspases and their target substrates; specifically nuclear lamins. Results obtained from our studies in pure beta cells [INS-1 832/13], primary rodent and human islets strongly suggest that glucotoxicity induced pancreatic beta cell damage involves the degradation of nuclear lamins A and B, via ER stress-mediated activation of executioner caspases 3 and 6. We confirmed this by employing pharmacological approaches [inhibitors of -ER stress, -caspase activation and calcium channel activation] to gain mechanistic insights into beta cell dysfunction under the duress of chronic hyperglycemia. Further, we were able to corroborate these findings in the ZDF rat, an animal model for T2DM and in islets obtained from human donors with T2DM. Also, our findings revealed significant attenuation of glucose-stimulated insulin secretion [GSIS] in beta cells exposed to glucotoxic conditions suggesting cellular dysfunction under these conditions. Post-translational prenylation of lamins is important for their localization into the nuclear membrane, and subsequent interaction with other proteins. Our results indicate that inhibition of prenylation by simvastatin and a site-specific inhibitor of protein farnesylation [FTI-277], promoted mitochondrial and nuclear defects as evidenced by caspase activation and lamin degradation in INS-1 832/13 cells and normal rodent islets. Our findings also suggest that inhibition of protein prenylation leads to increase in stress kinase [p38 kinase] and inhibition of ERK1/2, known for its cell survival roles. Collectively, these alterations in cell signaling pathways could promote intracellular stress and demise. We hope that data accrued in these studies will provide fresh insights into the identification of the intracellular mechanisms involved in beta cell malfunction in nutrient overload and metabolic stress. These studies will also aid in the identification of potential drug targets for the management and/or prevention of diabetes