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Access Type

WSU Access

Date of Award

January 2022

Degree Type


Degree Name



Pharmaceutical Sciences

First Advisor

Anjaneyulu Kowluru


Defects in insulin secretion from pancreatic islet beta- cells leads to long term complications such as type 2 diabetes mellitus. The mechanism and regulation of glucose stimulated insulin secretion (GSIS) as well as factors contributing to pancreatic islet beta-cell demise are yet poorly understood. Previous work from our laboratory demonstrated that Ras-related C3 botulinum toxin substrate 1 (Rac1), a small G- protein is involved in GSIS as well as in culminating dysfunction under metabolic stress. Cycling of Rac1 between its inactive and active form is considered a vital event in glucose stimulated insulin secretion. This conversion is made possible by at least three types of regulatory proteins/ factors. [Guanine nucleotide exchange factors (GEFs)- that activates Rac1 by assisting in conversion of GDP- bound/ inactive Rac1 to GTP-bound/ active Rac1, Guanine nucleotide dissociation inhibitors (GDIs)- that prevents Rac1 activation by preventing GDP dissociation and GTP-ase activating proteins (GAPs)- that converts active Rac1 to its inactive form by completing the hydrolytic cycle.] Metabolic stress on islet beta- cells lead to sustained activation of Rac1, Nox2 mediated oxidative stress and downstream activation of MAPK. My project was aimed on investigating the roles of novel GEF, phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1 (P-Rex1)- a Rac1 specific GEF, and a novel scaffolding protein, caspase recruitment domain containing protein-9 (CARD9) in insulin secreting clonal pancreatic islet beta- cells. Methodical experimentation using INS-1 832/13 cells, showed that P-Rex1 is a key regulator/GEF for glucose-induced Rac1 activation and GSIS with additional roles of membrane targeting of Rac1 under acute glucose stimulatory conditions. CARD9 regulates GSIS via a Rac1-independent and p38MAPK-dependent signaling module. Under the duress of metabolic stress CARD9 mediates cellular dysfunction via accelerating the Rac- p38MAPK axis, culminating in endoplasmic reticulum stress and oxidative stress. Further, CARD9 is involved activation of NF-kB p65 signaling pathway in islet beta- cells. This study reports original contributory roles of different classes of regulatory proteins on small G- protein mediated islet beta- cell function, that may serve as therapeutic targets to alleviate insulin secretory defects.

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