PhD Graduate: Li Hong Yu
Thesis Title: Functional Role of BIG3 in the Regulated Secretory Pathway

Abstract
The beta cell dysfunction in insulin secretion is one of the key factors in the pathophysiology of diabetes. However the mechanisms that underline the development of the beta cell dysfunction in humans still remain elusive. Arf-GEFs are a family of Sec7 domain proteins that regulate intracellular vesicle trafficking. BIG3 is identified as a putative member of the Sec7 protein family and distantly related to BIG/Sec7p subfamily. BIG3 mRNA expression profile shows it is selectively expressed with high levels in the brain and islet. This study therefore investigates the function of endogenous BIG3 in islet cells. BIG3 protein was found highly expressed in beta cells, and preferentially localized to the secretory granules. Investigations on BIG3 knockdown and knockout beta cells demonstrated that the deficiency of BIG3 caused increased amount of secretory granules and secretory proteins in the cells, and elevated secretion upon stimulation. The study on BIG3 knockout mice revealed that in the absence of BIG3, the mice exhibited relatively elevated blood insulin level, disturbed glucose homeostasis, impaired glucose tolerance, reduced insulin sensitivity, fatty liver disease, disturbed energy expenditure and activity, and reduced testosterone level. Up-regulated insulin storage and secretion in beta cells may account for the elevated blood insulin level. The metabolic abnormalities could be in part due to the excessively secreted insulin. These data demonstrate for the first time that BIG3 has a functional role in the regulated secretory pathway to modulate the insulin secretion, and therefore to affect the whole body metabolic homeostasis.

Figure Legend:
Increased insulin granule number in absence of BIG3. BIG3 knockout mice were generated. Beta cells from wild type (+/+) and knockout (-/-) mice were examined by electron microscopy. The dense core granules represent the insulin granules in beta cells. The granule number in BIG3-/- beta cell was found increased by ~ 2.5 folds. The numbers were presented as per 100µm2. p<0.001, n=20. The granule size was not significantly altered in BIG3 -/- beta cells. p=0.955, n=20.

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