Distinct Roles of Class 1 PI3K Isoforms in the Regulation of Beta Cell Exocytosis and Insulin Secretion Open Access
- Other title
- Type of item
- Degree grantor
University of Alberta
- Author or creator
- Supervisor and department
Dr. Patrick MacDonald (Department of Pharmacology)
- Examining committee member and department
Dr. Frederick Tse (Department of Pharmacology)
Dr. Catherine Chan (Dept. of Agricultural, Food & Nutritional Science)
Dr. John Chang (Department of Biological Sciences)
Dr. Debbie Thurmond (Department of Biochemistry & Molecular Biology, Department of Cellular & Integrative Physiology)
Department of Pharmacology
- Date accepted
- Graduation date
Doctor of Philosophy
- Degree level
Type 2 diabetes (T2D) is characterized by peripheral insulin resistance and an insufficiency of insulin secretion from the pancreatic beta cell. The incidence of T2D is rising worldwide at an alarming rate. An increase in population growth, increased prevalence of obesity, and an aging population are all thought to be contributing to this rise in T2D incidence. The economic burden of this disease is increasing globally; but more importantly, despite numerous treatment options, many type 2 diabetic patients still suffer from a decreased life expectancy. The mechanisms that regulate insulin secretion from the pancreatic beta cell are still not fully understood. Thus in order to understand beta cell dysfunction in disease state, it is essential to fully understand the mechanisms that regulate insulin secretion from the healthy pancreatic beta cell. The present thesis will thus investigate the role of class 1 phosphoinositide 3-kinase (PI3K) isoforms in the regulation of beta cell exocytosis and insulin secretion. The PI3K family of enzymes is linked to a large number of diverse cellular functions, and is essential to almost all aspects of cell and tissue biology. PI3Ks are known to have critical roles in the control of islet mass and function, and alterations in PI3K signaling are shown to be associated with T2D. The chronic genetic impairment of upstream PI3K signaling in islets results in impaired insulin secretion; but this is contrasted by findings showing that pharmacologic PI3K inhibition increases glucose-stimulated insulin secretion. However, PI3Ks are a diverse family of enzymes, and recently there has been a broadening recognition of the importance of distinct PI3K isoforms. The work presented here confirms the expression of three class 1 PI3K isoforms: p110alpha, beta and gamma in mouse and human islets, and identifies a distinct role for each in insulin secretion and beta cell exocytosis. Using selective pharmacologic inhibition and shRNA-mediated knockdown, p110alpha is shown to negatively regulate glucose-stimulated insulin secretion (GSIS) by limiting Ca2+-dependent exocytosis in beta cells. p110beta however, exerts a positive insulinotropic effect upstream of exocytosis, by promoting insulin granule localization to the plasma membrane, independent of its catalytic activity. Finally, the G-protein coupled p110gamma is shown to be a positive regulator of insulin secretion and exocytosis. It plays an important role in maintaining a membrane-docked, readily releasable pool of secretory granules, (at least in part) through the regulation of cortical F-actin polymerization. The requirement for p110gamma signaling in GIP-R and GLP-1-R induced insulin secretion is also examined in this thesis. p110gamma inhibition or shRNA-mediated knockdown impairs the insulinotropic effects of GIP-R (but not GLP-1-R) activation in mouse and human islets. We propose that this is due to GIPs inability to induce actin depolymerization following p110gamma inhibition. We suggest that this p110gamma-dependent pathway facilitates insulin granule access to the plasma membrane (in concert with classical cAMP/PKA-dependent signaling) to potentiate exocytosis and insulin secretion.
- This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
- Citation for previous publication
Jelena Kolic, Aliya F. Spigelman, Greg Plummer, Eric Leung, Catherine Hajmrle, Tatsuya Kin, James AM. Shapiro, Jocelyn E. Manning Fox, Patrick E. MacDonald. (2013) Distinct and opposing roles for p110α and p110β in the regulation of insulin secretion from rodent and human beta cells. Diabetologia 56(6): 1339-1349.Gary M. Pigeau*, Jelena Kolic*, Brandon J. Ball, Michael B. Hoppa, Ying W. Wang, Thomas Rückle, Minna Woo, Jocelyn E. Manning Fox, and Patrick E. MacDonald (2009) Distinct and opposing roles for p110α and p110β in the regulation of insulin secretion from rodent and human beta cells. Diabetes 58(9): 2084-1349.Ferdaoussi M, Bergeron V, Zarrouki B, Kolic J, Cantley J, Fielitz J, Olson EN, Prentki M, Biden T, MacDonald PE, Poitout V. (2012) G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1. Diabetologia 55(10):2682-92.
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