Title: Deletion of G Protein Subunit Alpha Z Protects from Obesity-Induced Diabetes by Maintaining Islet Integrity
Abstract: The islets of Langerhans in the pancreas, which contains insulin-producing beta cells, glucagon-producing alpha cells, and somatostatin-producing delta cells, are key to glucose homeostasis. Type II Diabetes Mellitus (T2DM) is characterized by a combination of dysfunction, dedifferentiation, and death of beta cells, resulting in impaired glucose clearance and hyperglycemia. Expression of EP3, a prostaglandin receptor, is elevated in islets in models of diabetes and obesity, and blockade of EP3 signaling by deletion of its component G protein (Gaz) has been found to increase adenylyl cyclase activity and raise islet cAMP levels, which can improve insulin production. We modeled obesity induced beta cell dysfunction using Black and Tan Brachyuri mice that are genetically leptin deficient (BTBR OB). These mice have irregular islet architecture and impaired glucose-stimulated insulin secretion (GSIS), resulting in hyperglycemia. We discovered that deletion of Gaz elevates cAMP levels, improves islet GSIS, and alleviates fasting hyperglycemia in BTBR OB mice. Immunofluorescent staining of pancreas sections shows that loss of Gaz rescues normal structure of islets. Preliminary findings suggest that BTBR OB islets have a higher proportion of alpha and delta cells that is alleviated by loss of Gaz. Beta cells in BTBR OB islets that continue to produce insulin have decreased Urocortin-3 expression, which is a marker of beta cell maturity, suggesting dedifferentiation of beta cells. Although deletion of Gaz does not rescue beta cells maturity, loss of UCN3 is a sign of early dedifferentiation and we are currently testing whether loss of Gaz restores the progression of further beta cell dedifferentiation using other maturity markers. Together, our findings demonstrate that EP3 signaling is a component of disease progression in obesity-induced diabetes and establish Gaz as a potential target for therapeutic intervention that can elevate islet cAMP levels, prevent alpha and delta cell hyperplasia, and maintain healthy islet architecture.
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