Type 2 diabetes (T2D) is a costly and complex chronic illness and a serious public health problem. The children of today have an overall lifetime risk of developing diabetes of nearly 50%. Therefore, developing new methods for preventing T2D and identifying and properly treating T2D patients is very timely and of great significance. The pathophysiology of T2D is increasingly being linked with inflammatory molecules such as prostaglandin E2 (PGE2), a major arachidonic acid metabolite. Beta-cells themselves express all of the enzymes required for synthesis of PGE2, which is thought to act in an autocrine or paracrine fashion to regulate insulin secretion and possibly even beta-cell growth, proliferation, and survival. Even with the clear importance of this pathway in the normal and dysfunctional beta-cell, few studies have explored the impact of modulating the production or signaling of PGE2 at the level of the beta-cell, in part because of insufficient knowledge of th molecular mechanisms important in these pathways. Our long-term goal is to fully characterize the PGE2 synthesis and signaling pathways in the normal and diabetic beta-cell, determining steps that become dysfunctional in the diabetic state, and ultimately modulating these steps for preventative and therapeutic purposes. The overall objective of this work is to elucidate critical molecular interactions at distinct steps that have remained relatively uncharacterized, with the rationale that in gaining a complete understanding of this important beta-cell signaling pathway, we will be better able to target the dysfunctional beta-cell in T2D prevention and therapy using novel and innovative approaches. Our central hypothesis is that the PGE2 synthesis and signaling pathway is a critical mediator of diabetic beta-cell dysfunction and can be specifically targeted at one or more key steps besides the well-studied cyclooxygenase-2 (COX-2;or prostaglandin-endoperoxidase synthase 2, PTGS2) step. We will test our central hypothesis and, thereby, accomplish the objective of this application, by pursuing the following three specific aims: (1) Identify the role of arachidonic acid membrane incorporation and release in diabetic beta-cell dysfunction;(2) Determine the role of C-terminal splice variants of the EP3 isoform of the PGE2 receptor in coupling to G-protein signaling partners;and (3) Elucidate the signaling mechanisms downstream of EP3 in promoting beta-cell function, replication, and survival. With the completion of these aims, we anticipate a much more complete understanding of the pathway from arachidonic acid to PGE2 and other metabolites, including how PGE2 activation of its cellular receptor impacts on the diabetic beta-cell. Such results are anticipated to have an important positive impact on the field, as in delineating this long-known but relatively uncharacterized pathway we may be able to meld the discrepant results in the literature and reveal and confirm new targets for the prevention and therapy of T2D.
Diabetes is a costly and complex chronic illness and a serious public health problem, responsible for a host of complications that significantly decrease healthy lifespan. The underlying issue in diabetes is the failure of the pancreas cells to release enough of the hormone, insulin, into the bloodstream to properly control blood sugar levels. The aims of this proposal are to characterize new cellular targets to promote proper insulin release, ultimately improving the care and treatment of diabetic patients.
|Fenske, Rachel J; Kimple, Michelle E (2018) Targeting dysfunctional beta-cell signaling for the potential treatment of type 1 diabetes mellitus. Exp Biol Med (Maywood) 243:586-591|
|Yu, Deyang; Yang, Shany E; Miller, Blake R et al. (2018) Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms. FASEB J 32:3471-3482|
|Cummings, Nicole E; Williams, Elizabeth M; Kasza, Ildiko et al. (2018) Restoration of metabolic health by decreased consumption of branched-chain amino acids. J Physiol 596:623-645|
|Neuman, Joshua C; Fenske, Rachel J; Kimple, Michelle E (2017) Dietary polyunsaturated fatty acids and their metabolites: Implications for diabetes pathophysiology, prevention, and treatment. Nutr Healthy Aging 4:127-140|
|Hernandez, Reinier; Graves, Stephen A; Gregg, Trillian et al. (2017) Radiomanganese PET Detects Changes in Functional ?-Cell Mass in Mouse Models of Diabetes. Diabetes 66:2163-2174|
|Neuman, Joshua C; Schaid, Michael D; Brill, Allison L et al. (2017) Enriching Islet Phospholipids With Eicosapentaenoic Acid Reduces Prostaglandin E2 Signaling and Enhances Diabetic ?-Cell Function. Diabetes 66:1572-1585|
|Fenske, Rachel J; Cadena, Mark T; Harenda, Quincy E et al. (2017) The Inhibitory G Protein ?-Subunit, G?z, Promotes Type 1 Diabetes-Like Pathophysiology in NOD Mice. Endocrinology 158:1645-1658|
|Brill, Allison L; Wisinski, Jaclyn A; Cadena, Mark T et al. (2016) Synergy Between G?z Deficiency and GLP-1 Analog Treatment in Preserving Functional ?-Cell Mass in Experimental Diabetes. Mol Endocrinol 30:543-56|
|Busch, Rebecca A; Heneghan, Aaron F; Pierre, Joseph F et al. (2016) Bombesin Preserves Goblet Cell Resistin-Like Molecule ? During Parenteral Nutrition but Not Other Goblet Cell Products. JPEN J Parenter Enteral Nutr 40:1042-9|
|Fontana, Luigi; Cummings, Nicole E; Arriola Apelo, Sebastian I et al. (2016) Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health. Cell Rep 16:520-530|
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