The long-term goal of my lab is to identify and elucidate the mechanisms and causes of diabetes and metabolic disorders by investigating dysfunctions in islet physiology. Diabetes mellitus is a metabolic disease that results from either a complete or relative deficiency of the hormone insulin and currently affects 20.8 million people in the U.S. and is increasing in incidence. The cost of caring for this disease is enormous, exceeding 135 billion dollars annually. Increasing evidence suggests that inflammation and immune responses lead to the destruction of insulin-producing beta-cells in pancreatic islets not only in type 1 diabetes (T1DM), but that these factors also contribute to beta-cell loss in type 2 diabetes (T2DM) and other metabolic disorders. Although glucose-stimulated insulin secretion (GSIS) is the standard measure of islet function, preliminary data suggest a more sensitive indicator of islet dysfunction is intracellular calcium ([Ca2+]i), which is closely linked with insulin secretion. Preliminary data show that pro-inflammatory cytokines induce dysfunction in islet [Ca2+]i handling at much lower cytokine concentrations than required to negatively impact insulin secretion. The working model of this proposal is that deficiencies in endogenous [Ca2+]i oscillations and glucose-stimulated changes in [Ca2+]i are indicators of early stages of damage to islet function and viability. Benefits of genetic or pharmacologic interventions to prevent or reverse diabetes will be predicted by [Ca2+]i measurements.
The aims of this proposal are to develop more sensitive and accurate methods of assessing islet health (aim1), determine mechanisms of inflammatory cytokine-induced islet dysfunction (aim2), and test novel anti-inflammatory treatments to improve islet health using both novel and standard methods (aim3).
The specific aims of this proposal are designed, in part, to evaluate human islets for transplantation, however, the proposed studies will have far greater impact. Accurate, sensitive, and systematic evaluations of islet dysfunction will be used to identify early indicators of dysfunction at the islet level and to elucidate their mechanism in diseases such as T1DM and T2DM, as well as to assess potential therapies for diabetes at the islet level. In addition, the source(s) of dysfunctional calcium handling will also be investigated as a possible mechanism(s) of islet damage;chiefly ER-stress, glycolytic disruption, and ion channels will be examined using a combination of physiological, molecular, and genetic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK081621-02
Application #
7667333
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2008-09-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
2
Fiscal Year
2009
Total Cost
$107,541
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Sharma, Poonam R; Mackey, Aaron J; Dejene, Eden A et al. (2015) An Islet-Targeted Genome-Wide Association Scan Identifies Novel Genes Implicated in Cytokine-Mediated Islet Stress in Type 2 Diabetes. Endocrinology 156:3147-56
Nunemaker, Craig S; Chung, H Grace; Verrilli, Gretchen M et al. (2014) Increased serum CXCL1 and CXCL5 are linked to obesity, hyperglycemia, and impaired islet function. J Endocrinol 222:267-76
O'Neill, Christina M; Lu, Christine; Corbin, Kathryn L et al. (2013) Circulating levels of IL-1B+IL-6 cause ER stress and dysfunction in islets from prediabetic male mice. Endocrinology 154:3077-88
Corbin, Kathryn L; Hall, Thomas E; Haile, Ruth et al. (2011) A novel fluorescence imaging approach for comparative measurements of pancreatic islet function in vitro. Islets 3:14-20
Ramadan, James W; Steiner, Stephen R; O'Neill, Christina M et al. (2011) The central role of calcium in the effects of cytokines on beta-cell function: implications for type 1 and type 2 diabetes. Cell Calcium 50:481-90
Dula, Stacey B; Jecmenica, Mladen; Wu, Runpei et al. (2010) Evidence that low-grade systemic inflammation can induce islet dysfunction as measured by impaired calcium handling. Cell Calcium 48:133-42
Ma, K; Nunemaker, C S; Wu, R et al. (2010) 12-Lipoxygenase Products Reduce Insulin Secretion and {beta}-Cell Viability in Human Islets. J Clin Endocrinol Metab 95:887-93
Crim, William S; Wu, Runpei; Carter, Jeffrey D et al. (2010) AGI-1067, a novel antioxidant and anti-inflammatory agent, enhances insulin release and protects mouse islets. Mol Cell Endocrinol 323:246-55
Carter, Jeffrey D; Dula, Stacey B; Corbin, Kathryn L et al. (2009) A practical guide to rodent islet isolation and assessment. Biol Proced Online 11:3-31
Evans-Molina, Carmella; Robbins, Reiesha D; Kono, Tatsuyoshi et al. (2009) Peroxisome proliferator-activated receptor gamma activation restores islet function in diabetic mice through reduction of endoplasmic reticulum stress and maintenance of euchromatin structure. Mol Cell Biol 29:2053-67

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