The overall objective of this proposal is to better understand the pathophysiology of Type 2 diabetes mellitus (T2DM). Increased cytoplasmic Ca2+ concentration ([Ca2+]c) in pancreatic ?- cells stimulates insulin secretion. Much is known about K+ and voltage-gated Ca2+ currents that contribute to Ca2+-dependent signal transduction and insulin secretion;relatively little is known about other Ca2+ channels that regulate ?-cell Ca2+ signaling dynamics. Our published work suggests that store-operated cation (SOC) channels regulate glucose-stimulated changes in ?-cell [Ca2+]c and insulin secretion. Preliminary evidence also suggests that store-operated Ca2+ entry (SOCE) is abnormal in islets of Langerhans isolated from a mouse model of T2DM. Knowledge about SOC channels (ISOC) in ?-cells is limited: we neither know their molecular identity, nor have complete understanding of the biophysical properties or mechanisms that control ISOC activation. We will focus on defining the molecular basis of SOCE in mouse and human ?-cells. We will use a novel and innovative combination of experimental approaches that includes biosensor imaging technology, patch-clamp electrophysiology, molecular engineering with RNA interference (RNAi) and conditional gene deletion in transgenic mice to: [A] define the molecular basis and biophysical properties of ISOC in ?-cells, [B] determine the molecular mechanisms that activate SOCE, [C] define the roles of SOCE in ?-cell function, and [D] determine whether defects in SOCE contribute to ?-cell defects associated with T2DM. Our proposed studies will provide exciting new information essential for advancing understanding of stimulus-secretion coupling mechanisms in ?-cells, novel insights into ?-cell failure in T2DM, and suggest new molecular targets for treatment of T2DM.

Public Health Relevance

Type 2 diabetes mellitus is a significant and growing health problem in the United States. Insulin secretion failure plays a major role in the initiation and progression of diabetes. Insulin secretion is dependent on metabolism and ionic signals in insulin-secreting cells. Here, we propose to study the molecular mechanisms that regulate these ionic signals in mouse and human insulin-secreting cells.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Silva, Corinne M
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Upstate Medical University
Internal Medicine/Medicine
Schools of Medicine
United States
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Leech, Colin A; Kopp, Richard F; Nelson, Heather A et al. (2017) Stromal Interaction Molecule 1 (STIM1) Regulates ATP-sensitive Potassium (KATP) and Store-operated Ca2+ Channels in MIN6 ?-Cells. J Biol Chem 292:2266-2277
Fridlyand, Leonid E; Philipson, Louis H (2016) Pancreatic Beta Cell G-Protein Coupled Receptors and Second Messenger Interactions: A Systems Biology Computational Analysis. PLoS One 11:e0152869
Chepurny, Oleg G; Holz, George G; Roe, Michael W et al. (2016) GPR119 Agonist AS1269574 Activates TRPA1 Cation Channels to Stimulate GLP-1 Secretion. Mol Endocrinol 30:614-29
Kim, Kyuho; Oh, Chang-Myung; Ohara-Imaizumi, Mica et al. (2015) Functional role of serotonin in insulin secretion in a diet-induced insulin-resistant state. Endocrinology 156:444-52
Oropeza, Daniel; Jouvet, Nathalie; Bouyakdan, Khalil et al. (2015) PGC-1 coactivators in ?-cells regulate lipid metabolism and are essential for insulin secretion coupled to fatty acids. Mol Metab 4:811-22
Kopp, Richard F; Leech, Colin A; Roe, Michael W (2014) Resveratrol Interferes with Fura-2 Intracellular Calcium Measurements. J Fluoresc 24:279-84
Tamarina, Natalia A; Roe, Michael W; Philipson, Lh (2014) Characterization of mice expressing Ins1 gene promoter driven CreERT recombinase for conditional gene deletion in pancreatic *-cells. Islets 6:
Burov, Stanislav; Tabei, S M Ali; Huynh, Toan et al. (2013) Distribution of directional change as a signature of complex dynamics. Proc Natl Acad Sci U S A 110:19689-94
Kaihara, Kelly A; Dickson, Lorna M; Jacobson, David A et al. (2013) ?-Cell-specific protein kinase A activation enhances the efficiency of glucose control by increasing acute-phase insulin secretion. Diabetes 62:1527-36
Brickley, Deanna R; Agyeman, Abena S; Kopp, Richard F et al. (2013) Serum- and glucocorticoid-induced protein kinase 1 (SGK1) is regulated by store-operated Ca2+ entry and mediates cytoprotection against necrotic cell death. J Biol Chem 288:32708-19

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