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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK092616-03
Application #
8691801
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Silva, Corinne M
Project Start
2012-08-16
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Upstate Medical University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Syracuse
State
NY
Country
United States
Zip Code
13210
Kono, Tatsuyoshi; Tong, Xin; Taleb, Solaema et al. (2018) Impaired Store-Operated Calcium Entry and STIM1 Loss Lead to Reduced Insulin Secretion and Increased Endoplasmic Reticulum Stress in the Diabetic ?-Cell. Diabetes 67:2293-2304
Nelson, Heather A; Leech, Colin A; Kopp, Richard F et al. (2018) Interplay between ER Ca2+ Binding Proteins, STIM1 and STIM2, Is Required for Store-Operated Ca2+ Entry. Int J Mol Sci 19:
Nelson, Heather A; Roe, Michael W (2018) Molecular physiology and pathophysiology of stromal interaction molecules. Exp Biol Med (Maywood) 243:451-472
Vierra, Nicholas C; Dickerson, Matthew T; Philipson, Louis H et al. (2018) Simultaneous Real-Time Measurement of the ?-Cell Membrane Potential and Ca2+ Influx to Assess the Role of Potassium Channels on ?-Cell Function. Methods Mol Biol 1684:73-84
Bergeron, Valérie; Ghislain, Julien; Vivot, Kevin et al. (2018) Deletion of Protein Kinase D1 in Pancreatic ?-Cells Impairs Insulin Secretion in High-Fat Diet-Fed Mice. Diabetes 67:71-77
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

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