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Principal Investigator: David Aaron Jacobson
Organization: VANDERBILT UNIVERSITY
Fiscal Year: 2023
Award: $449,622
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary
Islet glucose-stimulated somatostatin (Sst) secretion is lost in patients with type-2 diabetes (T2D) and in animal
models of the disease, which contributes to disrupted glucagon and insulin secretion. It is generally accepted
that Sst secretion from -cells occurs in response to elevated intracellular Ca2+, which primarily results from
endoplasmic reticulum (ER) Ca2+ (Ca2+ER) release. However, the mechanisms that control -cell Ca2+ER handling
and how they are altered in T2D are largely unknown. Data from our lab finds that the islet-enriched two-pore-
domain K+ channel, TALK-1, is an ER localized channel in that provides a countercurrent for -cell Ca2+ER release
and Ca2+ER leak. TALK-1-mediated augmentation of the electrochemical driving force for -cell Ca2+ER leak con-
strains Ca2+ER storage, which limits glucose-stimulated Ca2+ER release and Sst secretion. Further data show that
-cell Ca2+ER release and Sst secretion are amplified by glucose-induced allosteric activation of -cell Ca2+-sens-
ing receptors (CaSRs). Finally, our preliminary data provide the first evidence that diabetic conditions diminish
-cell Ca2+ER storage, which contributes to perturbations in glucose-stimulated Ca2+ handling and Sst secretion
under diabetic conditions. Based on these exciting preliminary data, the overall objective of this proposal is to
elucidate how -cell Ca2+ER is controlled and becomes disrupted during the pathogenesis of diabetes. This project
will test the central hypothesis that glucose-stimulated -cell Sst secretion is amplified by CaSR-mediated Ca2+ER
release, which is controlled by TALK-1 channel constraint of Ca2+ER storage. The rationale that underlies this
project is that understanding how CaSR and TALK-1 control -cell Ca2+ER handling and Sst secretion will expose
novel therapeutic targets for restoring glucose-stimulated Sst secretion and islet hormone secretion in T2D. This
project will be accomplished with the following two specific aims: 1) Determine how -cell CaSR controls Ca2+ER
handling, Sst secretion, and islet hormone secretion; and 2) Determine how TALK-1 channel control of Ca2+ER
release modulates -cell function and dysfunction. Under the first aim, transgenic mice with -cell ablation of
CaSR as well as human pseudoislets with ShRNA knockdown of -cell CaSR will be utilized to assess the roles
of the Ca2+-sensing receptor during secretagogue modulation of -cell Ca2+ handling and Sst secretion. Aim1 will
also determine how depletion of -cell Ca2+ER stores under diabetic conditions impacts CaSR signaling and Sst
secretion. Under the second aim, the function TALK-1 channels on -cell Ca2+ER handling and function will be
determined in mice with -cell specific ablation of TALK-1 and in human pseudoislets containing either -cells
with knockdown of TALK-1 or expressing dominant negative TALK-1 channel subunits. Furthermore, Aim2 will
determine how TALK-1 augmentation of -cell Ca2+ER depletion under the stressful conditions associated with
diabetes contributes to -cell dysfunction. This project is significant because it is expected to illuminate mecha-
nisms that alter -cell Ca2+ER handling and disrupt islet hormone secretion in T2D. Moreover, this project will
identify pharmacological strategies for normalizing Sst secretion and reducing islet dysfunction in T2D.
Terms: <Ablation><Adult-Onset Diabetes Mellitus><Amino Acids><Animal Disease Models><Antidiabetic Hormone><Antimorphic mutation><Autoregulation><B9 endocrine pancreas><CASR Protein><Ca-Sensing Receptor><Ca2+-Sensing Receptor><Calcium Receptors><Calcium-Sensing Receptor Protein><Calcium-Sensing Receptors><Cell Body><Cell Communication and Signaling><Cell Function><Cell Process><Cell Signaling><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Coupled><Cyclic Somatostatin><Cytoplasm><D-Glucose><Data><Dextrose><Diabetes Mellitus><Disease><Disorder><Dominant Negative><Dominant-Negative Mutant><Dominant-Negative Mutation><Dysfunction><Endocrine Pancreas><Endoplasmic Reticulum><Ergastoplasm><Extracellular Calcium-Ion Sensing Receptor><Functional disorder><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G alpha q Protein><G-Protein-Coupled Receptors><GPCR><Galphaq Protein><Glucagon><Glucose><Glukagon><Goals><Gq G-Protein><Gq Protein><Gq alpha Family G-Protein><Growth Hormone Inhibiting Factors><Growth Hormone-Inhibiting Hormone><Gαq Protein><HG-Factor><Homeostasis><Hormone secretion><Human><Humulin R><Hyperglycemic-Glycogenolytic Factor><Insulin><Intracellular Communication and Signaling><Islands of Langerhans><Islets of Langerhans><K channel><Ketosis-Resistant Diabetes Mellitus><Knowledge><Lab Findings><Laboratory Finding><MODY><Maturity-Onset Diabetes Mellitus><Mediating><Medical><Membrane Potentials><Mice><Mice Mammals><Modern Man><Molecular><Murine><Mus><NIDDM><Nesidioblasts><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><Pancreas><Pancreatic><Pancreatic Islets><Pancreatic Somatostatin Cell><Pancreatic Somatostatin Secreting Cell><Pancreatic delta Cell><Pancreatic δ Cell><Pars endocrina pancreatis><Pathogenesis><Pathway interactions><Patients><Physiologic><Physiological><Physiological Homeostasis><Physiopathology><Population><Potassium Channel><Potassium Ion Channels><R-Series Research Projects><R01 Mechanism><R01 Program><Receptor Protein><Receptor Signaling><Regular Insulin><Research><Research Grants><Research Project Grants><Research Projects><Resting Potentials><Role><SRIH><SRIH-14><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Somatostatin><Somatostatin Cell of the Pancreas><Somatostatin Secreting Cell of the Pancreas><Somatostatin-14><Somatotropin Release Inhibiting Factors><Somatotropin Release-Inhibiting Hormone><Stable Diabetes Mellitus><Stress><Subcellular Process><T2 DM><T2D><T2DM><Testing><Transgenic Mice><Transmembrane Potentials><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><adult onset diabetes><aminoacid><biological signal transduction><blood glucose regulation><diabetes><diabetes pathogenesis><diabetic><driving force><experiment><experimental research><experimental study><experiments><gain of function mutation><glucose control><glucose homeostasis><glucose regulation><growth hormone release inhibiting factor><hormonal secretion><insight><insulin secretion><islet><islet progenitor><ketosis resistant diabetes><knock-down><knockdown><maturity onset diabetes><maturity onset diabetes in youth><maturity onset diabetes of the young><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pancreas delta cell><pathophysiology><pathway><pharmacologic><receptor><response><shRNA><short hairpin RNA><small hairpin RNA><social role><type 2 DM><type II DM><type two diabetes>