The combined syndromes of type 1 (T1D) and type 2 (T2D) diabetes mellitus affect nearly one in four Veterans and over 422 million individuals worldwide. Inadequate insulin secretion from the pancreatic ? cell plays a primary role in the pathogenesis of both major forms of diabetes. However, the mechanisms responsible for ? cell failure in this disease remain poorly understood. The long-term goal of our research program is to delineate the role of altered ? cell Ca2+ homeostasis in diabetes pathophysiology and to understand how Ca2+ dyshomeostasis activates common and overlapping stress pathways in T1D and T2D. Store-operated calcium entry (SOCE) is a process activated in response to endoplasmic reticulum (ER) Ca2+ depletion and is initiated when Ca2+ dissociates from the ER Ca2+ sensor, STIM1, leading to STIM1 oligomerization and translocation to the plasma membrane. Here, STIM1 associates with the selection Ca2+ channel Orai alone or as part of a multi-protein complex consisting of Orai and nonselective TRPC cation channels. The formation of these complexes ultimately leads to refilling of ER Ca2+ stores via transfer of Ca2+ from the extracellular space. To date, the role of SOCE in the pancreatic ? cell remains largely uncharacterized, but our preliminary data has identified alterations in STIM1 expression and SOCE activity in models of both T1D and T2D and shows that inhibition of SOCE as well as STIM1 knockdown leads to decreased glucose-stimulated insulin secretion, altered ? cell calcium signaling, depletion of ER Ca2+ stores, and increased ? cell ER stress. Thus, we hypothesize that Ca2+ dyshomeostasis arising from alterations in SOCE is a key determinant of the diminished insulin secretory capacity and reduced ? cell survival observed in diabetes. The specific goals of this work are to: (1) define a role for store-operated calcium entry in the maintenance of pancreatic ? cell function using genetic and pharmacologic in vivo and in vitro STIM1 loss and gain of function models; (2) test whether loss of STIM1 and SOCE dysregulation in the ? cell contributes to defects observed in T1D and T2D; and (3) define the molecular and signaling pathways leading to decreased STIM1 expression and the impaired ability of SOCE to replenish ER Ca2+ stores in rodent and human models of diabetes. This work will fill an important knowledge gap in the field and define a novel role for impaired ? cell SOCE in diabetes mellitus. The translational impact of this work will be the identification of pathways that can be targeted clinically to improve ? cell health under disease conditions.

Public Health Relevance

Diabetes mellitus (DM) is a disorder of glucose homeostasis that affects over 29 million Americans and nearly one in four Veterans. DM is a leading cause of blindness, kidney failure, and cardiovascular disease, and the incidence of this disorder is expected to double by 2050, suggesting increased numbers of Veterans will seek care for DM and that increased expenditures will be needed to provide this care. Pancreatic ? cell dysfunction is a central component of the pathophysiology of both major forms of DM, yet current therapies do little to address this facet of the disease. The goal of this proposal is to define how altered calcium regulation in the pancreatic ? cell impacts insulin production and secretion. The translational impact of this work will be the identification of novel pathways that can be targeted clinically as a means of preserving ? cell function and survival in DM.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001733-06
Application #
9591264
Study Section
Endocriniology A (ENDA)
Project Start
2013-04-01
Project End
2021-09-30
Budget Start
2018-10-01
Budget End
2019-09-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Rlr VA Medical Center
Department
Type
DUNS #
608434697
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Saeed, Zeb; Taleb, Solaema; Evans-Molina, Carmella (2016) A case of extragastrointestinal stromal tumor complicated by severe hypoglycemia: a unique presentation of a rare tumor. BMC Cancer 16:930

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