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.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
Project #
Application #
Study Section
Endocriniology A (ENDA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rlr VA Medical Center
United States
Zip Code
Ocaña, Gail J; Pérez, Liliana; Guindon, Lynette et al. (2017) Inflammatory stress of pancreatic beta cells drives release of extracellular heat-shock protein 90?. Immunology 151:198-210
Maddatu, Judith; Anderson-Baucum, Emily; Evans-Molina, Carmella (2017) Smoking and the risk of type 2 diabetes. Transl Res 184:101-107
Hatanaka, Masayuki; Anderson-Baucum, Emily; Lakhter, Alexander et al. (2017) Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation. Sci Rep 7:3758
Ferrara, Christine Therese; Geyer, Susan Michelle; Liu, Yuk-Fun et al. (2017) Excess BMI in Childhood: A Modifiable Risk Factor for Type 1 Diabetes Development? Diabetes Care 40:698-701
Bone, Robert N; Evans-Molina, Carmella (2017) Combination Immunotherapy for Type 1 Diabetes. Curr Diab Rep 17:50
Xiong, Xiwen; Wang, Gaihong; Tao, Rongya et al. (2016) Sirtuin 6 regulates glucose-stimulated insulin secretion in mouse pancreatic beta cells. Diabetologia 59:151-60
Meah, Farah A; DiMeglio, Linda A; Greenbaum, Carla J et al. (2016) The relationship between BMI and insulin resistance and progression from single to multiple autoantibody positivity and type 1 diabetes among TrialNet Pathway to Prevention participants. Diabetologia 59:1186-95
Watkins, Renecia A; Evans-Molina, Carmella; Terrell, Jennifer K et al. (2016) Proinsulin and heat shock protein 90 as biomarkers of beta-cell stress in the early period after onset of type 1 diabetes. Transl Res 168:96-106.e1
Sims, Emily K; Chaudhry, Zunaira; Watkins, Renecia et al. (2016) Elevations in the Fasting Serum Proinsulin-to-C-Peptide Ratio Precede the Onset of Type 1 Diabetes. Diabetes Care 39:1519-26
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

Showing the most recent 10 out of 34 publications