# Regulation of calcium homeostasis in the pancreatic beta cell

> **NIH VA I01** · RLR VA MEDICAL CENTER · 2022 · —

## Abstract

PROJECT SUMMARY/ABSTRACT
Diabetes mellitus affects nearly one in four Veterans and over 463 million individuals worldwide. Inadequate
insulin secretion from the pancreatic β cell plays a primary role in diabetes pathogenesis; however, the
mechanisms responsible for β cell failure in diabetes remain poorly understood. The long-term goal of our VA-
funded research program is to identify how altered β cell calcium (Ca2+) homeostasis contributes to diabetes
pathophysiology. During the last funding cycle, we identified a previously unappreciated role for impaired store-
operated calcium entry (SOCE) in human and rodent models of type 2 diabetes. SOCE is a process that is
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 complexes with the Ca2+ selective ion channel, Orai1, leading to Orai1 opening, Ca2+ influx from the
extracellular space, and subsequent transfer of Ca2+ into the ER. To study the in vivo role of SOCE, mice with
β cell specific loss of STIM1 (STIM1Δβ) were generated and challenged with a high fat diet to model type 2
diabetes. Our results revealed an unusual sexually dimorphic phenotype, where female (but not male) STIM1Δβ
mice displayed significantly impaired glucose tolerance as well as reduced insulin secretion and β cell mass that
was associated with reduced expression of key β cell identity markers and a reciprocal increase in α cell mass.
Unbiased as well as targeted transcriptional analysis revealed a reduction in G-protein coupled estrogen receptor
(GPER) expression that was linked with reduced estradiol and GPER-mediated signaling. This finding was
notable because loss of endogenous estradiol signaling has been linked with reduced β cell function and
increased diabetes susceptibility, while estradiol has beneficial effects in both male and female β cells. Against
this background, we hypothesize that impaired SOCE leads to reduced estradiol-mediated signaling through
GPER, resulting in β cell de-differentiation and reduced β cell function in type 2 diabetes. To test this hypothesis,
two Specific Aims are proposed in this VA Merit renewal application. In Aim 1, lineage tracing experiments will
be performed to track the fate of β cells in female STIM1Δβ mice fed a high fat diet, allowing us to define whether
there is bona fide β cell de-differentiation in this model. We will test whether mice with a β cell specific deletion
of Orai1 (Orai1Δβ) exhibit a similar sexually dimorphic phenotype and loss of β cell identity. Finally, we will
determine whether naturally occurring loss of function mutations in STIM1 and Orai1 impact directed
differentiation of induced pluripotent stem cells into β cells. In Aim 2, experiments will be performed to determine
how GPER and SOCE interact to regulate β cell function. Here, an ovariectomy model will be leveraged to test
whet...

## Key facts

- **NIH application ID:** 10261087
- **Project number:** 2I01BX001733-09
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** Carmella Evans-Molina
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2013-04-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10261087

## Citation

> US National Institutes of Health, RePORTER application 10261087, Regulation of calcium homeostasis in the pancreatic beta cell (2I01BX001733-09). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10261087. Licensed CC0.

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