# Molecular Mechanisms Regulating Pancreatic Delta Cell Function and Dysfunction

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2022 · $449,622

## Abstract

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 stressf...

## Key facts

- **NIH application ID:** 10443333
- **Project number:** 1R01DK129340-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** David Aaron Jacobson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $449,622
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10443333

## Citation

> US National Institutes of Health, RePORTER application 10443333, Molecular Mechanisms Regulating Pancreatic Delta Cell Function and Dysfunction (1R01DK129340-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10443333. Licensed CC0.

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