# Ion channel regulation of pancreatic islet cell function

> **NIH VA I01** · ST. LOUIS VA MEDICAL CENTER · 2021 · —

## Abstract

Project Summary/Abstract
It is estimated that 1 in 4 Veterans suffer from diabetes, and, in the Veteran population, this is largely Type 2
diabetes. This condition drives heart disease, stroke, retinopathy, nephropathy and neuropathy, all of which
are a cause of significant morbidity and mortality among our Veterans. As such, understanding the biology of
diabetes, discovering novel molecules that regulate b-cell function and developing innovative therapeutic
approaches will have a significant impact on the health of our aging veteran population. Type 2 diabetes is
characterized by both a loss of insulin sensitivity and, ultimately, a relative loss of insulin-secretion from the
pancreatic b-cell. Insulin secretion from the pancreatic b-cell is triggered by Ca2+ influx through voltage-gated
Ca2+ channels (VGCC) to trigger insulin vesicle fusion with the b-cell plasma membrane.
We recently reported that SWELL1 (LRRC8a), a member of the Leucine Rich Repeat Containing protein
family, is required for ICl,SWELL in β-cells. SWELL1-mediated ICl,SWELL activates upon b-cell swelling induced by
glucose import, and this generates a depolarizing current contributing to VGCC activation, thereby regulating
insulin secretion and systemic glycemia. Indeed, mice with SWELL1-deficient β-cells exhibit impaired glucose-
stimulated insulin secretion and glucose intolerance. Moreover, we find that ICl,SWELL is reduced in both mouse
and humans in the context of Type 2 diabetes (T2D) indicating that reduced SWELL1 signaling is associated
with impaired b-cell function in T2D. The objective of the current proposal is to delineate the mechanisms by
which SWELL1 signaling regulates b-cell function, under basal conditions, and in the setting of Type 2
diabetes. Our central hypothesis is that SWELL1 regulates both glucose-stimulated insulin secretion and
PI3K-AKT-mTOR signaling in b-cells to maintain systemic glycaemia, and that impaired SWELL1
signaling contributes to b-cell failure in Type 2 diabetes. The contribution of this proposal is significant
because it explores the innovative concept the SWELL1 utilizes dual signaling domains (channel versus
LRRD) to regulate b-cell function in health and T2D. Importantly, this proposal will also define the relationship
between b-cell SWELL1 and T2D and test the notion that reduced SWELL1 signaling may drive impaired b-cell
function in T2D. We propose the following two AIMs:
AIM#1: Delineate the mechanism(s) of SWELL1-mediated regulation of excitation-secretion coupling.
AIM#2: Dissect the molecular mechanisms of SWELL1 macro-complex regulation of AKT-mTOR
signaling in b-cells.
The contribution of this proposal is innovative because it delineates a novel SWELL1 signaling pathway that
connects glucose-mediated b-cell swelling to b-cell depolarization and insulin-release - a form of b-cell swell-
activation or “swell-secretion” coupling. This proposal will enhance our understanding of b-cell biology and help
direct novel therapeutic app...

## Key facts

- **NIH application ID:** 10249948
- **Project number:** 5I01BX005072-02
- **Recipient organization:** ST. LOUIS VA MEDICAL CENTER
- **Principal Investigator:** Rajan Sah
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249948

## Citation

> US National Institutes of Health, RePORTER application 10249948, Ion channel regulation of pancreatic islet cell function (5I01BX005072-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10249948. Licensed CC0.

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