# ArpC3-mediated actin remodeling in insulin granule exocytosis and diabetes

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $374,400

## Abstract

PROJECT SUMMARY
Insulin secretion deficiency is a hallmark of diabetes. In this process, the cortical actin of β cells has recently
been recognized as a critical player contributing to diabetes pathogenesis. β cells from type-2 diabetes (T2D)
patients show significant signaling alteration associated with cortical actin remodeling, and restoring such
abnormality rescues insulin secretion to normal levels. Cortical actin is thought initially as a simple barrier to
prevent insulin secretion, but recent studies challenge this view and imply an active role. Mounting evidence
further indicates that cortical actin is a converging point and effector of multiple metabolic signals in β cells.
However, the molecule and nanostructure basis of its remodeling remains unresolved. Addressing this question
becomes imperative to understanding the regulation of insulin secretion and developing new therapeutics to
restore β cell function in T2D. This proposal will investigate ArpC3, a gene encoding a subunit of the Arp2/3
complex that dictates actin filament branching and cortical remodeling. Although multiple signaling pathways
converge on Arp2/3, the mechanism downstream Arp2/3 activity to regulate insulin secretion remains unknown.
Based on recent progress in the field and our new data on β cell imaging and functional assays, we hypothesize
that ArpC3-dependent actin polymerization regulates insulin exocytosis by driving the local cortical actin
disassembly-reassembly cycles. Through this remodeling, cortical actin filaments may actively coordinate the
critical steps of granule trafficking and insulin secretion. We have assembled a team of investigators with
expertise in diabetes, β cell biology, vesicle trafficking, and super-resolution microscopy to test this hypothesis.
We will focus on three specific aims. First, determine the in vivo role of ArpC3-mediated cortical actin remodeling
in insulin secretion and glucose homeostasis. We have generated a new mouse model where ArpC3 is deleted
selectively in adult β cells to ablate Arp2/3 activity and cortical actin branching. Second, define ArpC3 function
in cortical actin nano-remodeling and its role in insulin granule recruitment, docking, and exocytosis. Third,
evaluate the role of cortical actin branching in human β cells and its dysfunction in T2D patients. The results from
this work will fill a long-standing knowledge gap between cortical actin remodeling and insulin secretion, providing
mechanistic insights into T2D pathogenesis induced by cortical actin dysfunction.

## Key facts

- **NIH application ID:** 10755719
- **Project number:** 5R01DK132088-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** XUELIN LOU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $374,400
- **Award type:** 5
- **Project period:** 2023-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10755719

## Citation

> US National Institutes of Health, RePORTER application 10755719, ArpC3-mediated actin remodeling in insulin granule exocytosis and diabetes (5R01DK132088-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10755719. Licensed CC0.

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