# Decipher the Function of C2cd4a in Metabolism

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $399,271

## Abstract

Project Summary
Type 2 diabetes (T2D) is caused by insulin resistance in peripheral tissues and pancreatic beta-cell
dysfunction. Insulin resistance precedes beta-cell failure, and the beta-cell’s inability to keep up with the
increased demand of insulin production and secretion leads to glucose intolerance and hyperglycemia. The
human C2CD4B-C2CD4A-VPS13C locus harbors a pancreatic beta-cell super-enhancer, and is heavily
decorated by T2D risk-associated GWAS SNPs from virtually every ethnic group studied to date. There are
only ~20 publications on “C2cd4a” in PubMed, the majority of which are association studies linking this
locus to human diabetes susceptibility. Through a multi-omics approach followed by functional analysis in
mice, we found that beta cell-specific C2cd4a ablation impairs insulin secretion. In this proposal, through
C2cd4a we provide a basis to link exercise-induced hypoglycemia and type 2 diabetes treatment. We will
investigate C2cd4a-regulated beta cell function, and build a pathway centered on C2cd4a. Two Aims are
envisioned: in Aim 1, we will map the repressor domain using truncated versions of human and mouse
C2CD4A, and investigate the mechanism of exercise-induced hypoglycemia in beta cell-specific C2cd4a
knockout mice. In Aim 2, we will solidify C2cd4a’s role in the nucleus as a transcription cofactor, acting on
promoters and enhancers of key beta cell genes. We will examine the regulation of C2cd4a by a novel
intergenic long noncoding RNA. These Aims will advance our understanding of C2cd4a as a human diabetes
susceptibility gene, and provide a blueprint to leverage human genetics data into biological insight that will
eventually benefit patients.

## Key facts

- **NIH application ID:** 10594862
- **Project number:** 1R01DK132227-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Taiyi Diana Kuo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $399,271
- **Award type:** 1
- **Project period:** 2023-01-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10594862

## Citation

> US National Institutes of Health, RePORTER application 10594862, Decipher the Function of C2cd4a in Metabolism (1R01DK132227-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10594862. Licensed CC0.

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