# Regulation and Function of the Type 2 Diabetes-Associated C2CD4A/B Locus

> **NIH NIH R01** · JACKSON LABORATORY · 2020 · $416,265

## Abstract

PROJECT SUMMARY
Diabetes afflicts approximately 29 million adult Americans (9.3% of the total population), 90-95% of whom have
type 2 diabetes (T2D). T2D is a complex disease with both genetic and environmental components and
ultimately manifests when pancreatic islets fail to secrete sufficient insulin to compensate for increased insulin
resistance. Despite the success of genome-wide association studies (GWAS) in linking >100 loci to islet
dysfunction and T2D, we still lack the mechanistic insights necessary to develop novel treatments and
preventions. Detailed molecular and phenotypic analyses of each T2D-associated GWAS locus are thus
essential to determine how they contribute to islet dysfunction and diabetes. We have recently linked altered
C2CD4A/B expression to genetic risk of islet dysfunction and T2D. Our overall objective is to understand the
islet/beta cell regulation and function of the C2CD4A/B locus in physiologic and diabetogenic states. We
hypothesize that these genes regulate stimulus-secretion coupling and that chronic activation of C2CD4A/B by
genetic and/or environmental risk factors contributes to the declines in first-phase insulin secretion that are
hallmarks of the early stages of T2D. To test this hypothesis, we will determine the regulatory circuitry
controlling C2CD4A/B responses to inflammatory stressors and determine the effect of T2D-associated GWAS
variants on C2CD4A/B activity (Aim 1). In parallel, we will dissect the beta cell functions of C2CD4A and
C2CD4B in glucose-stimulated insulin secretion (Aim 2). Finally, we will assess the in vivo effects of deleting
these genes in a polygenic T2D mouse model (Aim 3). Together, these aims will provide fundamental,
mechanistic insights into the regulation and function of the C2CD4A/B locus and will delineate the roles of
these genes in islet function and T2D pathogenesis. More broadly, we anticipate the study of this locus will
provide new perspectives/insights into the mechanics of insulin secretion and beta cell compensation. The
cellular and mouse models that we will create to dissect the regulation and function of the C2CD4A/B locus in
diabetes pathogenesis will empower future analyses of novel therapeutic molecules and approaches to target
this locus to prevent and treat diabetes.

## Key facts

- **NIH application ID:** 9840899
- **Project number:** 5R01DK117137-02
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** Michael Lee Stitzel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $416,265
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840899

## Citation

> US National Institutes of Health, RePORTER application 9840899, Regulation and Function of the Type 2 Diabetes-Associated C2CD4A/B Locus (5R01DK117137-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840899. Licensed CC0.

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