# The characterization of Cela2a, a novel disease gene for metabolic syndrome in health and diseases

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $668,781

## Abstract

Molecular mechanisms that regulate insulin resistance and its progression to type2 diabetes (T2D) are not
understood and might reveal a therapeutic opportunity to reduce the burden of T2D. We recently identified
causative loss-of-function mutations in the CELA2A gene (Esteghamat & Mani, Nat. Genet. 2019), which
encodes the pancreatic elastase Chymotrypsin-like ELAstase 2A in kindreds with extreme phenotypes of
metabolic syndrome, type 2 diabetes, and early-onset atherosclerosis. Interestingly, the genome-wide
association studies have also shown a strong association between common variants in the CELA2A gene and
blood pressure, LDL cholesterol and BMI, underscoring its role in the disease of the general population.
Although only known for its function as a pancreatic exocrine enzyme, we found it to be a circulating protein
that is expressed in the extrapancreatic tissues, including gut. Its plasma levels rise after each meal in parallel
to plasma insulin levels in healthy humans. Our characterization of CELA2A functions revealed its ability to
trigger insulin secretion and sensitivity. In contrast, the catalytically inactive mutant CELA2A proteins found in
the cohort increased platelet aggregation and reduced insulin sensitivity. Mechanistically, CELA2A was found
to proteolytically cleave GPCRs such as PAR2 and induce PAR2-dependent activation of AMPK, while mutant
CELA2As trigger different PAR2-dependent pathways, resulting in increased ERK and reduced AMPK
activation. Thus, CELA2A appears to be an endogenous ligand of PAR2, a GPCR that has been implicated in
the regulation of glucose homeostasis. These functions underscore CELA2A’s role as a novel risk factor and
an attractive therapeutic target for the treatment of T2D. We will investigate the physiological functions of
CELA2A and explore its molecular mechanisms of action in glucose homeostasis in global, acinar cell- and
gut-specific Cela2a knockout mice, with a focus PAR2-dependent pathways. Cela2a KO mice are ideal for
this goal as they show impaired insulin sensitivity and increased hepatic and plasma triglycerides that match
the phenotypes of humans.

## Key facts

- **NIH application ID:** 10794390
- **Project number:** 5R01DK134329-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Arya Mani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $668,781
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10794390

## Citation

> US National Institutes of Health, RePORTER application 10794390, The characterization of Cela2a, a novel disease gene for metabolic syndrome in health and diseases (5R01DK134329-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10794390. Licensed CC0.

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