ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Molecular and Cellular Pathology
This article is part of the Research TopicExploring Therapeutic Strategies Through Animal Models of Cellular and Molecular DysfunctionView all 4 articles
DNA2 acts as a brake on β cell insulin hypersecretion and diet-induced metabolic dysfunction
Provisionally accepted
- Sichuan University, Chengdu, China
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Purpose: DNA replication helicase/nuclease 2 (DNA2) is an evolutionarily conserved nuclease-helicase with known role in maintaining nuclear genome stability. However, its potential involvement in metabolic regulation and disease remains unclear. This study investigates the role of DNA2 in pancreatic β cell physiology and diabetes pathogenesis. Methods: β cell-specific DNA2 knockout mice (DNA2INS2-/-) were generated and fed either a chow diet (CD) or high-fat diet (HFD). Metabolic phenotyping, insulin secretion assays, transcriptomic profiling, mitochondrial function analysis, and ultrastructural imaging were performed. INS-1 cells were used to assess the functions of DNA2 in vitro through knockdown, overexpression and site-directed mutagenesis. Results: DNA2INS2-/- mice exhibited normal metabolic profiles under CD, but developed severe hyperglycemia, hyperinsulinemia, insulin resistance, and ectopic lipid deposition upon HFD feeding. This phenotype was accompanied by increased β cell proliferation and glucose-stimulated insulin secretion. RNA sequencing revealed the dysregulation of mitochondrial regulatory genes in DNA2-deficient islets. Functional assays confirmed that DNA2 deletion enhanced mitochondrial ATP production and oxidative phosphorylation, whereas its overexpression suppressed mitochondrial activity. Domain-specific mutagenesis demonstrated that both nuclease and helicase activities are essential for DNA2-mediated metabolic regulation. Conclusions: Our findings identify DNA2 as a negative regulator of mitochondrial bioenergetics and insulin secretion in β cells. By limiting mitochondrial activity, DNA2 serves as a rheostat that prevents β cell overactivation during metabolic stress, thereby preserving systemic glucose homeostasis.
Keywords: DNA2, hyperinsulinemia, insulin secretion, mitochondrial activity, β cell proliferation
Received: 27 Oct 2025; Accepted: 04 Feb 2026.
Copyright: © 2026 Xu, Tang, Yang, Ma, Tian and Fu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Yan Tian
Xianghui Fu
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