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DNA2 acts as a brake on β cell insulin hypersecretion and diet-induced metabolic dysfunction
Haixia Xu1, Dongmei Tang2, Na Yang1
1State Key Laboratory of Biotherapy and Cancer Center, Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Frontiers in Cell and Developmental Biology
|March 20, 2026
Summary
DNA replication helicase/nuclease 2 (DNA2) regulates pancreatic beta cell function. It acts as a rheostat, limiting mitochondrial activity to prevent overactivation during metabolic stress and maintain glucose homeostasis.
Area of Science:
- Cell Biology
- Metabolic Regulation
- Genomics
Background:
- DNA replication helicase/nuclease 2 (DNA2) is crucial for nuclear genome stability.
- Its role in metabolic regulation and disease, particularly in pancreatic beta cells, is not well understood.
Purpose of the Study:
- To investigate the function of DNA2 in pancreatic beta cell physiology.
- To determine the involvement of DNA2 in the pathogenesis of diabetes.
Main Methods:
- Generated beta cell-specific DNA2 knockout mice (DNA2INS2-/-).
- Performed metabolic phenotyping, insulin secretion assays, transcriptomic profiling, and mitochondrial function analysis.
- Utilized INS-1 cells for in vitro studies involving DNA2 knockdown, overexpression, and mutagenesis.
Main Results:
- DNA2INS2-/- mice on a high-fat diet developed hyperglycemia, hyperinsulinemia, insulin resistance, and ectopic lipid deposition.
- DNA2 deficiency led to increased beta cell proliferation and glucose-stimulated insulin secretion.
- RNA sequencing revealed dysregulated mitochondrial genes; DNA2 deletion enhanced mitochondrial ATP production and oxidative phosphorylation, while overexpression suppressed it.
Conclusions:
- DNA2 acts as a negative regulator of mitochondrial bioenergetics and insulin secretion in beta cells.
- DNA2 functions as a rheostat, preventing beta cell overactivation under metabolic stress.
- This regulation is critical for preserving systemic glucose homeostasis.
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