Tissue-resolved transcriptomic and proteomic profiling reveals organ-specific molecular signatures associated with inter-animal variation in glycemic response to metformin in obese diabetic Mongolian gerbils
- 1Clinical Medicine Laboratory, Department of Medical Genetics and Developmental Biology, School of Basic Medical Sciences, Capital Medical University
- 2Department of Endocrinology, Aviation General Hospital
Abstract
Background: Type 2 diabetes mellitus (T2DM) affects hundreds of millions of people worldwide. Metformin remains first-line therapy for obese T2DM; yet, 30–40% of patients fail to achieve adequate glycemic control with monotherapy, the magnitude of HbA1c reduction varies two- to threefold between individuals, and the multi-organ coordination underlying this inter-animal variation in glycemic response remains unclear.
Methods: Obese diabetic Mongolian gerbils were administered metformin (100 mg/kg/day, oral gavage; n = 4) or vehicle (n = 3) for 5 weeks. We performed matched transcriptomic (RNA-seq) and data-independent acquisition proteomic profiling of liver, skeletal muscle, and inguinal white adipose tissue. Cross-omics analyses were anchored to glycemic parameters, and key hepatic findings were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Gut microbiota were profiled via metagenomic sequencing.
Results: Metformin lowered 2-hour post-load glucose (2hPG) and ameliorated hepatic steatosis. In the liver, integrated transcriptomic–proteomic analysis revealed concordant downregulation of mitochondrial substrate carriers (Slc25a47, Slc25a29, Slc25a30) and lipid-handling factors (e.g. Apoa5, Apoc2), correlating with systemic glycemic burden among treated animals. In skeletal muscle, pathway-level integration supported the activation of metabolic remodeling programs, including PPAR signaling, that were tracked with the degree of glycemic improvement among treated animals. In iWAT, transcriptomic enrichment of immune and chemokine pathways, supported by proteomic trends, suggested that, among treated animals, higher residual inflammatory activity was associated with a weaker glycemic response. Gut metagenomic profiling revealed no detectable alterations in microbial diversity or community structure.
Conclusion: Hepatic mitochondrial-lipid remodeling and muscle metabolic activation aligned with glycemic improvement, while adipose tissue immune signatures may contribute to inter-animal variation in glycemic response, providing a multi-organ, data-supported framework for metformin’s systemic pharmacology.
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BibTeX
@article{gao2026tissueresolved,
title = {{Tissue-resolved transcriptomic and proteomic profiling reveals organ-specific molecular signatures associated with inter-animal variation in glycemic response to metformin in obese diabetic Mongolian gerbils}},
author = {Zheng Gao and Hongjuan Fang and Feiyang Li and Mo Wang and Zishan Zhang and Xueyun Huo and Xiaoyan Du},
journal = {Frontiers in Endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1954533},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1954533/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Tissue-resolved transcriptomic and proteomic profiling reveals organ-specific molecular signatures associated with inter-animal variation in glycemic response to metformin in obese diabetic Mongolian gerbils
AU - Zheng Gao
AU - Hongjuan Fang
AU - Feiyang Li
AU - Mo Wang
AU - Zishan Zhang
AU - Xueyun Huo
AU - Xiaoyan Du
PY - 2026
DA - 2026/10/23
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1954533
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1954533/full
AB - Background: Type 2 diabetes mellitus (T2DM) affects hundreds of millions of people worldwide. Metformin remains first-line therapy for obese T2DM; yet, 30–40% of patients fail to achieve adequate glycemic control with monotherapy, the magnitude of HbA1c reduction varies two- to threefold between individuals, and the multi-organ coordination underlying this inter-animal variation in glycemic response remains unclear. Methods: Obese diabetic Mongolian gerbils were administered metformin (100 mg/kg/day, oral gavage; n = 4) or vehicle (n = 3) for 5 weeks. We performed matched transcriptomic (RNA-seq) and data-independent acquisition proteomic profiling of liver, skeletal muscle, and inguinal white adipose tissue. Cross-omics analyses were anchored to glycemic parameters, and key hepatic findings were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Gut microbiota were profiled via metagenomic sequencing. Results: Metformin lowered 2-hour post-load glucose (2hPG) and ameliorated hepatic steatosis. In the liver, integrated transcriptomic–proteomic analysis revealed concordant downregulation of mitochondrial substrate carriers (Slc25a47, Slc25a29, Slc25a30) and lipid-handling factors (e.g. Apoa5, Apoc2), correlating with systemic glycemic burden among treated animals. In skeletal muscle, pathway-level integration supported the activation of metabolic remodeling programs, including PPAR signaling, that were tracked with the degree of glycemic improvement among treated animals. In iWAT, transcriptomic enrichment of immune and chemokine pathways, supported by proteomic trends, suggested that, among treated animals, higher residual inflammatory activity was associated with a weaker glycemic response. Gut metagenomic profiling revealed no detectable alterations in microbial diversity or community structure. Conclusion: Hepatic mitochondrial-lipid remodeling and muscle metabolic activation aligned with glycemic improvement, while adipose tissue immune signatures may contribute to inter-animal variation in glycemic response, providing a multi-organ, data-supported framework for metformin’s systemic pharmacology.
SN - 1664-2392
ER -