Insulin resistance reverses despite weight gain with pan-PPAR agonism, revealing its plasma molecular correlates in type 2 diabetes
Insulin resistance (IR) and body weight are closely linked in type 2 diabetes (T2D), so their molecular correlates are hard to separate in observational data. Pan-PPAR agonism offers a test, because it improves insulin sensitivity while body weight increases. In the ChiHOPE cohort of 835 T2D patients from two randomized phase 3 trials of chiglitazar, 53% of chiglitazar-treated patients with HOMA-IR-defined IR at baseline no longer met the IR threshold after treatment, compared with 29% with placebo and 32% with sitagliptin, while BMI rose. We integrated plasma metabolomics and proteomics into a molecular estimate of HOMA-IR. It outperformed routine clinical measures, disagreed with HOMA-IR classification in 27% of patients, and identified adverse lipid, liver and inflammatory profiles within each HOMA-IR class. With chiglitazar, the molecular estimate fell despite weight gain, with lower proteoglycan 4 and higher glutamine and glycine. Circulating markers of IR can therefore improve without weight loss.
Authors
- Weiping Jia (ORCID: https://orcid.org/0000-0002-6244-2168)
- Antonio Vidal‐Puig (ORCID: https://orcid.org/0000-0003-4220-9577)
- Linong Ji (ORCID: https://orcid.org/0000-0002-3262-2168)
- Shanyue Sun (ORCID: https://orcid.org/0000-0002-3134-7299)
- Xintong Yao (ORCID: https://orcid.org/0000-0003-2478-0278)
- Ziyu Yuan (ORCID: https://orcid.org/0000-0002-3447-7961)
- Qianqian Peng (ORCID: https://orcid.org/0000-0002-2018-5706)
- Wanwan Hou (ORCID: https://orcid.org/0000-0002-9813-4554)
- Zehui Cao (ORCID: https://orcid.org/0000-0001-6105-3104)
- Xingdong Chen (ORCID: https://orcid.org/0000-0003-3763-160X)
- Yaqing Liu (ORCID: https://orcid.org/0000-0003-0172-4214)
- Wenran Li (ORCID: https://orcid.org/0000-0002-1712-6895)
- Qi Wang (ORCID: https://orcid.org/0000-0002-1973-8510)
- Qiaochu Chen (ORCID: https://orcid.org/0000-0002-7384-7574)
- Yan Zheng (ORCID: https://orcid.org/0000-0003-4877-7292)
- Ying Yu (ORCID: https://orcid.org/0009-0008-0631-7128)
- Chen Ding (ORCID: https://orcid.org/0000-0001-8673-3464)
- Haonan Chen (ORCID: https://orcid.org/0000-0002-9818-2783)
- Jia Li (ORCID: https://orcid.org/0000-0003-3152-3253)
- Zhiqiang Ning
- Yuanbang Mai
- Jiucun Wang (ORCID: https://orcid.org/0000-0003-2765-0620)
- Jun Chang
- Yanpeng An
- Yuanting Zheng (ORCID: https://orcid.org/0000-0003-4480-8303)
- Sijia Wang
- Desi Pan
- Xianping Lu
- Binghua Jiang
- Li Jin
- Hao Wu
- Jingze Tan
- Leming Shi
- Dejing Pan
- Tao Xu
- You Wang
- Naixin Zhang
- Qingxia Huang
Institutions
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Sciences (CN)
- University of Cambridge (GB)
- Fudan University (CN)
- Zhengzhou University (CN)
- Soochow University (CN)
- Fudan University Shanghai Cancer Center (CN)
- Shanghai Institute of Nutrition and Health (CN)
- Shenzhen Bay Laboratory (CN)
- Institute of Biophysics (CN)
- Wellcome/MRC Institute of Metabolic Science (GB)
- Peking University People's Hospital (CN)
- Zhongshan Hospital (CN)
- Shanghai Sixth People's Hospital (CN)
- University of Chinese Academy of Sciences (CN)
- MRC Metabolic Diseases Unit (GB)
- Shenzhen Chipscreen Biosciences Co. (CN)
- Guangzhou Laboratory (CN)
Publication Details
- Journal
- medRxiv
- Published
- 2026-11-08
- DOI
- https://doi.org/10.64898/2026.11.06.26367120
- Primary Topic
- Peroxisome Proliferator-Activated Receptors
- Type
- preprint
Funders
- National Natural Science Foundation of China
- State Key Laboratory of Genetic Engineering
- Higher Education Discipline Innovation Project