Insulin resistance reverses despite weight gain with pan-PPAR agonism, revealing its plasma molecular correlates in type 2 diabetes
- 1State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Department of Pathology, Zhongshan Hospital, Fudan University,
Abstract
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.
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BibTeX
@misc{cao2026insulin,
title = {{Insulin resistance reverses despite weight gain with pan-PPAR agonism, revealing its plasma molecular correlates in type 2 diabetes}},
author = {Z. Cao and J. Li and N. Zhang and H. Chen and D. Pan and Q. Chen and Y. Mai and X. Yao and S. Sun and Y. Liu and W. Hou and Y. Yu and Y. An and Z. Yuan and J. Tan and X. Chen and Y. Zheng and H. Wu and J. Wang and J. Chang and C. Ding and Q. Huang and Q. Wang and B. Jiang and S. Wang and Q. Peng and W. Li and D. Pan and Y. Wang and T. Xu and L. Ji and W. Jia and L. Jin and Z. Ning and A. Vidal-Puig and X. Lu and L. Shi and Y. Zheng},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.06.26367120},
url = {https://www.medrxiv.org/content/10.64898/2026.11.06.26367120v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Insulin resistance reverses despite weight gain with pan-PPAR agonism, revealing its plasma molecular correlates in type 2 diabetes
AU - Z. Cao
AU - J. Li
AU - N. Zhang
AU - H. Chen
AU - D. Pan
AU - Q. Chen
AU - Y. Mai
AU - X. Yao
AU - S. Sun
AU - Y. Liu
AU - W. Hou
AU - Y. Yu
AU - Y. An
AU - Z. Yuan
AU - J. Tan
AU - X. Chen
AU - Y. Zheng
AU - H. Wu
AU - J. Wang
AU - J. Chang
AU - C. Ding
AU - Q. Huang
AU - Q. Wang
AU - B. Jiang
AU - S. Wang
AU - Q. Peng
AU - W. Li
AU - D. Pan
AU - Y. Wang
AU - T. Xu
AU - L. Ji
AU - W. Jia
AU - L. Jin
AU - Z. Ning
AU - A. Vidal-Puig
AU - X. Lu
AU - L. Shi
AU - Y. Zheng
PY - 2026
DA - 2026/11/06
PB - medRxiv
DO - 10.64898/2026.11.06.26367120
UR - https://www.medrxiv.org/content/10.64898/2026.11.06.26367120v1
AB - 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.
ER -