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.