Predominance of Insulin Resistance Over Beta-Cell Dysfunction as a Diabetes Risk Factor in Chinese Adults: Impact of Obesity in a Nationwide Prospective Study

Background: National investigations on the interaction of insulin resistance, beta-cell dysfunction, and obesity with the development of diabetes are scarce in China. Methods: In this prospective cohort study, we analyzed a nationwide sample of 97,828 adults aged 40 years or older, using data from the China Cardiometabolic Disease and Cancer Cohort Study, between 2011 and 2016. Glucose regulation status was defined according to the American Diabetes Association 2010 criteria. We examined the contributions of insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]) and beta-cell dysfunction (HOMA of beta-cell function [HOMA-B]) to diabetes risk, and evaluated the impact of obesity on these associations. Findings: High HOMA-IR was associated with a greater risk of diabetes (hazard ratio [HR] per unit increase in z score, 2·17; 95% CI, 2·10-2·24) than low HOMA-B (HR per unit decrease in z score: HR, 1·91; 95% CI, 1·84-1·99). The HRs for diabetes were 1·84 (95% CI, 1·74-1·96) per unit increase in z score of HOMA-IR and 2·04 (95% CI, 1·87-2·22) per unit decrease in z score of HOMA-B among participants with normal weight; the corresponding HRs for diabetes were 2·01 (95% CI, 1·92-2·10) and 1·88 (95% CI, 1·78-1·97) among participants with obesity (P[interaction] =0·006). The stronger association of HOMA-IR with diabetes than that of HOMA-B was diminished after adjusting for BMI. These associations and interactions were similar for participants with normal glucose regulation or prediabetes. Interpretation: Insulin resistance exhibited a stronger association with diabetes risk than beta-cell dysfunction; such association pattern was mainly modified by obesity. Funding Statement: This work was funded by the Chinese Ministry of Finance. It is also supported by the 973 Foundation (grant 2015CB553601), National Key R&D Program of China (grants 2016YFC1305600, 2016YFC1305202, 2016YFC0901200, 2016YFC1304904, 2017YFC1310700, and 2018YFC1311800), National Natural Science Foundation of China (grants 81622011 and 81621061), Shanghai Pujiang Program (grant 18PJ1409600), and the Shanghai Municipal Education Commission–Gaofeng Clinical Medicine Grant Support from Shanghai Jiao Tong University School of Medicine (grant 20171901). Declaration of Interests: Dr Ralph A. DeFronzo has been a member of the Advisory Board for Astra Zeneca, Novo Nordisk, Janssen, Boehringer-Ingelheim, Intarcia, and Elcelyx; a speaker for Novo Nordisk and Astra Zeneca; and an investigator for Boehringer-Ingelheim, Astra Zeneca, Janssen, and Merck. No other conflicts of interest relevant to this article were reported. Ethics Approval Statement: This study was approved by the Medical Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University. All study participants provided written informed consent.