Context: Betatrophin has recently attracted increasing interests as a potential beta-cell regenerative therapy in diabetes. However, differences in betatrophin profiles in patients with type 2 diabetes mellitus (T2DM) remain unclear. Objective: The objective of the study was to examine circulating betatrophin levels in subjects with different glucose tolerance status and its correlation with insulin resistance. Design, Setting, and Participants: Serum betatrophin levels were measured using an ELISA in age-, sex-, body mass index-, and blood lipid-matched subjects with normal glucose tolerance (n = 137), isolated impaired fasting glucose (n = 69), isolated impaired glucose tolerance (n = 120), and newly diagnosed T2DM (n = 112) from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal study. Results: Serum betatrophin levels were elevated in patients with T2DM compared with subjects with normal glucose tolerance, isolated impaired fasting glucose, or isolated impaired glucose tolerance (798.6 +/- 42.5 vs 692.7 +/- 29.0, P < .05, vs 682.7 +/- 43.0, P < .05, vs 646.8 +/- 34.3 pg/mL, P < .01). Betatrophin levels positively correlated with the index of homeostasis model assessment of insulin resistance (partial r = 0.11); inversely correlated with quantitative insulin sensitivity check index (partial r = -0.11), the Gutt insulin sensitivity index (partial r = -0.12), and the Matsuda insulin sensitivity index (partial r = -0.11) after controlling for age, sex, body mass index, andblood lipid in all participants (all values of P < .05). Conclusion: Circulating betatrophin levels are increased in patients withT2DMand associated with indexes of insulin resistance.