We hypothesized that (1) BCKAs, glutamate/glutamine and uric acid are associated with insulin resistance at baseline and 6‐month‐follow‐up; (2) weight reduction and improved insulin sensitivity during lifestyle intervention are associated with decreases in BCKAs, glutamate/glutamine and uric acid; (3) baseline BCKAs, glutamate/glutamine and uric acid predict subsequent changes in weight and insulin sensitivity and (4) BCKAs, glutamate/glutamine and uric acid levels are regulated in a sex‐dependent manner. The gene discussed is INS; the disease is Insulin resistance.