ABSTRACT: To examine associations of baseline insulin dynamics with changes in body composition and resting energy expenditure (REE) following weight loss.Twenty-one participants with overweight or obesity achieved 10-15% weight loss and then received 3 weight loss maintenance diets (high-carbohydrate, moderate-carbohydrate, and low-carbohydrate) in random order, each for 4 weeks. Body composition was measured at baseline and after weight loss. Insulin 30 min after glucose consumption (insulin-30; insulin response), C-peptide deconvolution analysis, HOMA, hepatic insulin sensitivity (IS), and REE were assessed at baseline and after each maintenance diet.Insulin-30, but not maximal insulin secretion, hepatic IS, or HOMA, predicted changes in fat mass (standardized ??=?0.385, 1.7 kg difference between 10th and 90th centile of insulin-30, P?=?0.04) after weight loss. Insulin-30 (??=?-0.341, -312 kcal day(-1) , P?=?0.008), maximal insulin secretion (??=?-0.216, -95 kcal day(-1) , P?=?0.0002), HOMA (??=?-0.394, -350 kcal day(-1) , P?=?0.002), and hepatic IS (??=?0.217, 225 kcal day(-1) , P?=?0.0003) predicted change in REE during weight loss maintenance, independent of changes in body composition. The inverse relationship between insulin-30 and REE was substantially attenuated when the low-carbohydrate diet was consumed first.These findings distinguish a novel phenotype, characterized by high insulin response, at risk for weight regain, and identify a dietary approach to ameliorate this risk.