Abstract Background and aim The role of dietary protein and glycemic index on insulin resistance (based on TyG index) within a nutritional program for weight loss and weight maintenance was examined. Methods This study analyzed 744 adults with overweight/obesity within the DIOGenes project. Patients who lost at least 8% of their initial weight (0–8 weeks) after a low-calorie diet (LCD) were randomly assigned to one of five ad libitum diets designed for weight maintenance (8–34 weeks): high/low protein (HP/LP) and high/low glycemic index (HGI/LGI), plus a control. The complete nutritional program (0–34 weeks) included both LCD plus the randomized diets intervention. The TyG index was tested as marker of body mass composition and insulin resistance. Results In comparison with the LP/HGI diet, the HP/LGI diet induced a greater BMI loss (p