Melatonin potentiates the effects of metformin on glucose metabolism and food intake in high‐fat‐fed rats

Summary Background Melatonin is a hormone synthesized mainly by the pineal gland, and secreted only at night. Melatonin has been proposed as a modulator of glucose metabolism. Methods Here we studied the metabolic effects of melatonin administration alone (s.c. 10 mg/kg) or in combination with metformin (p.o. 300 mg/kg), a widely used anti‐diabetic drug. These treatments were tested on glucose tolerance, insulin sensitivity and food intake in Zucker fatty rats (i.e., bearing a missense mutation in the leptin receptor gene) and high‐fat fed Sprague‐Dawley rats. Results Melatonin alone or in combination did not significantly modify glucose tolerance in either model. Melatonin alone in high‐fat fed Sprague‐Dawley improved insulin sensitivity to the level of metformin. In addition, combined treatment further ameliorated insulin sensitivity (+13%), especially during the late phase of rising glycemia. The lack of similar effects in Zucker rats suggests an involvement of leptin signaling in mediating the positive effects of melatonin. Body mass gain in Sprague‐Dawley rats was decreased by both metformin, and combined metformin and melatonin. While melatonin alone did not markedly affect food intake, its combination with metformin led to a more pronounced anorexia (‐17% food intake during the last week), as compared to metformin alone. Conclusions Melatonin improves the beneficial effects of metformin on insulin sensitivity and body mass gain in high‐fat fed Sprague‐Dawley rats. Therefore, the combination of melatonin and metformin could be beneficial to develop dual therapies to treat or delay type 2 diabetes associated with obesity. Melatonin improves the beneficial effects of metformin on insulin sensitivity and body mass gain in high‐fat‐fed Sprague Dawley rats, but not in Zucker rats. The combination of melatonin and metformin could be beneficial to develop dual therapies to treat or delay type 2 diabetes associated with obesity.