Intermittent administration of brain-derived neurotrophic factor (BDNF) ameliorates glucose metabolism and prevents pancreatic exhaustion in diabetic mice

We previously demonstrated that repetitive administration of brain-derived neurotrophic factor (BDNF) ameliorates glucose metabolism and energy expenditure in obese diabetic db/ db mice. However, we have not evaluated in detail the effect of single or intermittent BDNF administration on glucose metabolism in a diabetic animal model. The objectives of this study were to examine the dose-response effect and dosing interval of BDNF administration in db/ db mice and to evaluate the effect of intermittent BDNF administration on pancreatic function in db/ db mice. We evaluated the dose-response effect of BDNF by single administration in db/ db mice. First, single administration of BDNF greater than 70 mg/kg significantly reduced blood glucose concentration one day after administered, and the BDNF effect was maintained for 6 d. Next, the effects of BDNF administered twice a week at 4, 10, 25, and 62.5 mg/kg on blood glucose concentration, and the effects of BDNF administered once a week at 10, 20, 30, 50, and 70 mg/kg on blood glucose concentration were examined in db/ db mice. In the intermittent treatment studies, BDNF dose-dependently ameliorated glucose metabolism by not only the twice-a-week administration but also the once-a-week administration. Lastly, because BDNF reduces the food intake of obese hyperphagic diabetic mice, the effects of BDNF administered once or twice a week on the blood glucose concentration and plasma and pancreatic insulin concentrations in db/ db mice were compared with those of the vehicle under pair-fed conditions. Under pair-fed conditions, the intermittent administration of BDNF (25 mg/kg, twice a week, or 50 mg/kg, once a week) significantly reduced the blood glucose concentration and increased the plasma and pancreatic insulin concentrations compared with those in the pair-fed vehicle-treated db/ db mice. This indicates that the prolonged hypoglycemic effect of BDNF is not simply due to the reduction of food intake. In conclusion, we demonstrated that the intermittent administration of BDNF ameliorates glucose metabolism and prevents pancreatic exhaustion in obese diabetic mice. These findings indicate that BDNF may have potential as a unique hypoglycemic agent for the treatment of diabetes at a fundamental level with good patient compliance.