Protective effect of brain-derived neurotrophic factor on pancreatic islets in obese diabetic mice

We have previously demonstrated that brain-derived neurotrophic factor (BDNF) ameliorates glucose metabolism and energy expenditure in obese diabetic db/db mice. In the present study, the effect of BDNF treatment on pancreatic islets of db/db mice was examined, using vehicle-treated pair-fed db/db mice as controls. Brain-derived neurotrophic factor (10 mg/kg) or vehicle was subcutaneously administered to male dbldb mice for 4 weeks. The food intake of vehicle-treated dbldb mice was restricted and precisely synchronized with that of BDNF-treated dbldb mice using a pellet pair-feeding apparatus because BDNF decreases food intake in hyperphagic mice. Repetitive administration of BDNF significantly lowered the blood glucose concentration compared with pair-fed vehicle-treated dbldb mice. The pancreatic insulin and glucagon concentrations were measured in dbldb mice to evaluate the effect of BDNF on the pancreas. Although the insulin concentration in the pancreas of pair-fed vehicle-treated dbldb mice was lower than in nondiabetic control +m/+m mice, it was higher in BDNF-treated dbldb mice than in vehicle-treated pair-fed dbldb mice and comparable to the concentration in +m/+m mice. The glucagon concentration in the pancreas of vehicle-treated pair-fed dbldb mice was higher than in +m/+m mice, and BDNF partially decreased the glucagon concentration in the pancreas of dbldb mice compared with vehicle. Histologic analyses of pancreatic sections were performed to characterize the mechanism through which BDNF modulates the hormonal concentration in the pancreas of dbldb mice. Although there were no significant differences in the number and total area of islets between the BDNF- and vehicle-treated groups, immunostaining with an anti-insulin antibody indicated that the islet beta-cell area in BDNF-treated dbldb mice was larger than that in vehicle-treated pair-fed dbldb mice. Furthermore, immunostaining with an antiglucagon antibody indicated that BDNF normalized the delocalization of non-beta cells in islets of dbldb mice. Electron microscopic images of beta cells indicated a decrease in secretory granules in vehicle-treated pair-fed dbldb mice; this change was reversed in BDNF-treated dbldb mice and reached a level comparable to that found in +m/+m mice. These findings suggest that BDNF prevents exhaustion of the pancreas in diabetic mice by maintaining the histologic cellular organization of beta cells and non-beta cells in pancreatic islets and restoring the level of insulin-secreting granules in beta cells. (c) 2006 Elsevier Inc. All rights reserved.