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

Metabolism. 2006 Oct;55(10):1286-92. doi: 10.1016/j.metabol.2006.04.017.


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 db/db mice for 4 weeks. The food intake of vehicle-treated db/db mice was restricted and precisely synchronized with that of BDNF-treated db/db 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 db/db mice. The pancreatic insulin and glucagon concentrations were measured in db/db mice to evaluate the effect of BDNF on the pancreas. Although the insulin concentration in the pancreas of pair-fed vehicle-treated db/db mice was lower than in nondiabetic control +m/+m mice, it was higher in BDNF-treated db/db mice than in vehicle-treated pair-fed db/db mice and comparable to the concentration in +m/+m mice. The glucagon concentration in the pancreas of vehicle-treated pair-fed db/db mice was higher than in +m/+m mice, and BDNF partially decreased the glucagon concentration in the pancreas of db/db 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 db/db 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 db/db mice was larger than that in vehicle-treated pair-fed db/db mice. Furthermore, immunostaining with an antiglucagon antibody indicated that BDNF normalized the delocalization of non-beta cells in islets of db/db mice. Electron microscopic images of beta cells indicated a decrease in secretory granules in vehicle-treated pair-fed db/db mice; this change was reversed in BDNF-treated db/db 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.

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Brain-Derived Neurotrophic Factor / pharmacology*
  • Brain-Derived Neurotrophic Factor / therapeutic use
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / pathology*
  • Glucagon / blood
  • Glucagon / metabolism
  • Immunohistochemistry
  • Insulin / blood
  • Insulin / metabolism
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / ultrastructure
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Microscopy, Electron
  • Obesity / drug therapy*
  • Obesity / pathology*
  • Pancreas / metabolism
  • Pancreas / pathology
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use


  • Blood Glucose
  • Brain-Derived Neurotrophic Factor
  • Insulin
  • Recombinant Proteins
  • Glucagon