PMID:16979397

Citation	Yamanaka, M, Itakura, Y, Inoue, T, Tsuchida, A, Nakagawa, T, Noguchi, H and Taiji, M (2006) Protective effect of brain-derived neurotrophic factor on pancreatic islets in obese diabetic mice. Metab. Clin. Exp. 55:1286-92
Abstract	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.
Links	PubMed Online version:10.1016/j.metabol.2006.04.017
Keywords	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
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:GBRB3	part_of	GO:0005886: plasma membrane	ECO:0000314: direct assay evidence used in manual assertion		C	part_of:(CL:0002609)	Seeded From UniProt	complete

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