title: Hypothalamic brain-derived neurotrophic factor regulates glucagon secretion mediated by pancreatic efferent nerves.
abstract: Understanding the molecular mechanism of the regulation of glucagon secretion is critical for treating the dysfunction of α cells observed in diabetes. Glucagon-like peptide (GLP)-1 analogues reduce plasma glucagon and are assumed to contribute to their action to lower blood glucose. It has previously been demonstrated that the central administration of brain-derived neurotrophic factor (BDNF) improves glucose metabolism by a mechanism independent of feeding behaviour in obese subjects. Using male rats, we examined whether BDNF influences glucagon secretion from α cells via the the central nervous system. We investigate whether: (i) the central infusion of BDNF stimulates glucagon and/or insulin secretion via the pancreatic efferent nerve from the hypothalamus; (ii) the intraportal infusion of GLP-1 regulates glucose metabolism via the central and peripheral nervous system; and (iii) BDNF receptor and/or BDNF-positive fibres are localised near α cells of islets. The portal glucagon level decreased with the central administration of BDNF (n = 6, in each; P < 0.05); in contrast, there was no significant change in portal insulin, peripheral glucagon and insulin levels with the same treatment. This reduction of glucagon secretion was abolished by pancreatic efferent denervation (n = 6, in each; P < 0.05). In an immunohistochemical study, pancreatic α cells were stained specifically with BDNF and tyrosine-related kinase B, a specific receptor for BDNF, and α cells were also co-localised with BDNF. Moreover, intraportal administration of GLP-1 decreased glucagon secretion, as well as blood glucose, whereas it increased the BDNF content in the pancreas; these effects were inhibited with the central infusion of BDNF antibody (n = 6, in each; P < 0.05). BDNF and GLP-1 affect glucose metabolism and modulate glucagon secretion from pancreatic α cells via the central and peripheral nervous systems.
authors.affiliation: Department of Internal Medicine 1, Faculty of Medicine, Oita University, Yufu, Japan. gotokoro@oita-u.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Gotoh
authors.forename: T
authors.initials: T
authors.lastname: Masaki
authors.forename: S
authors.initials: S
authors.lastname: Chiba
authors.forename: H
authors.initials: H
authors.lastname: Ando
authors.forename: K
authors.initials: K
authors.lastname: Fujiwara
authors.forename: T
authors.initials: T
authors.lastname: Shimasaki
authors.forename: K
authors.initials: K
authors.lastname: Mitsutomi
authors.forename: I
authors.initials: I
authors.lastname: Katsuragi
authors.forename: T
authors.initials: T
authors.lastname: Kakuma
authors.forename: T
authors.initials: T
authors.lastname: Sakata
authors.forename: H
authors.initials: H
authors.lastname: Yoshimatsu
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D004525:Efferent Pathways; D005934:Glucagon / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005951:Glucose Tolerance Test; D007031:Hypothalamus / Q000378:metabolism*; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D008297:Male; D010179:Pancreas / Q000294:innervation*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon