Biological actions of glucagon gene-derived peptides in the peripheral nervous system of mice

Background: Glucagon gene-derived peptides are produced as glucagon-like peptide 1 (GLP-1) in intestinal L cells and glucagon in pancreatic α cells, and play an important physiological role. However, the physiological roles of those peptides in various tissues are not fully elucidated. In this study, we examined the physiological roles of these peptides in the peripheral nervous system (PNS). Methods: Expression of glucagon receptor in the PNS was examined in 18-21 week-old C57BL6/J (WT) mice utilizing immunohistochemical staining. Neurite outgrowth was assessed after 24-48 hours of primary culture of dorsal root ganglion (DRG) neurons supplemented with or without glucagon (10⁻⁷ to 10⁻⁵ mol/l). Furthermore, the sensory function of the plantar pedis was evaluated by thermal plantar test in glucagon gene deficient mice (gcg+/⁻, gcg⁻/⁻) of 8, 12, 18, 24, and 30 week-old. Results: The immunohistological staining validated the expression of glucagon receptor in most DRG neurons and satellite glial cells. In the primary culture of DRG neurons, the neurite length was significantly increased in the group cultured with glucagon. (control: 761.4±294.9 μm/cell, glucagon 10⁻⁵ mol/l: 2276.5±835.6 μm/cell, p <0.01). The thermal plantar test revealed a hypersensitivity in 12 week-old gcg-/- mice (WT: 8.8 second, gcg ⁺/⁻: 6.9, gcg⁻/⁻: 5.5, p < 0.01: WT vs. gcg⁻/⁻) and in 18 week-old gcg-/- and gcg+/- mice (WT: 8.8, gcg⁺/⁻: 7.1, gcg⁻/⁻: 6.6, p < 0.01: WT vs. gcg⁺/⁻ or gcg⁻/⁻). However, the hypersensitivity disappeared in 24 week-old mice (WT: 8.4, gcg+/-: 8.9, gcg⁻/⁻: 8.5). Discussion: These data suggested that glucagon may have a protective role for DRG neurons. Further investigation should be performed to elucidate the role of glucagon gene-derived peptides in the PNS in the future. Disclosure M. Motegi: None. T. Himeno: None. H. Kamiya: Other Relationship; Self; MSD K.K., Ono Pharmaceutical Co., Ltd., Sanofi K.K., AstraZeneca, Astellas Pharma KK, Eli Lilly and Company, Novartis Pharma K.K., Dainippon Sumitomo Pharma Co., Ltd, Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Co., Ltd, Ono Pharmaceutical Co., Ltd.. H. Shimoda: None. M. Kato: None. Y. Yamada: None. E. Miura-Yura: None. M. Kondo: None. S. Tsunekawa: None. Y. Kato: Speaker's Bureau; Self; Merck Sharp & Dohme Corp., Sanofi, Takeda Pharmaceutical Company, Eli Lilly Japan. Y. Hayashi: Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Kissei Pharmaceutical Co., Ltd., Takeda Pharmaceuticals Co., Ltd., Novartis Pharma K.K., Novo Nordisk A/S, Astellas Pharma US, Inc. J. Nakamura: Other Relationship; Self; Astellas Pharma US, Inc., AstraZeneca, Ono Pharmaceutical Co., Ltd., MSD K.K., Kyowa Hakko Kirin Co., Ltd., Kowa Pharmaceuticals America, Inc., Sanofi K.K., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Mitsubishi Tanabe Pharma Corporation, Eli Lilly and Company, Novartis Pharma K.K., Pfizer Inc..