title: Bioactive insulin-like growth factors as a possible molecular target for non-islet cell tumor hypoglycemia.
abstract: Non-islet cell tumor hypoglycemia (NICTH) is a paraneoplastic syndrome characterized by persistent, severe hypoglycemia with a wide variety of solid tumors. It is considered to cause hypoglycemia by increasing the insulin-like bioactivity of the circulating insulin-like growth factor (IGF) system, however, the precise mechanism of hypoglycemia remains unclear. In this manuscript, we report on a patient suffering from NICTH caused by a small cell carcinoma of the colon. This is the first report focusing on the role of bioactive IGFs for this pathological condition. First, we demonstrated that the IGF signal pathway has been activated in this tumor in an autocrine and/or paracrine manner using immunohistochemical analysis. Second, we confirmed that bioactive IGFs in the patient's serum were increased using a modified kinase receptor activation assay, thus bioactive IGFs (mainly IGF-2) could be considered to play a major pathogenic role in enhanced hypoglycemic insulin-like activity. Third, increased IGF bioactivity in the patient's serum was completely inhibited by an anti-IGF neutralizing antibody in vitro. These results suggest that neutralization of bioactive IGFs might become a novel therapeutic strategy for NICTH to relieve the hypoglycemic symptoms together with the tumor suppressive effect.
authors.affiliation: a Department of Gastroenterology and Hepatology ; Kyoto University Graduate School of Medicine ; Sakyo-ku , Kyoto , Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Setoyama
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Takahiro
authors.initials: T
authors.lastname: Horimatsu
authors.forename: Taro
authors.initials: T
authors.lastname: Funakoshi
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Nikaido
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Kodama
authors.forename: Sachiko
authors.initials: S
authors.lastname: Minamiguchi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamabata
authors.forename: Manabu
authors.initials: M
authors.lastname: Muto
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D018288:Carcinoma, Small Cell / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007003:Hypoglycemia / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009384:Paraneoplastic Endocrine Syndromes / Q000175:diagnosis; D013002:Somatomedins / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D013002:Somatomedins
keywords: Anti-IGF neutralizing antibody; HMW IGF-2, high molecular weight IGF-2; IGF, insulin-like growth factor; IGF-1R, IGF type 1 receptor; IGFBP, IGF binding protein; IR; Insulin-like growth factor (IGF-1); Insulin-like growth factor-2 (IGF-2); KIRA, the kinase receptor activation assay; Kinase receptor activation assay (KIRA); NICTH, non-islet cell tumor hypoglycemia; Non-islet cell tumor hypoglycemia (NICTH); bioactive IGF; free IGF; insulin receptor