title: Tumors, IGF-2, and hypoglycemia: insights from the clinic, the laboratory, and the historical archive.
abstract: Tumors of mesenchymal and epithelial origin produce IGF-2, which activates pathways in the tumors. In a minority of patients, the tumors (hepatomas, fibromas, and fibrosarcomas are the most common among many) release into the circulation enough IGF-2-related peptides to mimic the fasting hypoglycemia characteristic of patients with insulin-producing islet-cell tumors. Rarely, markedly elevated IGF-2 levels produce somatic changes suggestive of acromegaly. Typically, the elevated IGF-2 levels are associated with suppressed plasma levels of insulin, IGF-1, and GH. Complicating the pathophysiology are the IGF binding proteins (IGFBPs) that can bind IGF-2 and IGF-1, modifying hormone metabolism and action. IGFBP concentrations are often altered in the presence of these tumors. At the cellular level, the 3 hormone-related ligands, IGF-2, IGF-1, and insulin, all bind to 4 (or more) types of IGF-1 receptor (IGF-1R) and insulin receptor (IR). Each receptor has its own characteristic affinity for each ligand, a tyrosine kinase, and overlapping profiles of action in the target cells. The IGF-2R, in addition to binding mannose-6-phosphate-containing proteins, provides an IGF-2 degradation pathway. Recent evidence suggests IGF-2R involvement also in signal transduction. Surgery, the treatment of choice, can produce a cure. For patients not cured by surgery, multiple therapies exist, for the tumor and for hypoglycemia. Potential future therapeutic approaches are sketched. From 1910 to 1930, hypoglycemia, insulin, insulinomas, and non-islet-cell tumors were recognized. The latter third of the century witnessed the emergence of the immunoassay for insulin; the IGFs, their binding proteins, and assays to measure them; and receptors for the insulin-related peptides as well as the intracellular pathways beyond the receptor. In closing, we replace non-islet-cell tumor hypoglycemia, an outdated and misleading label, with IGF-2-oma, self-explanatory and consistent with names of other hormone-secreting tumors.
authors.affiliation: MD, FACP, Investigator, Feinstein Institute for Medical Research, Laboratory of Diabetes and Diabetes-Related Research, 350 Community Drive, Manhasset, NY 11030. jesserothmd@hotmail.com.
authors.forename: Yevgeniya
authors.initials: Y
authors.lastname: Dynkevich
authors.forename: Kristina I
authors.initials: KI
authors.lastname: Rother
authors.forename: Ian
authors.initials: I
authors.lastname: Whitford
authors.forename: Sana
authors.initials: S
authors.lastname: Qureshi
authors.forename: Sneha
authors.initials: S
authors.lastname: Galiveeti
authors.forename: Alessandra L
authors.initials: AL
authors.lastname: Szulc
authors.forename: Ann
authors.initials: A
authors.lastname: Danoff
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Breen
authors.forename: Nargess
authors.initials: N
authors.lastname: Kaviani
authors.forename: Michael H
authors.initials: MH
authors.lastname: Shanik
authors.forename: Derek
authors.initials: D
authors.lastname: Leroith
authors.forename: Riccardo
authors.initials: R
authors.lastname: Vigneri
authors.forename: Christian A
authors.initials: CA
authors.lastname: Koch
authors.forename: Jesse
authors.initials: J
authors.lastname: Roth
mesh_terms: D000172:Acromegaly / Q000175:diagnosis / Q000378:metabolism; D000818:Animals; D015551:Autoimmunity; D006801:Humans; D007003:Hypoglycemia / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism; D018969:Insulin-Like Growth Factor Binding Proteins / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000009:adverse effects* / Q000378:metabolism* / Q000502:physiology; D009369:Neoplasms / Q000150:complications* / Q000453:epidemiology / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin