title: Use of in vitro clonogenic assays to differentiate acquired from genetic causes of insulin resistance.
abstract: Insulin resistance may be due directly to genetically programmed disorders of insulin action or acquired defects in which environmental factors influence insulin action. To address the issue of this distinction, we studied the ability of insulin to stimulate colony formation in primary cultures of erythroid progenitors (assumed to retain environmental influences) and immortalized T lymphocytes (presumed to reflect only genetic influences). Four patients with hyperinsulinemia and disturbed glucose metabolism were studied (2 patients with acanthosis nigricans, 1 of whom had circulating anti-insulin-receptor antibodies, 1 with partial lipodystrophy, and 1 with Cushing's syndrome). The mean colony-forming ability of their erythroid progenitor cells in response to insulin stimulation (less than or equal to 1.6 pM) was significantly blunted compared with control cells (P less than 0.05). The mean responsiveness of their immortalized T-lymphoblast cell lines to similar insulin concentrations was no different than that of control T-lymphocyte lines, consistent with an acquired cause for the observed insulin resistance in each case. A T-lymphocyte line from a patient with leprechaunism, however, showed no stimulation in response to physiological concentrations of insulin. With these same in vitro methodologies, there was normal T-lymphocyte line responsiveness to insulinlike growth factor I (IGF-I) or insulin concentrations greater than 8.6 pM; both of these responses could be completely blocked by preincubation with an antibody to the IGF-I receptor. These findings suggest that, despite resistance to physiological levels of insulin, the high circulating insulin concentrations present in the serum of these patients could mediate unwanted tissue-specific growth through an intact IGF-I receptor-effector mechanism.
authors.affiliation: Department of Pediatrics, University of California, Los Angeles, Medical Center 90024.
authors.forename: M E
authors.initials: ME
authors.lastname: Geffner
authors.forename: N
authors.initials: N
authors.lastname: Bersch
authors.forename: J M
authors.initials: JM
authors.lastname: Nakamoto
authors.forename: M
authors.initials: M
authors.lastname: Scott
authors.forename: N B
authors.initials: NB
authors.lastname: Johnson
authors.forename: D W
authors.initials: DW
authors.lastname: Golde
mesh_terms: D000052:Acanthosis Nigricans / Q000503:physiopathology; D000293:Adolescent; D002478:Cells, Cultured; D002648:Child; D003114:Colony-Forming Units Assay; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics / Q000503:physiopathology*; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007700:Kinetics; D011956:Receptors, Cell Surface / Q000032:analysis; D017451:Receptors, Somatomedin; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
chemical_list: D007328:Insulin; D011956:Receptors, Cell Surface; D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I