title: Increased glucose transport by human fibroblasts with a heritable defect in insulin binding.
abstract: Insulin and IGF-I binding and their regulation of hexose transport were evaluated in skin fibroblasts cultured from a family (Atl) whose proband had leprechaunism, hypoglycemia, and severe insulin resistance. High affinity insulin binding to proband Atl cells was absent, and partially, but equally, impaired in fibroblasts from his related parents. IGF-I binding to his cultured fibroblasts was within the normal range. Cells from proband Atl had insulin receptor mRNAs similar to control fibroblasts. 3-O-Methyl-D-glucose (OMG) transport by proband Atl was threefold higher than in control fibroblasts (37.7 v 7.6-11 nmol/mL/s) and was insulin-insensitive. Proband Atl fibroblasts had a threefold increase in the Vmax for OMG entry and a concomitant increase in the number of D-glucose-inhibitable cytochalasin B binding sites on their plasma membrane. Similar levels of glucose transporter mRNA were observed in control and proband Atl fibroblasts. These results suggest that fibroblasts from patient Atl have a genetically transmitted mutation in the alpha subunit of their insulin receptor. In the homozygous affected proband, this mutation impairs insulin binding and causes elevated, insulin-insensitive glucose transport. The dysfunction resulting from this mutation is similar to that introduced in Chinese hamster ovary cells by transfection with a truncated alpha subunit.
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, GA 30322.
authors.forename: N
authors.initials: N
authors.lastname: Longo
authors.forename: L D
authors.initials: LD
authors.lastname: Griffin
authors.forename: R C
authors.initials: RC
authors.lastname: Shuster
authors.forename: S
authors.initials: S
authors.lastname: Langley
authors.forename: L J
authors.initials: LJ
authors.lastname: Elsas
mesh_terms: D019325:3-O-Methylglucose; D000328:Adult; D001693:Biological Transport, Active; D002478:Cells, Cultured; D002675:Child, Preschool; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007223:Infant; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008661:Metabolism, Inborn Errors / Q000378:metabolism*; D008757:Methylglucosides / Q000378:metabolism*; D008759:Methylglycosides / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification; D011972:Receptor, Insulin / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D017451:Receptors, Somatomedin; D012016:Reference Values; D012867:Skin / Q000378:metabolism*; D013577:Syndrome
chemical_list: D008757:Methylglucosides; D008759:Methylglycosides; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017451:Receptors, Somatomedin; D019325:3-O-Methylglucose; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin