title: Human insulin receptor and insulin signaling proteins in hepatic disease.
abstract: Insulin regulates hepatocellular metabolism and growth following insulin receptor (IR) autophosphorylation and activation of the intracellular adapter protein, insulin receptor substrate 1 (IRS-1). IRS-1 activates SH2 domain proteins such as Grb2, which may be vital to hepatocyte growth. To determine if these substances are abnormally expressed under pathophysiologic conditions, IR, IRS-1, Grb2 protein, and IR mRNA were studied in normal human liver (n = 10), cirrhotic liver (n = 10), and hepatocellular carcinoma (HCC) (n = 10) that had been procured during operative procedures. IR mRNA was quantified by S1-nuclease assay using a 195-bp digoxigenin-labeled IR DNA probe and normalized to the level of expression of the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene. Protein concentrations were determined by immunoblot analysis following SDS-PAGE of liver homogenate samples. Labeled DNA and antibody-complexed protein were detected by chemiluminescent means and quantified by densitometric analysis (mean densitometric units +/- standard error). Similar levels of IR mRNA were observed in normal tissue, cirrhosis, and HCC. IR protein concentration was significantly greater in HCC than in normal liver (1.82 +/- 0.2 vs 1. 25 +/- 0.17; P < 0.05). IRS-1 was significantly increased in cirrhosis compared to normal liver (1.61 +/- 0.31 vs 0.86 +/- 0.21; P < 0.05). No differences were observed in Grb2 in the three tissue types. Insulin receptor overexpression, previously seen in other tumor types, may confer an insulin-mediated growth advantage in HCC if added receptors reflect functional high affinity binding sites. Although an altered mass of IRS-1 protein was not observed in HCC, an IRS-1 increase in cirrhosis may favor hepatic regeneration.
authors: Surgical Service, VA Connecticut Healthcare System, West Haven, Connecticut 06516, USA.
authors: S A
authors: SA
authors: Spector
authors: E T
authors: ET
authors: Olson
authors: A A
authors: AA
authors: Gumbs
authors: H
authors: H
authors: Friess
authors: M W
authors: MW
authors: Büchler
authors: N E
authors: NE
authors: Seymour
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D051380:GRB2 Adaptor Protein; D015870:Gene Expression; D006801:Humans; D015151:Immunoblotting; D055504:Insulin Receptor Substrate Proteins; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D011506:Proteins; D012333:RNA, Messenger; D011972:Receptor, Insulin