Human insulin receptor and insulin signaling proteins in hepatic disease

Seth A. Spector, Eric T. Olson, Andrew A. Gumbs, Helmut Friess, Markus W. Büchler, Neal E. Seymour

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)32-35
Number of pages4
JournalJournal of Surgical Research
Volume83
Issue number1
DOIs
StatePublished - May 1 1999
Externally publishedYes

Keywords

  • Cirrhosis
  • Hepatocellular carcinoma
  • Insulin receptor
  • IRS-1
  • Liver

ASJC Scopus subject areas

  • Surgery

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