Liver protein profiles in insulin receptor-knockout mice reveal novel molecules involved in the diabetes pathophysiology

Barbara Capuani, David Della-Morte, Giulia Donadel, Sara Caratelli, Luca Bova, Donatella Pastore, Michele De Canio, Simona D’Aguanno, Andrea Coppola, Francesca Pacifici, Roberto Arriga, Alfonso Bellia, Francesca Ferrelli, Manfredi Tesauro, Massimo Federici, Anna Neri, Sergio Bernardini, Paolo Sbraccia, Nicola Di Daniele, Giuseppe SconocchiaAugusto Orlandi, Andrea Urbani, Davide Lauro

Research output: Contribution to journalArticlepeer-review


Liver has a principal role in glucose regulation and lipids homeostasis. It is under a complex control by substrates such as hormones, nutrients, and neuronal impulses. Insulin promotes glycogen synthesis, lipogenesis, and lipoprotein synthesis and inhibits gluconeogenesis, glycogenolysis, and VLDL secretion by modifying the expression and enzymatic activity of specific molecules. To understand the pathophysiological mechanisms leading to metabolic liver disease, we analyzed liver protein patterns expressed in a mouse model of diabetes by proteomic approaches. We used insulin receptor-knockout (IR-/-) and heterozygous (IR+/-) mice as a murine model of liver metabolic dysfunction associated with diabetic ketoacidosis and insulin resistance. We evaluated liver fatty acid levels by microscopic examination and protein expression profiles by orthogonal experimental strategies using protein 2-DE MALDI-TOF/TOF and peptic nLC-MS/MS shotgun profiling. Identified proteins were then loaded into Ingenuity Pathways Analysis to find possible molecular networks. Twenty-eight proteins identified by 2-DE analysis and 24 identified by nLC-MS/MS shotgun were differentially expressed among the three genotypes. Bioinformatic analysis revealed a central role of high-mobility group box 1/2 and huntigtin never reported before in association with metabolic and related liver disease. A different modulation of these proteins in both blood and hepatic tissue further suggests their role in these processes. These results provide new insight into pathophysiology of insulin resistance and hepatic steatosis and could be useful in identifying novel biomarkers to predict risk for diabetes and its complications.

Original languageEnglish
Pages (from-to)E744-E755
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number9
Publication statusPublished - 2015


  • High-mobility group-B1
  • Huntigtin
  • Insulin resistance
  • Proteomics

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)


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