Role of transglutaminase 2 in glucose tolerance: Knockout mice studies and a putative mutation in a MODY patient

Francesca Bernassola, Massimo Federiciz, Marco Corazzari, Alessandro Terrinoni, Marta L. Hribal, Vincenzo De Laurenzi, Marco Ranalli, Ornella Massa, Giorgio Sesti, W. H. Irwin Mclean, Gennaro Citro, Fabrizio Barbetti, Gerry Melino

Research output: Contribution to journalArticlepeer-review

Abstract

Transglutaminase 2 (TGase 2) is a Ca+2-dependent enzyme that catalyzes both intracellular and extracellular cross-linking reactions by transamidation of specific glutamine residues. TGase 2 is known to be involved in the membrane-mediated events required for glucose-stimulated insulin release from the pancreatic β cells. Here we show that targeted disruption of TGase 2 impairs glucose-stimulated insulin secretion. TGase 2-/- mice show glucose intolerance after intraperitoneal glucose loading. TGase 2-/- mice manifest a tendency to develop hypoglycemia after administration of exogenous insulin as a consequence of enhanced insulin receptor substrate 2 (IRS-2) phosphorylation. We suggest that the increased peripheral sensitivity to insulin partially compensates for the defective secretion in this animal model. TGase 2-/- mouse phenotype resembles that of the maturity-onset diabetes of young (MODY) patients. In the course of screening for human TGase 2 gene in Italian subjects with the clinical features of MODY, we detected a missense mutation (N333S) in the active site of the enzyme. Collectively, these results identify TGase 2 as a potential candidate gene in type 2 diabetes.

Original languageEnglish
Pages (from-to)1371-1378
Number of pages8
JournalFASEB Journal
Volume16
Issue number11
DOIs
Publication statusPublished - Sep 2002

Keywords

  • Diabetes
  • Insulin
  • Mature-onset diabetes of the young

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

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