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(The FASEB Journal. 2002;16:1371-1378.)
© 2002 FASEB

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

FRANCESCA BERNASSOLA, MASSIMO FEDERICI*, MARCO CORAZZARI, ALESSANDRO TERRINONI, MARTA L. HRIBAL*, VINCENZO DE LAURENZI, MARCO RANALLI, ORNELLA MASSA{dagger}, GIORGIO SESTI{ddagger}, W.H. IRWIN MCLEAN§, GENNARO CITRO||, FABRIZIO BARBETTI{dagger},{dagger}{dagger} and GERRY MELINO1

Biochemistry Laboratory, IDI-IRCCS, Department of Experimental Medicine and Biochemical Sciences and
* Department of Internal Medicine, University of Rome ‘Tor Vergata’, 00133 Rome, Italy;
{dagger} IBCIT-Biomedical Science Park Rome S. Raffaele, 00144 Rome, Italy;
{ddagger} Department of Clinical and Experimental Medicine, University of Catanzaro ‘Magna Grecia’, 88100 Catanzaro, Italy;
§ Epithelial Genetics Group, Human Genetics Unit, Department of Molecular and Cellular Pathology, Ninewells Medical School, Dundee, DD1 9SY, Scotland, UK;
|| SSD-SAFU, Ist. Regina Elena Institute, IFO, Rome, Italy; and
{dagger}{dagger} IRCCS ‘Bambino Gesù’ Children’s Hospital, 00165 Rome, Italy

1Correspondence: IDI-IRCCS, Biochemistry Lab, c/o Dep. Experimental Medicine, D26/F153, University of Rome ‘Tor Vergata’, Via Tor Vergata 135, 00133 Rome, Italy. E-mail: gerry.melino{at}uniroma2.it

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 ß 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.—Bernassola, F., Federici, M., Corazzari, M., Terrinoni, A., Hribal, M. L., De Laurenzi, V., Ranalli, M., Massa, O., Sesti, G., Mclean, W. H. I., Citro, G., Barbetti, F., Melino, G. Role of transglutaminase 2 in glucose tolerance: knockout mice studies and a putative mutation in a MODY patient.


Key Words: insulin • diabetes • mature-onset diabetes of the young




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