TY - JOUR
T1 - Role of transglutaminase 2 in glucose tolerance
T2 - Knockout mice studies and a putative mutation in a MODY patient
AU - Bernassola, Francesca
AU - Federiciz, Massimo
AU - Corazzari, Marco
AU - Terrinoni, Alessandro
AU - Hribal, Marta L.
AU - De Laurenzi, Vincenzo
AU - Ranalli, Marco
AU - Massa, Ornella
AU - Sesti, Giorgio
AU - Irwin Mclean, W. H.
AU - Citro, Gennaro
AU - Barbetti, Fabrizio
AU - Melino, Gerry
PY - 2002/9
Y1 - 2002/9
N2 - 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.
AB - 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.
KW - Diabetes
KW - Insulin
KW - Mature-onset diabetes of the young
UR - http://www.scopus.com/inward/record.url?scp=0036720319&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036720319&partnerID=8YFLogxK
U2 - 10.1096/fj.01-0689com
DO - 10.1096/fj.01-0689com
M3 - Article
C2 - 12205028
AN - SCOPUS:0036720319
VL - 16
SP - 1371
EP - 1378
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 11
ER -