Role of transglutaminase 2 in glucose tolerance: knockout mice studies and a putative mutation in a MODY patient.
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 beta 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.
Biochemistry Laboratory, IDI-IRCCS, Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy.
Francesca
F
Bernassola
Massimo
M
Federici
Marco
M
Corazzari
Alessandro
A
Terrinoni
Marta L
ML
Hribal
Vincenzo
V
De Laurenzi
Marco
M
Ranalli
Ornella
O
Massa
Giorgio
G
Sesti
W H Irwin
WH
McLean
Gennaro
G
Citro
Fabrizio
F
Barbetti
Gerry
G
Melino
D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D002478:Cells, Cultured; D002648:Child; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000201:enzymology; D007700:Kinetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011972:Receptor, Insulin / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D011503:Transglutaminases / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*
D001786:Blood Glucose; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D011972:Receptor, Insulin; D019204:GTP-Binding Proteins