In vivo activation of gelatinase B/MMP-9 by trypsin in acute pancreatitis is a permissive factor in streptozotocin-induced diabetes.
Matrix metalloproteinases, in particular gelatinase B/MMP-9, are key mediators in autoimmune diseases like multiple sclerosis and rheumatoid arthritis, but their pathogenic roles in diabetes are not well established. Gelatinase B has previously been shown to be upregulated in pancreas tissue from patients with acute and chronic pancreatitis and was suggested to exacerbate diabetes by cleaving insulin. In this study, the role of gelatinase B in diabetes was investigated using two streptozotocin-induced animal models of type I diabetes. In both a hyperacute and a subacute model, gelatinase B upregulation was found to be associated with disease activity. However, gelatinase B deficiency did not significantly protect against diabetes development, and wild-type and gelatinase B-deficient animals behaved similarly in terms of beta-cell apoptosis or necrosis. The fact that gelatinase B was found almost exclusively as the inactive pro-enzyme in most of the streptozotocin-induced diabetic animals may explain the lack of a gelatinase B effect. On the contrary, gelatinase B was completely activated in a minority (15%) of wild-type animals. This coincided with exocrine pancreatic inflammation, as revealed by the presence of active trypsin. The discovery of in vivo activation of progelatinase B by trypsin in acute pancreatitis is extended in a model of caerulein-induced pancreatitis. In the latter model, trypsinogen activation is systematically achieved and gelatinase B is found in its active form. In conclusion, gelatinase B itself is not a causative factor but, when activated by endogenous trypsin, is a permissive factor for insulin degradation and diabetes.
Descamps
Francis J
FJ
Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, Minderbroederstraat 10, B-3000 Leuven, Belgium.
Martens
Erik
E
Ballaux
Florence
F
Geboes
Karel
K
Opdenakker
Ghislain
G
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001786:Blood Glucose / Q000032:analysis; D002108:Ceruletide; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D007515:Islets of Langerhans / Q000378:metabolism / Q000503:physiopathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000097:blood / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis / Q000378:metabolism; D046790:Pancreas, Exocrine / Q000378:metabolism / Q000503:physiopathology; D010195:Pancreatitis / Q000201:enzymology / Q000378:metabolism*; D014357:Trypsin / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
D001786:Blood Glucose; D002108:Ceruletide; D014357:Trypsin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9