In vivo activation of gelatinase B/MMP-9 by trypsin in acute pancreatitis is a permissive factor in streptozotocin-induced diabetes

• Published in: The Journal of pathology Vol. 204; no. 5; pp. 555 - 561
• Main Authors: Descamps, Francis J, Martens, Erik, Ballaux, Florence, Geboes, Karel, Opdenakker, Ghislain
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.12.2004; Wiley
• Subjects: Acute Disease; Animals; Apoptosis - physiology; Biological and medical sciences; Blood Glucose - analysis; Ceruletide; diabetes; Diabetes Mellitus, Experimental - metabolism; Enzyme Activation - physiology; Gastroenterology. Liver. Pancreas. Abdomen; Investigative techniques, diagnostic techniques (general aspects); Islets of Langerhans - metabolism; Islets of Langerhans - physiopathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - blood; Matrix Metalloproteinase 9 - deficiency; Matrix Metalloproteinase 9 - metabolism; matrix metalloproteinase-9; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Necrosis - metabolism; Other diseases. Semiology; Pancreas, Exocrine - metabolism; Pancreas, Exocrine - physiopathology; pancreatitis; Pancreatitis - enzymology; Pancreatitis - metabolism; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; streptozotocin; trypsin; Trypsin - metabolism; Up-Regulation - physiology; Endocrinopathy; Animal model; Serine endopeptidases; Enzyme; matrix metalloproteinase-9; Acute; Diabetes mellitus; Pancreatitis; Metalloendopeptidases; Activation; Gelatinase B; Peptidases; In vivo; Anatomic pathology; Trypsin; Digestive diseases; Hydrolases; Streptozotocin; diabetes; Pancreatic disease
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.1669

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 β‐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. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.