Gelatinase B is diabetogenic in acute and chronic pancreatitis by cleaving insulin.
Genetic, endocrine, and environmental factors contribute to the development of diabetes. Much information has been gathered on the homeostasis mechanisms of glucose regulation by insulin-producing pancreatic beta cells. Here we demonstrate high expression levels of gelatinase B (matrix metalloproteinase-9, MMP-9) by neutrophils in acute pancreatitis and by ductular epithelial cells in chronic pancreatitis. Because gelatinase B processes cytokines and chemokines, we investigated whether and how gelatinase B cleaves insulin. Pure human neutrophil gelatinase B was found to destroy insulin by cleavage at 10 sites. Pancreatic islet and ductular cells are relatively spared in comparison with the complete destruction of acinar cells of the exocrine pancreas in chronic pancreatitis. High expression levels of gelatinase B are maintained in the immediate proximity of insulin-secreting beta cells. Consequently, diabetes may be worsened by enzymatic degradation of insulin by gelatinase B and by the consequent enhancement of the autoimmune process. Gelatinase B is diabetogenic in acute and chronic pancreatitis by cleaving insulin.
Descamps
Francis J
FJ
Rega Institute for Medical Research, Laboratory of Molecular Immunology, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
Van den Steen
Philippe E
PE
Martens
Erik
E
Ballaux
Florence
F
Geboes
Karel
K
Opdenakker
Ghislain
G
D000208:Acute Disease; D000595:Amino Acid Sequence; D001665:Binding Sites; D002908:Chronic Disease; D003920:Diabetes Mellitus / Q000201:enzymology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007328:Insulin / Q000737:chemistry / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D010195:Pancreatitis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation
D007328:Insulin; D010446:Peptide Fragments; D020780:Matrix Metalloproteinase 9