title: Matrix metalloproteinase-9 is essential for physiological Beta cell function and islet vascularization in adult mice.
abstract: The availability of paracrine factors in the islets of Langerhans, and the constitution of the beta cell basement membrane can both be affected by proteolytic enzymes. This study aimed to investigate the effects of the extracellular matrix-degrading enzyme gelatinase B/matrix metalloproteinase-9 (Mmp-9) on islet function in mice. Islet function of Mmp9-deficient (Mmp9(-/-)) mice and their wild-type littermates was evaluated both in vivo and in vitro. The pancreata of Mmp9(-/-) mice did not differ from wild type in islet mass or distribution. However, Mmp9(-/-) mice had an impaired response to a glucose load in vivo, with lower serum insulin levels. The glucose-stimulated insulin secretion was reduced also in vitro in isolated Mmp9(-/-) islets. The vascular density of Mmp9(-/-) islets was lower, and the capillaries had fewer fenestrations, whereas the islet blood flow was threefold higher. These alterations could partly be explained by compensatory changes in the expression of matrix-related proteins. This in-depth investigation of the effects of the loss of MMP-9 function on pancreatic islets uncovers a deteriorated beta cell function that is primarily due to a shift in the beta cell phenotype, but also due to islet vascular aberrations. This likely reflects the importance of a normal islet matrix turnover exerted by MMP-9, and concomitant release of paracrine factors sequestered on the matrix.
authors: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors: Gustaf
authors: G
authors: Christoffersson
authors: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors: Tomas
authors: T
authors: Waldén
authors: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors: Monica
authors: M
authors: Sandberg
authors: Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, KU Leuven, Leuven, Belgium.
authors: Ghislain
authors: G
authors: Opdenakker
authors: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors: Per-Ola
authors: PO
authors: Carlsson
authors: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. Electronic address: mia.phillipson@mcb.uu.se.
authors: Mia
authors: M
authors: Phillipson
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000473:pathology; D004198:Disease Susceptibility; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D018149:Glucose Intolerance / Q000150:complications / Q000235:genetics / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000502:physiology* / Q000648:ultrastructure; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D012039:Regional Blood Flow; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D007328:Insulin; D020780:Matrix Metalloproteinase 9; D005947:Glucose