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• W2082083375 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. 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. The presence of matrix metalloproteinases in pancreatic islets was described more than 15 years ago,1Tomita T. Iwata K. Gelatinases and inhibitors of gelatinases in pancreatic islets and islet cell tumors.Mod Pathol. 1997; 10: 47-54PubMed Google Scholar, 2Barro C. Zaoui P. Morel F. Benhamou P.Y. Matrix metalloproteinase expression in rat pancreatic islets.Pancreas. 1998; 17: 378-382Crossref PubMed Scopus (12) Google Scholar but their exact role for islet function has still not been determined. Some of these enzymes have been implicated as important in pancreas development and islet morphogenesis,3Miralles F. Battelino T. Czernichow P. Scharfmann R. TGF-beta plays a key role in morphogenesis of the pancreatic islets of Langerhans by controlling the activity of the matrix metalloproteinase MMP-2.J Cell Biol. 1998; 143: 827-836Crossref PubMed Scopus (155) Google Scholar, 4Miettinen P.J. Huotari M. Koivisto T. Ustinov J. Palgi J. Rasilainen S. Lehtonen E. Keski-Oja J. Otonkoski T. Impaired migration and delayed differentiation of pancreatic islet cells in mice lacking EGF-receptors.Development. 2000; 127: 2617-2627Crossref PubMed Google Scholar whereas other reports indicate that, at least, the most studied metalloproteinases, matrix metalloproteinase-2 (MMP-2) and MMP-9 are dispensable in this aspect.5Perez S.E. Cano D.A. Dao-Pick T. Rougier J.P. Werb Z. Hebrok M. Matrix metalloproteinases 2 and 9 are dispensable for pancreatic islet formation and function in vivo.Diabetes. 2005; 54: 694-701Crossref PubMed Scopus (39) Google Scholar Proteinases hold the potential to affect the morphology and function of pancreatic islets not only by direct effects, but preferentially by regulating the availability of different growth factors and chemokines bound to the extracellular matrix.6Van den Steen P.E. Dubois B. Nelissen I. Rudd P.M. Dwek R.A. Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9).Crit Rev Biochem Mol Biol. 2002; 37: 375-536Crossref PubMed Scopus (739) Google Scholar, 7Vandooren J. Van den Steen P.E. Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): the next decade.Crit Rev Biochem Mol Biol. 2013; 48: 222-272Crossref PubMed Scopus (529) Google Scholar Thus, the predominant proangiogenic effect of MMP-9 is mediated by the release of vascular endothelial growth factor A (VEGF-A) from macromolecules during matrix degradation, which turns VEGF-A accessible as a mitogen for endothelial cells.8Bergers G. Brekken R. McMahon G. Vu T.H. Itoh T. Tamaki K. Tanzawa K. Thorpe P. Itohara S. Werb Z. Hanahan D. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis.Nat Cell Biol. 2000; 2: 737-744Crossref PubMed Scopus (2275) Google Scholar Indeed, MMP-9 has been implicated as a key player in the angiogenic shift during development of islet tumors, as well as in revascularization of transplanted pancreatic islets.8Bergers G. Brekken R. McMahon G. Vu T.H. Itoh T. Tamaki K. Tanzawa K. Thorpe P. Itohara S. Werb Z. Hanahan D. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis.Nat Cell Biol. 2000; 2: 737-744Crossref PubMed Scopus (2275) Google Scholar, 9Olsson R. Maxhuni A. Carlsson P.O. Revascularization of transplanted pancreatic islets following culture with stimulators of angiogenesis.Transplantation. 2006; 82: 340-347Crossref PubMed Scopus (46) Google Scholar, 10Christoffersson G. Vagesjo E. Vandooren J. Liden M. Massena S. Reinert R.B. Brissova M. Powers A.C. Opdenakker G. Phillipson M. VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue.Blood. 2012; 120: 4653-4662Crossref PubMed Scopus (235) Google Scholar The importance of the islet vasculature for the endocrine function of the pancreatic islets has gained considerable interest in recent years. The islets are among the best blood-perfused organs in the body,11Lifson N. Lassa C.V. Dixit P.K. Relation between blood flow and morphology in islet organ of rat pancreas.Am J Physiol. 1985; 249: E43-E48PubMed Google Scholar, 12Jansson L. The regulation of pancreatic islet blood flow.Diabetes Metab Rev. 1994; 10: 407-416Crossref PubMed Scopus (156) Google Scholar where each beta cell is in direct contact with at least one endothelial cell.13Bonner-Weir S. Orci L. New perspectives on the microvasculature of the islets of Langerhans in the rat.Diabetes. 1982; 31: 883-889Crossref PubMed Google Scholar Thus, the endothelial cells are constantly interacting with the endocrine cells through paracrine influence,14Peiris H. Bonder C.S. Coates P.T. Keating D.J. Jessup C.F. The beta-cell/EC axis: how do islet cells talk to each other?.Diabetes. 2014; 63: 3-11Crossref PubMed Scopus (70) Google Scholar and several endothelial cell–derived factors such as laminins,15Nikolova G. Jabs N. Konstantinova I. Domogatskaya A. Tryggvason K. Sorokin L. Fassler R. Gu G. Gerber H.P. Ferrara N. Melton D.A. Lammert E. The vascular basement membrane: a niche for insulin gene expression and Beta cell proliferation.Dev Cell. 2006; 10: 397-405Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar, 16Johansson A. Lau J. Sandberg M. Borg L.A. Magnusson P.U. Carlsson P.O. Endothelial cell signalling supports pancreatic beta cell function in the rat.Diabetologia. 2009; 52: 2385-2394Crossref PubMed Scopus (75) Google Scholar thrombospondin-1,17Drott C.J. Olerud J. Emanuelsson H. Christoffersson G. Carlsson P.O. Sustained Beta-cell dysfunction but normalized islet mass in aged thrombospondin-1 deficient mice.PLoS One. 2012; 7: e47451Crossref PubMed Scopus (13) Google Scholar and hepatocyte growth factor18Johansson M. Mattsson G. Andersson A. Jansson L. Carlsson P.O. Islet endothelial cells and pancreatic beta-cell proliferation: studies in vitro and during pregnancy in adult rats.Endocrinology. 2006; 147: 2315-2324Crossref PubMed Scopus (171) Google Scholar have been shown to be of importance for beta cell function, differentiation, and proliferation in the adult. The high level of tortuous vascularization of the islets is due to the release of VEGF-A from beta cells, and mice incapable of beta cell synthesis of VEGF-A exhibit markedly decreased islet capillary density, as well as nonoptimal blood glucose control in the adult.19Lammert E. Gu G. McLaughlin M. Brown D. Brekken R. Murtaugh L.C. Gerber H.P. Ferrara N. Melton D.A. Role of VEGF-A in vascularization of pancreatic islets.Curr Biol. 2003; 13: 1070-1074Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar The maintained release of VEGF-A from beta cells is of importance also during adulthood to preserve the high level of vascularization as well as keeping the microvascular endothelium in a highly fenestrated state.20Reinert R.B. Brissova M. Shostak A. Pan F.C. Poffenberger G. Cai Q. Hundemer G.L. Kantz J. Thompson C.S. Dai C. McGuinness O.P. Powers A.C. Vascular endothelial growth factor-a and islet vascularization are necessary in developing, but not adult, pancreatic islets.Diabetes. 2013; 62: 4154-4164Crossref PubMed Scopus (74) Google Scholar, 21Kamba T. Tam B.Y. Hashizume H. Haskell A. Sennino B. Mancuso M.R. Norberg S.M. O'Brien S.M. Davis R.B. Gowen L.C. Anderson K.D. Thurston G. Joho S. Springer M.L. Kuo C.J. McDonald D.M. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature.Am J Physiol Heart Circ Physiol. 2006; 290: H560-H576Crossref PubMed Scopus (656) Google Scholar Genetic interference with the VEGF-A gene in beta cells in the adult mouse will not affect islet mass or insulin secretion in vitro, but rather will affect the islet endothelium to reduce fenestration and thereby delay insulin release.20Reinert R.B. Brissova M. Shostak A. Pan F.C. Poffenberger G. Cai Q. Hundemer G.L. Kantz J. Thompson C.S. Dai C. McGuinness O.P. Powers A.C. Vascular endothelial growth factor-a and islet vascularization are necessary in developing, but not adult, pancreatic islets.Diabetes. 2013; 62: 4154-4164Crossref PubMed Scopus (74) Google Scholar Here, we tested the hypothesis that MMP-9 plays a critical role in beta-cell function and islet vascular homeostasis in postnatal islets. This was addressed in Mmp9-deficient (Mmp9−/−) mice by both in vivo and in vitro experiments to be able to discriminate between alterations of the beta-cell phenotype and indirect effects on blood glucose homeostasis mediated by vascular changes, ie, alterations in vascular density, blood perfusion, or capillary fenestrations. Male Mmp9−/− mice,22Dubois B. Masure S. Hurtenbach U. Paemen L. Heremans H. van den Oord J. Sciot R. Meinhardt T. Hämmerling G. Opdenakker G. Arnold B. Resistance of young gelatinase B-deficient mice to experimental autoimmune encephalomyelitis and necrotizing tail lesions.J Clin Invest. 1999; 104: 1507-1515Crossref PubMed Scopus (243) Google Scholar backcrossed 12 generations to C57Bl/6 and their wild-type (WT) littermates (25 to 30 g; Rega Institute, Leuven, Belgium), at 3 to 6 months of age had free access to tap water and pelleted food throughout the study. All experiments were approved by the Uppsala Regional Laboratory Animal Ethics Committee. Glucose [2.5 g/kg body weight (b.w.); Fresenius-Kabi, Uppsala, Sweden] was injected i.p. into the mice, and plasma glucose concentrations were measured before injection, and at 15, 30, 60, and 120 minutes after injection using blood glucose reagent strips (FreeStyle, Abbott, Alameda, CA). Insulin aspart (2 U/kg b.w.; NovoRapid; Novo Nordisk, Bagsvaerd, Denmark) was injected i.p., and plasma glucose levels were determined immediately before and 15, 30, 60, 90, 120, 180, 240, and 300 minutes after injection using blood glucose reagent strips. Pancreata from WT and Mmp9−/− mice were retrieved, weighed, fixed in 10% (v/v) formaldehyde, and embedded in paraffin. Sections (5 μm thick) of the pancreata were stained with a guinea pig antibody for insulin (ICN Biomedicals, Aurora, OH),23Mattsson G. Jansson L. Carlsson P.O. Decreased vascular density in mouse pancreatic islets after transplantation.Diabetes. 2002; 51: 1362-1366Crossref PubMed Scopus (173) Google Scholar and counterstained with hematoxylin. Some of the sections were also stained for endothelium with the lectin Bandeiraea simplicifolia-1 (BS-1; Sigma-Aldrich, St. Louis, MO).23Mattsson G. Jansson L. Carlsson P.O. Decreased vascular density in mouse pancreatic islets after transplantation.Diabetes. 2002; 51: 1362-1366Crossref PubMed Scopus (173) Google Scholar From each animal, ≥5 tissue sections were systematically assessed to reflect all parts of the pancreas. The fraction of the pancreas that was composed of endocrine tissue was measured by a direct point-counting method24Weibel E.R. Morphometry of the human lung: the state of the art after two decades.Bull Eur Physiopathol Respir. 1979; 15: 999-1013PubMed Google Scholar and used for calculation of the endocrine mass compensating for differences in pancreatic weight between animals. Islet vascular numbers were also counted in a microscope. The area of the investigated islets was determined using ImageJ software version 1.49g (NIH, Bethesda, MD). Pancreatic islets from WT and Mmp9−/− mice were isolated using a collagenase digestion protocol,25Andersson A. Isolated mouse pancreatic islets in culture: effects of serum and different culture media on the insulin production of the islets.Diabetologia. 1978; 14: 397-404Crossref PubMed Scopus (263) Google Scholar and maintained free floating in groups of 150 islets at 37°C (air/carbon dioxide, 95:5) overnight in 5 mL of tissue culture medium composed of RPMI1640 medium supplemented with 2 mmol/L l-glutamine, 11.1 mmol/L glucose, and 10% (v/v) fetal calf serum before the islet function assays (cf. below). After 3 to 4 days of culture, groups of 10 islets, from WT and from Mmp9−/− mice, were transferred to vials containing Krebs-Ringer bicarbonate buffer supplemented with 10 mmol/L HEPES, 3 mg/mL bovine serum albumin (ICN Biomedicals, Santa Ana, CA), and 10 mmol/L glucosamine; hereafter referred to as KRBH buffer. The KRBH buffer contained 1.67 mmol/L d-glucose during the first hour of incubation at 37°C (oxygen/carbon dioxide, 95:5). The medium was then removed and replaced by KRBH supplemented with 16.7 mmol/L glucose and the islets were then incubated for a second hour. After this second incubation, the islets were harvested, following retrieval of the medium, and homogenized by sonication in 200 μL of redistilled water. A fraction of the homogenate was mixed with acid-ethanol [0.18 mol/L HCl in 95% (v/v) ethanol] from which insulin was extracted overnight. Thus, these measurements were performed after exposure to both low and high glucose in all islets. Insulin contents in incubation media and homogenates were determined by a mouse insulin enzyme-linked immunosorbent assay kit (Mercodia AB, Uppsala, Sweden). Duplicate groups of 10 isolated islets from WT and Mmp9−/− mice were size matched and incubated for 120 minutes in 100 μL of KRBH supplemented with 2 mg/mL bovine serum albumin, 16.7 mmol/L glucose, and l-[4,5-3H] leucine to measure the incorporation of tritiated leucine during (pro)insulin and total protein biosynthesis. Assays were performed as described previously.16Johansson A. Lau J. Sandberg M. Borg L.A. Magnusson P.U. Carlsson P.O. Endothelial cell signalling supports pancreatic beta cell function in the rat.Diabetologia. 2009; 52: 2385-2394Crossref PubMed Scopus (75) Google Scholar Duplicate groups of 10 isolated islets from WT and Mmp9−/− mice were size matched, incubated in 100 μL of KRBH supplemented with d-[U-14C] glucose and nonradioactive glucose to give a high (16.7 mmol/L) glucose concentration. The vials containing the islets were incubated for 90 minutes in a slow-shaking water bath at 37°C before the glucose oxidation was terminated with 100 μL of 0.05 mmol/L antimycin A (Sigma-Aldrich). Additionally 100 μL of 0.4 mol/L Na2HPO4 (pH 6.0) was injected to release the carbon dioxide formed. The carbon dixode was trapped by the addition of Hyamine 10-X (New England Nuclear, Boston, MA) before another incubation period of 120 minutes at 37°C. Scintillation fluid (Ultima Gold, PerkinElmer, Waltham, MA) was added, and the radioactivity was measured in a liquid scintillation counter. The glucose oxidation rates were used as a measure of mitochondrial function.16Johansson A. Lau J. Sandberg M. Borg L.A. Magnusson P.U. Carlsson P.O. Endothelial cell signalling supports pancreatic beta cell function in the rat.Diabetologia. 2009; 52: 2385-2394Crossref PubMed Scopus (75) Google Scholar Mice were injected i.p. with 40 mg/kg streptozotocin (Sigma-Aldrich) in citrate buffer on five consecutive days in a multiple low-dose streptozotocin (MLDS) protocol.26Carlsson P.O. Flodstrom M. Sandler S. Islet blood flow in multiple low dose streptozotocin-treated wild-type and inducible nitric oxide synthase-deficient mice.Endocrinology. 2000; 141: 2752-2757Crossref PubMed Scopus (19) Google Scholar Blood glucose was monitored every third day using blood glucose reagent strips. Total RNA was isolated from freshly isolated islets and with RNeasy Micro Plus kit (Qiagen, Hilden, Germany). The quality of the mRNA as measured by the absorbance ratio at 260 nm and 280 nm (NanoDrop; Thermo Fischer, Wilmington, DE) was above 1.85 for all samples. Conversion of RNA into complementary DNA was performed with the High Capacity cDNA kit (Life Technologies Europe, Stockholm, Sweden). Custom-ordered TaqMan Array Micro Fluidic Cards (exon-spanning probes were used when available) were run on an Applied Biosystems 7E900HT Fast Real Time PCR system (Foster City, CA). The gene expression was profiled through the comparative CT method of relative quantification, with investigated genes (Supplemental Table S1) analyzed according to the manufacturer's instructions. β-Actin served as the reference gene. Sections of formalin-fixed, paraffin-embedded mouse pancreata were stained using antibodies against VEGF-A (clone EP1176Y; Abcam, Cambridge, UK), collagen 4 (rabbit polyclonal, Abcam), laminin α5 (rabbit polyclonal, Abcam), and laminin β2 (rabbit polyclonal; Novus Biologicals, Littleton, CO). Glycoproteins in the islets were stained by using the periodic acid-Schiff method. Staining intensity was assessed in 200× magnification micrographs using ImageJ software. For islet endothelial cell morphology and islet microvascular density, pancreata from WT and Mmp9−/− mice were cut into small pieces and fixed in 2% glutaraldehyde and 1% paraformaldehyde. These were embedded in Agar 100 epoxy resin (Oxford Instruments, Stockholm, Sweden). Ultrathin sections (50 to 60 nm) were contrasted with uranyl acetate and lead citrate. Electron microscopy was performed using a FEI Tecnai G2 (Hillsboro, OR) transmission electron microscope at an accelerating voltage of 80 kV. Mice were anesthetized by i.p. injections of avertin [2.5% (v/v) solution of 2,2,2-tribromoethanol (Sigma-Aldrich) in 2-methyl-2-butanol (Kemila, Stockholm, Sweden)] and placed on a heating pad to maintain body temperature. Animals were tracheostomized to facilitate respiration. Polyethylene catheters were inserted into the right carotid artery for blood pressure measurements and in the left femoral artery for blood sampling. After a 15-minute resting period, blood flow measurements were performed using a microsphere technique as previously described.27Kampf C. Bodin B. Kallskog O. Carlsson C. Jansson L. Marked increase in white adipose tissue blood perfusion in the type 2 diabetic GK rat.Diabetes. 2005; 54: 2620-2627Crossref PubMed Scopus (25) Google Scholar Briefly, approximately 1.5 × 105 black nonradioactive microspheres (10-μm diameter; Triton microspheres, San Diego, CA) were injected through the carotid catheter during 5 seconds. For a total of 60 seconds, arterial blood was collected by free flow from the catheter in the femoral artery. The exact withdrawal rate was confirmed by weighing the sample. The pancreas, both adrenal glands, and samples (approximately 40 mg each) from the colon, duodenum, and kidney were removed and weighed. The number of microspheres in the samples, including pancreatic islets was counted as previously described after visualization of islet microspheres by a freeze-thawing technique.28Jansson L. Hellerstrom C. A rapid method of visualizing the pancreatic islets for studies of islet capillary blood flow using non-radioactive microspheres.Acta Physiol Scand. 1981; 113: 371-374Crossref PubMed Scopus (127) Google Scholar The total number of islets and the total number of perfused islets were counted. Organ blood flow values were calculated according to the formula Qorg=Qref×Norg/Nref where Qorg is the organ blood flow, Qref is withdrawal rate of the reference sample, Norg is the number of microspheres in the organ, and Nref is the number of microspheres in the reference sample. The organ blood flow was expressed as milliliters per minute per gram tissue, whereas the islet perfusion was expressed as microliters per minute per gram pancreas. Adequate mixing of microspheres in the circulation was confirmed by comparing the blood flow values of the adrenal glands, which had to vary at most 10% within each animal. Values are expressed as mean ± SEM. Unpaired two-tailed t-tests or analysis of variance repeated measures were used for comparison between groups. P < 0.05 was considered as statistically significant. As previously described,29Descamps F.J. Martens E. Ballaux F. Geboes K. Opdenakker G. In vivo activation of gelatinase B/MMP-9 by trypsin in acute pancreatitis is a permissive factor in streptozotocin-induced diabetes.J Pathol. 2004; 204: 555-561Crossref PubMed Scopus (34) Google Scholar nonfasting blood glucose concentrations did not differ between Mmp9−/− mice and WT mice (time 0 min) (Figure 1A). However, an i.p. glucose tolerance test revealed that the Mmp9−/− mice had an impaired response to the glucose load (Figure 1A), which resulted in an increased area under the curve of plasma glucose values during the 120 minutes test (Figure 1B). To determine whether the delayed glucose handling in the Mmp9−/− mice was related to islet defects or peripheral insulin resistance, peak insulin values during the i.p. glucose load were investigated and i.p. insulin tolerance tests were performed. When analyzing the serum insulin levels of the mice at the peak of insulin release (15 minutes) during the glucose tolerance test, the Mmp9−/− mice had lower levels of insulin (Figure 1C). By contrast, the response to the insulin challenge was similar in both genotypes (Figure 1D). Mmp9−/− have been shown to have a defect in their growth plates,30Vu T.H. Shipley J.M. Bergers G. Berger J.E. Helms J.A. Hanahan D. Shapiro S.D. Senior R.M. Werb Z. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes.Cell. 1998; 93: 411-422Abstract Full Text Full Text PDF PubMed Scopus (1495) Google Scholar resulting in slight growth retardation and smaller body size (Supplemental Table S231Cauwe B. Martens E. Sagaert X. Dillen C. Geurts N. Li S. Mertens J. Thijs G. Van den Steen P.E. Heremans H. De Vos R. Blockmans D. Arnold B. Opdenakker G. Deficiency of gelatinase B/MMP-9 aggravates lpr-induced lymphoproliferation and lupus-like systemic autoimmune disease.J Autoimmun. 2011; 36: 239-252Crossref PubMed Scopus (25) Google Scholar, 32Dubois B. Arnold B. Opdenakker G. Gelatinase B deficiency impairs reproduction.J Clin Invest. 2000; 106: 627-628Crossref PubMed Scopus (63) Google Scholar, 33Plaks V. Rinkenberger J. Dai J. Flannery M. Sund M. Kanasaki K. Ni W. Kalluri R. Werb Z. Matrix metalloproteinase-9 deficiency phenocopies features of preeclampsia and intrauterine growth restriction.Proc Natl Acad Sci U S A. 2013; 110: 11109-11114Crossref PubMed Scopus (126) Google Scholar, 34Camp T.M. Tyagi S.C. Senior R.M. Hayden M.R. Tyagi S.C. Gelatinase B(MMP-9) an apoptotic factor in diabetic transgenic mice.Diabetologia. 2003; 46: 1438-1445Crossref PubMed Scopus (45) Google Scholar, 35Descamps F.J. Martens E. Proost P. Starckx S. Van den Steen P.E. Van Damme J. Opdenakker G. Gelatinase B/matrix metalloproteinase-9 provokes cataract by cleaving lens betaB1 crystallin.FASEB J. 2005; 19: 29-35Crossref PubMed Scopus (28) Google Scholar, 36Kowluru R.A. Mohammad G. dos Santos J.M. Zhong Q. Abrogation of MMP-9 gene protects against the development of retinopathy in diabetic mice by preventing mitochondrial damage.Diabetes. 2011; 60: 3023-3033Crossref PubMed Scopus (119) Google Scholar, 37Mishra P.K. Chavali V. Metreveli N. Tyagi S.C. Ablation of MMP9 induces survival and differentiation of cardiac stem cells into cardiomyocytes in the heart of diabetics: a role of extracellular matrix.Can J Physiol Pharmacol. 2012; 90: 353-360Crossref PubMed Google Scholar, 38Lingwal N. Padmasekar M. Samikannu B. Bretzel R.G. Preissner K.T. Linn T. Inhibition of gelatinase B (matrix metalloprotease-9) activity reduces cellular inflammation and restores function of transplanted pancreatic islets.Diabetes. 2012; 61: 2045-2053Crossref PubMed Scopus (16) Google Scholar, 39Kundu S. Pushpakumar S.B. Tyagi A. Coley D. Sen U. Hydrogen sulfide deficiency and diabetic renal remodeling: role of matrix metalloproteinase-9.Am J Physiol Endocrinol Metab. 2013; 304: E1365-E1378Crossref PubMed Scopus (65) Google Scholar, 40Li S.Y. Huang P.H. Yang A.H. Tarng D.C. Yang W.C. Lin C.C. Chen J.W. Schmid-Schonbein G. Lin S.J. Matrix metalloproteinase-9 deficiency attenuates diabetic nephropathy by modulation of podocyte functions and dedifferentiation.Kidney Int. 2014; 86: 358-369Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 41Mohammad G. Vandooren J. Siddiquei M.M. Martens E. Abu El-Asrar A.M. Opdenakker G. Functional links between gelatinase B/matrix metalloproteinase-9 and prominin-1/CD133 in diabetic retinal vasculopathy and neuropathy.Prog Retin Eye Res. 2014; 43: 76-91Crossref PubMed Scopus (17) Google Scholar, 42Hu J. Van den Steen P.E. Sang Q.X. Opdenakker G. Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases.Nat Rev Drug Discov. 2007; 6: 480-498Crossref PubMed Scopus (659) Google Scholar). The size of the pancreas in relation to the total body weight was, however, unaffected by the gelatinase deficiency (WT versus Mmp9−/−; 0.96 ± 0.06% versus 0.86 ± 0.02% pancreas weight of total b.w., P = 0.14). Matrix-degrading enzymes have also been postulated to affect migration of tissue cells during embryonal development, which may affect islet distribution and development. In the histological examination of pancreata from WT and Mmp9−/− mice, we observed no difference in islet mass (Figure 1E), and a normal distribution of islets in the pancreas (Figure 1, F and G). Because no reduction in islet mass could be observed, we investigated whether the defective insulin secretion of Mmp9−/− mice in vivo remained in vitro, which would indicate a change in beta-cell phenotype. Indeed, islets from Mmp9−/− mice exhibited an impaired insulin release in response to a high glucose concentration when compared to islets of WT mice (Figure 2A). However, the content of insulin in the islets was similar in both the genotypes (Figure 2B), and so was glucose-stimulated (pro)insulin biosynthesis (Figure 2C), which indicate that the insulin-producing machinery was intact in Mmp9−/− islets. Moreover, the mitochondrial function seemed normal, because the glucose oxidation rate did not differ between the genotypes (Figure 2D). MMP-9 has previously been suggested to be involved in development of diabetes.43Aston-Mourney K. Zraika S. Udayasankar J. Subramanian S.L. Green P.S. Kahn S.E. Hull R.L. Matrix metalloproteinase-9 reduces islet amyloid formation by degrading islet amyloid polypeptide.J Biol Chem. 2013; 288: 3553-3559Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 44Jackson A.M. Kanak M.A. Grishman E.K. Chaussabel D. Levy M.F. Naziruddin B. Gene expression changes in human islets exposed to type 1 diabetic serum.Islets. 2012; 4: 312-319Crossref PubMed Scopus (8) Google Scholar The multiple low-dose streptozotocin (MLDS) protocol is a way of mimicking an autoimmune destruction of the islets of Langerhans occurring during onset of type 1 diabetes.26Carlsson P.O. Flodstrom M. Sandler S. Islet blood flow in multiple low dose streptozotocin-treated wild-type and inducible nitric oxide synthase-deficient mice.Endocrinology. 2000; 141: 2752-2757Crossref PubMed Scopus (19) Google Scholar, 29Descamps F.J. Martens E. Ballaux F. Geboes K. Opdenakker G. In vivo activation of gelatinase B/MMP-9 by trypsin in acute pancreatitis is a permissive factor in streptozotocin-induced diabetes.J Pathol. 2004; 204: 555-561Crossref PubMed Scopus (34) Google Scholar Mice of both genotypes were subjected to this protocol, and their blood glucose levels were monitored for 51 days. In our hands, this protocol gave mild diabetes with a slow onset. The blood glucose le" @default.
• W2082083375 created "2016-06-24" @default.
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• W2082083375 date "2015-04-01" @default.
• W2082083375 modified "2023-10-02" @default.
• W2082083375 title "Matrix Metalloproteinase-9 Is Essential for Physiological Beta Cell Function and Islet Vascularization in Adult Mice" @default.
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