[How I treat and manage a candidate for pancreatic islets transplantation].
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Diabetes Mellitus, Type 1↗
Biomedical subjects
P Y Benhamou
Publications and source records attributed to P Y Benhamou.
[Cell therapy of diabetes mellitus: is there anything really new?].
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Diabetes Mellitus↗
Morbidity associated with intraportal islet transplantation.
INTRODUCTION: Complications associated with intraportal islet infusion have been reported. In this study, we analyzed the relationship between occurrence of complications and islet preparation characteristics/infusion technique. METHODS: We reviewed all intraportal islet infusions from 1992 to 2003. RESULTS: Sixteen islet autotransplantations were performed without infusion-related complications. The tissue volume injected was 13 +/- 11 mL with basal and peak portal pressures of 13 +/- 6 and 21 +/- 6 mm Hg. Seventy-seven intraportal islet allotransplantations were performed in 51 patients. Fifteen islet infusions were done by laparotomy during simultaneous islet/kidney transplantation without complication. Among 62 percutaneous transhepatic injections, nine complications (two portal branch thrombosis and seven intra-abdominal hemorrhages) were recorded. Rise in portal pressure was related to tissue volume injected (P <.05). Basal and peak portal pressures were 14 +/- 5 and 18 +/- 6 mm Hg in uncomplicated infusions, 14 +/- 9 and 18 +/- 9 mm Hg in the thrombosis group, and 13 +/- 7 and 18 +/- 5 mm Hg in the hemorrhage group (P >.05). Complications occurred only after percutaneous islet infusion (P <.03). CONCLUSIONS: Procedure-related morbidity of intraportal islet infusion is low. Changes in portal pressure are related to volume of tissue injected but do not seem to be associated with the occurrence of complications. Percutaneous infusion is a minimally invasive procedure, but this advantage must be balanced by the higher rate of complications.
Hemorrhage↗
Protection of insulin-secreting INS-1 cells against oxidative stress through adenoviral-mediated glutathione peroxidase overexpression.
OBJECTIVES: A large fraction of an islet graft can be lost early following allotransplantation from various non specific mechanisms including oxidative stress. Overexpression of antioxidant enzymes could confer a beneficial effect on islets exposed to reactive oxygen and nitrogen species. We examined the viability of beta cells driven to overexpress glutathione peroxidase (GPx) and exposed to a superoxide donor (hypoxanthine/xanthine oxidase HX/XO) and a nitric oxide donor (3-morpholinosydnonimine SIN-1). METHODS: Cultured INS-1 rat-derived insulin-secreting cells were transfected by an E1-deleted adenovirus carrying GPx cDNA (AdGPx). Additional experiments were performed with an adenovector carrying Cu/Zn superoxide dismutase cDNA (AdSOD). Cellular viability was tested by the WST-1 colorimetric assay and functionality by static incubation. RESULTS: AdGPx increased GPx activity within 48 hours from 0 (untransfected cells) to 60 +/- 11 U/g (cells transfected at an MOI of 25: 1). GPx overexpression significantly reduced cytotoxicity induced by HX/XO from 10.81 +/- 1.41 to 5.42 +/- 2.62% at 10 mU/ml and from 61.19 +/- 4.17 to 52.9 +/- 4.39% at 20 mU/ml (p=0.0002, transfected cells vs control cells). Doses of SIN-1 from 600 to 1000 micromol/l resulted in cytotoxicity ranging from 17.66 +/- 3.48 to 45.97 +/- 6.48% in control cells and from 5.65 +/- 1.37 to 35.80 +/- 5.59% in AdGPx transfected cells (p=0.015). The combination of AdGPx and AdSOD did not exhibit any synergistic cytoprotective effect. Control cells exposed to a HX/XO stress exhibited a reduction in glucose-theophylline stimulated insulin secretion by half, while stressed GPx overexpressing-cells maintained the same insulin secretion level than non-stressed cells. CONCLUSIONS: Adenoviral-induced overexpression of GPx enhances the resistance of a rat beta cell line to both reactive oxygen (ROS) and reactive nitrogen species (RNS) cytotoxicity. Transposition of these findings to human islet transplantation with a clinically-relevant procedure deserves further investigations.
Adenoviridae↗
Natural history, prognosis, and management of transplantation-induced diabetes mellitus.
Cardiovascular morbidity and mortality are increased in transplant recipients, and diabetes mellitus is among the main determinants of this increase. This review focuses on the influence of diabetes on survival and functional outcomes in transplant recipients, the prevalences of post-transplantation hyperglycaemia and diabetes, the mechanisms of diabetes in transplant recipients, the respective roles of immunosuppressive drugs, the predictive factors, and the practical implications. Although available studies show that calcineurin inhibitors have diabetogenic effects and that these are more marked with tacrolimus, emphasis should be put on the major diabetogenic role of corticosteroids. This warrants efforts to develop immunosuppressive regimens that eliminate or reduce the need for corticosteroids.
Diabetes Mellitus↗
Human islet transplantation network for the treatment of Type I diabetes: first data from the Swiss-French GRAGIL consortium (1999-2000). Groupe de Recherche Rhin Rhĵne Alpes Genève pour la transplantation d'Ilots de Langerhans.
AIMS/HYPOTHESIS: Improvements in islet transplantation require clinical series large enough to implement controlled new strategies. The goal of this study was to demonstrate the feasibility of a multicentre network for islet transplantation in Type I (insulin-dependent) diabetic patients. METHODS: The five centres (Besançon, Geneva, Grenoble, Lyon, Strasbourg) of the GRAGIL network allow pancreas procurement, recipient recruitment, transplantation procedure and follow-up. Islet isolation is, however, performed in one single laboratory (Geneva). Pancreata were procured in each of the five centres and transported to Geneva with an ischaemia time of less than 8 hours. Islets were isolated using a standard automated method. If the islet number was too low for a graft (< 6,000 Islet-equivalent/kg), islets were cultured up to 12 days until another isolation was possible. Islets were transplanted by percutaneous transhepatic intraportal injection. Immunosuppression consisted of cyclosporine, mycophenolate mofetil, steroids and an anti-interleukin 2 receptor antibody. RESULTS: From March 1999 to June 2000, 56 pancreata procurements were performed with an average yield of 234500 islet-equivalent, with 32 preparations over 200000 islet-equivalent. Ten C-peptide negative Type I diabetic patients (5 men and 5 women, median age 44 years, median diabetes duration 29 years) with an established kidney graft (> 6 months) received 9,030 +/- 1,090 islet-equivalent/kg with a median purity of 63 %. The number of pancreata required for each graft was 1 (n = 5) or 2 (n = 5). At the completion of a 12 month follow-up, we observed 0% primary nonfunction, 50% graft survival and 20% insulin-independence. CONCLUSIONS/INTERPRETATION: This study demonstrates the interest and the feasibility of a multicentre collaboration in human islet transplantation.
Adult↗
Variations of ambulatory blood pressure with position in patients with type 1 diabetes: influence of disease duration and microangiopathy in a pilot study.
OBJECTIVE: To study the influence of position changes on 24-h ambulatory blood pressure (ABP) in normotensive or mildly hypertensive normoalbuminuric patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: A cross-sectional evaluation of patients was staged according to the duration of diabetes (DD) and the presence of microangiopathy. We recruited 37 patients (30 men and 7 women), aged 38 +/- 12 years, who were normotensive or mildly hypertensive (diastolic blood pressure [DBP] <105 mmHg) and free of antihypertensive treatment and microalbuminuria. They were included according to DD (group 1, <5 years; group 2, > or =10 years). An additional group of seven diabetic patients with microalbuminuria and mild untreated hypertension was also investigated. We recorded 24-h ambulatory blood pressure every 15 min with a position sensor, which allowed for the discrimination between standing or supine/sitting position in the patient. RESULTS: Mean daytime (10:00 A.M. to 8:00 P.M.) ABP in supine/sitting position did not significantly differ between groups 1 and 2. However, standing ambulatory systolic blood pressure (ASBP) and ambulatory DBP (ADBP) were significantly higher than supine/sitting ASBP and ADBP in group 1 (DeltaSBP 4 +/- 5, DeltaDPB 4 +/- 6 mmHg, P < 0.01) but not in group 2 (DeltaSBP 2 +/- 8, DeltaDBP 2 +/- 4 mmHg, P = NS). Patients free of microangiopathy presented with significantly higher ABP in standing position than in sitting/lying position, whereas patients with retinopathy and/or nephropathy exhibited no significant increase of ABP during standing. CONCLUSION: The monitoring of position during ambulatory measurement of blood pressure in type 1 diabetic patients shows different patterns in relation to disease duration and the presence of microangiopathy.
Adult↗
Contribution of adenoviral-mediated superoxide dismutase gene transfer to the reduction in nitric oxide-induced cytotoxicity on human islets and INS-1 insulin-secreting cells.
AIMS/HYPOTHESIS: Vulnerability of pancreatic islets to oxygen free radicals and nitric oxide contributes to islet transplantation obstacles. This susceptibility can be linked to the low expression levels of antioxidant enzymes in islets. Our aim was to investigate the effect of overexpressing Cu/Zn superoxide dismutase in human islets through a simple procedure on the cytotoxic effects of two nitric oxide donors: 3-morpholinosydnonimine (SIN-1) and S-Nitroso-N-acetyl-D,L-penicillamine (SNAP). METHODS: Cultured human islets and INS-1 rat-derived insulin-secreting cells were transfected by an E1-deleted adenovirus carrying Cu/Zn SOD cDNA under the control of a cytomegalovirus (CMV) promoter (AdSOD). The viability of the cells was tested by the WST-1 assay (Roche, Indianapolis, Ind., USA). RESULTS: The AdSOD procedure allowed SOD activity to increase by twofold to threefold for 2 to 8 days following transfection. Adenovirus-driven SOD overexpression was associated with a significant reduction of SIN-1-induced cytotoxicity on human islets (69.9 +/- 10.5% protection at 200 micromol/l and 40.5 +/- 8.9% protection at 400 micromol/l) and INS-1 cells (82.2 8.8% protection at 200 micromol/l and 31.1 +/- 5.8% protection at 400 micromol/l). Protection against increasing doses of SNAP was AdSOD dose-dependent. Transfected islets released significantly more insulin than control islets in glucose-theophylline-stimulated conditions, without or following exposure to SNAP. CONCLUSIONS/INTERPRETATION: We thus established that adenoviral-induced overexpression of Cu/Zn SOD can be beneficial to human islet endocrine function and resistance to nitric oxide cytotoxicity. These data could be relevant for the development of new strategies aimed at preventing NO-induced beta-cell damage in an islet transplantation setting.
Adenoviridae↗
Improved quality and yield of islets isolated from human pancreata using a two-step digestion method.
A new approach, involving a two-step digestion process and Los Angeles preservation solution #1 (LAP-1), a cold storage solution, was developed for isolation of high-quality islets from human pancreata for transplantation. This approach markedly improves the islet yield, purity and viability, and the isolation success rate. In this method, the pancreas was digested first in warm collagenase solution for up to 20 minutes. After decanting the enzyme solution, partially digested tissue was dissociated by gentle agitation in cold LAP-1 solution without additional collagenase. The digested tissues were stored in cold LAP-1 solution until islet purification on Euro-Ficoll. Forty-six islet isolations were performed consecutively by the new method (group 1). These results were compared to those obtained earlier with 46 consecutive isolations, using our previous method that had been used before development of the new method (group 2). Our old method was a modification of Ricordi's method involving only warm collagenase digestion and the storage of digested tissues in cold Hanks balanced salt solution. All pancreata were partial, containing the body and tail. There were no significant differences in both groups with regard to the donor age, cold ischemic time, harvesting conditions, and pancreatic weight. Pancreas digestion was completed in approximately 1 hour in both groups. The isolation success rate as determined by viable islets after 2 days in culture was 93.5% (43 of 46 cases) in group 1, and 56.5% (26 of the 46) in group 2. Immediately after isolation, the new method yielded a total of 335,739 +/- 36,244 islets equivalent to 150 microm (IEQ) and 6,233 +/- 681 IEQ/g of pancreas with 83 +/- 2.5% purity, whereas the old method yielded a total of 195,587 +/- 25,242 IEQ and 3,763 +/- 5,509 IEQ/g with 69.2 +/- 4.7% purity. Isolated islets in group 1 maintained a good three-dimensional structure, displayed normal insulin release to high glucose stimulation in vitro, and restored euglycemia after transplantation into streptozotocin-diabetic athymic mice. The two-step digestion method provides a sufficient number of islets for transplantation from a single pancreas.
Adolescent↗
Ratio of triglycerides to HDL cholesterol is an indicator of LDL particle size in patients with type 2 diabetes and normal HDL cholesterol levels.
OBJECTIVE: In patients with type 2 diabetes, a normal HDL cholesterol level does not rule out that LDL particles may be small. Although techniques for analyzing LDL subfractions are not likely to be used in clinical practice, a prediction of LDL size based on a regular lipid profile may be useful for assessment of cardiovascular risk. RESEARCH DESIGN AND METHODS: Sixty patients with type 2 diabetes with acceptable glycemic control and an HDL cholesterol level > or = 1 mmol/l were recruited after cessation of lipid-altering treatments. LDL size was determined by 2-20% PAGE; patients having small LDL (n = 30) were compared with those having intermediate or large LDL (n = 30). RESULTS: Clinical characteristics, pharmacological therapies, lifestyle, and prevalence of diabetes-related complications were similar in both patient groups. LDL size correlated negatively with plasma triglycerides (TGs) (R2 = 0.52) and positively with HDL cholesterol (R2 = 0.14). However, an inverse correlation between the TG-to-HDL cholesterol molar ratio and LDL size was even stronger (R2 = 0.59). The ratio was > 1.33 in 90% of the patients with small LDL particles (95% CI 79.3-100) and 16.5% of those with larger LDL particles. A cutoff point of 1.33 for the TG-to-HDL cholesterol ratio distinguishes between patients having small LDL values better than TG cutoff of 1.70 and 1.45 mmol/l. CONCLUSIONS: The TG-to-HDL cholesterol ratio may be related to the processes involved in LDL size pathophysiology and relevant with regard to the risk of clinical vascular disease. It may be suitable for the selection of patients needing an earlier and aggressive treatment of lipid abnormalities.
Aged↗
[Health costs associated with the diabetic foot in developed countries.A plea for the creation of health care networks].
COST OF DIABETIC FOOT: A limited number of epidemiological and economical studies on diabetic foot in France is available. Studies conducted in other countries, namely USA, Netherlands, UK and especially Sweden, have evidenced major direct and indirect costs that generally are underestimated in overall economical cost of diabetes forecast. The rapid increase of diabetes prevalence throughout the world, combined with diabetic population aging, allows to speculate that this situation may dramatically worsen in the future. In order to reduce the economical and human burden of this complication, it is an urgent public health necessity in France to set multidisciplinary organisations, dealing with both in-patient care, which importance should be decreasing, and out-patient care, as well as prevention and foot care networks. The swedish experience figures an interesting model for our healthcare system.
Costs and Cost Analysis↗
Prediction of cardiovascular events in clinically selected high-risk NIDDM patients. Prognostic value of exercise stress test and thallium-201 single-photon emission computed tomography.
OBJECTIVE: We evaluated the prognostic value of an exercise stress test and thallium-201 scintigraphy for the prediction of cardiac events in selected high-risk NIDDM patients. RESEARCH DESIGN AND METHODS: NIDDM patients (n = 158, 105 men, aged 63 +/- 9 years) with two or more of the following criteria were prospectively included: age > or = 65 years, active smoking, hypertension > 160/95 mmHg, hypercholesterolemia (cholesterol > 5.70 mmol/l or LDL > 3.10 mmol/l), peripheral artery disease, abnormal rest electrocardiogram, or microalbuminuria (20-200 micrograms/min). An exercise-stress scintigraphy was performed in 77 patients able to exercise, while a dipyridamole scintigraphy was performed in 80 patients unable to exercise. Follow-up was 23 +/- 17 months. Major end points were cardiac deaths or nonfatal myocardial infarction. RESULTS: The annual event rate was 7.31% (deaths: 8, myocardial infarction: 14). Independent predictors of events were as follows: an age > 60 (P = 0.02), an abnormal rest electrocardiogram (P = 0.02), microalbuminuria (P = 0.001), the inability to exercise (P = 0.009), and the presence of more than two defects on scintigraphy (P = 0.001). A cardiac death occurred in 1.3% of patients able to exercise versus 8.8% of patients unable to exercise (odds ratio = 6.8, P = 0.001). Among patients unable to exercise, large perfusion defects corresponded to an annual mortality rate of 22.3%. Conversely, the negative predictive value of a normal scintigraphy for the occurrence of death was 97%. CONCLUSIONS: Inability to exercise and large perfusion defects on thallium-201 scan are major predictors of future death and myocardial infarction in high-risk NIDDM patients.
Activities of Daily Living↗
Huge progression of diabetes prevalence and incidence among dialysed patients in mainland France and overseas French territories. A second national survey six years apart. (UREMIDIAB 2 study).
In 1989, we conducted a survey (UREMIDIAB) on the prevalence of diabetes among the population on Renal Replacement Therapy (RRT) in Mainland France (MF), the lowest of the developed countries (6.9%) with a North-South gradient (higher prevalence in the North). This highlighted a possible (genetical or nutritional) "new french paradox" in mainland France populations. In 1992 we conducted a similar study in the french (mainly non caucasian) overseas territories (OT) hosting 3.2% of the total french population, and observed a prevalence of diabetes in RRT of 22.9%. The frequency of diabetes mellitus as a cause of ESRD increasing worldwide, we conducted a second survey in year 1995, in MF and the OT. This study, UREMIDIAB 2, included all of the 244 french dialysis centers. A "Center file" allowed us to determine the prevalence and incidence of diabetes in the french RRT population, (response rate 73%). Then a "Patient medical file" (response rate 64.8% for MF and 91% for the OT) provided detailed informations: type of diabetes (type 1 or 2), etiology of nephropathy, status of diabetic complications, family's geographic origin of the patient. In MF the prevalence of diabetics in RRT doubled within 6 years: 13.04% vs 6.9%, the incidence reached 15.7%. In the OT the prevalence and the incidence reached 25.7% and 35.6%, respectively. Type 2 diabetes represented 87% and 93% of the RRT diabetics in MF and the OT, respectively. Diabetic nephropathy was considered as the cause of renal failure in 91.3% of type 1 and 57.5% of type 2 diabetics under dialysis. We found: 14.7% of myocardial infarction, 12.7% of cerebral strokes, 17.6% of amputations (extreme 37% in some OT centers) among this diabetic RRT population. A North-East (higher prevalence) South-West (lower) gradient was confirmed. We conclude that, while an unusual low prevalence (< or = 13%) of diabetics under dialysis persists in some parts of Mainland France, the total prevalence has been doubled within 6 years (1989/95) and that in Overseas Territories, hosting similar mixed blood populations than USA (afro-caribbeans, asians, indians, micronesians and metis), the high incidence of diabetes in RRT has reached the US levels during the same period.
Diabetes Mellitus, Type 1↗
Adenovirus-mediated catalase gene transfer reduces oxidant stress in human, porcine and rat pancreatic islets.
Susceptibility of pancreatic islets to oxidant stress may affect islet viability and contribute to primary non function of allo- or xenogenic grafts. We investigated the influence of overexpression of catalase (CAT) on the viability of human, porcine and rat islets, as well as INS-1 beta-cell line. Islets were transfected with a replication-deficient adenovirus vector containing human CAT cDNA under the control of the adenovirus major late promoter (AdCAT) or a vector containing no foreign gene (AdNull) and used as a control. Oxidant stress was induced 48 h later by xanthine oxidase-hypoxanthine (XO 25 mU/ml, HX 0.5 mmol/l) or hydrogen peroxide (100 or 250 micromol/l). Islet cell viability was assessed 72 h after CAT transfer by 4-[3-(4-Idophenyl)-2-(4 nitrophenyl)-2H-5-tetrazolio]-1,2,benzene disulphonate (WST-1) test. Baseline catalase activity was three to fourfold lower in porcine than in human islets. CAT activity was reproducibly increased 2.5- to 7-fold in AdCAT infected islets, at least for 13 days. Overall, AdCAT conferred on human and pig islets a protection of 26.1 +/- 6.1 and 21.2 +/- 9.8% on XOHX injury and 35.4 +/- 4.2 and 57.9 +/- 10.5% on H2O2 stress. Similarly, rat islet cells and INS-1 cells were protected on XOHX stress by 17.8 +/- 2.3 and 30.8 +/- 8.7%, respectively. AdNull had no effect. Basal and stimulated insulin secretion was preserved in AdCAT-transfected human islets despite a XOHX challenge. This study validates adenovirus-mediated catalase gene transfer as a realistic approach to reduce non specific inflammation effects on human or porcine islet grafts. Moreover the relevance of defense mechanisms, previously suggested in human islets, is here illustrated in porcine islets.
Adenoviridae↗
Adenoviral-mediated catalase gene transfer protects porcine and human islets in vitro against oxidative stress.
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Animals↗
ApoE polymorphism and albuminuria in diabetes mellitus: a role for LDL in the development of nephropathy in NIDDM?
BACKGROUND: Chronic hyperglycaemia stands with diabetes duration as the main predicting factor for the development of nephropathy in insulin dependent diabetes mellitus (IDDM). In contrast, nephropathy in non-insulin-dependent diabetes mellitus (NIDDM) presents with a different natural history and, as well as atherosclerosis, can precede diabetes diagnosis and even the onset of patent hyperglycaemia. The role of lipid abnormalities in this matter remains debated. METHODS: We studied the prevalence of nephropathy (N+ = urinary albumin excretion rate (UAE) > 20 mg/d) in 134 Caucasian NIDDM patients ranked according to alipoprotein E (apoE) genotype (same distribution in 132 controls). Age, diabetes duration and sex ratio did not differ between N+ and N-. A patient with E2E4 (n = 1) was excluded from the analysis. RESULTS: The prevalence of nephropathy was significantly reduced in E2 allele carriers (36%, 8/22) vs 69% (77/111) in E2 non-carriers (P < 0.01). Relative risk (RR) of E2 carriers developing nephropathy was 0.52 (95% CI = 0.35-0.80). Both groups were comparable in terms of age (55 +/- 11 vs 57 +/- 11 years), diabetes duration (15 +/- 9 vs 14 +/- 10 years) and prevalence of retinopathy (59 vs 48%). Similar results were observed when patients with diabetes duration longer than 8 years were studied (n = 94). CONCLUSIONS: It has been largely established that low-density lipoprotein (LDL)-cholesterol level in E2 allele carriers (whether diabetic or not) was lower than in E2 non-carriers. The 2-fold increase of nephropathy in E2 non-carriers with NIDDM argues for a role for LDL in the development of human nephropathy in NIDDM patients. This result is in agreement with previous data established both in vitro and in vivo in animal models. These findings support evidence for the pathogenic and morphologic similarities between kidney disease and atherosclerosis in NIDDM patients.
Adult↗
LAP-1 cold preservation solution for isolation of high-quality human pancreatic islets.
The most critical factors that affect the outcome of clinical pancreatic islet transplantation are the number and quality of donor islets available for transplantation. Toward this goal, we attempted to obtain islets that are both of better quality and higher number than are obtainable by the islet-isolation process that is now widely used. We paid special attention to two critical components of the isolation procedure: minimizing the exposure of pancreatic tissue and freed islets to warm enzyme solution, and development of a preservation solution suitable for islets during cold storage of digested pancreatic tissue-free islets. For this purpose, we developed both a two-step procedure for pancreas digestion and a new cold preservation solution, the LAP-1 solution (Los Angeles preservation solution 1). In this study, we evaluated the effect of four preservation solutions by storing digested pancreatic tissues on ice for 90 min. After the cold storage, islets were purified on three layers of Euro-Ficoll solutions in a 50-ml tube, and the islet yield, viability, and function were determined. These experiments were performed by using samples from 10 consecutive islet isolations. Results with LAP-1, original University of Wisconsin solution (oUW), and modified UW solution (mUW;UW without hydroxyethyl starch) were compared with those obtained with Hank's balanced salt solution (HBSS). The islet yield was significantly higher in the LAP-1 and mUW groups as compared with the HBSS group (p < 0.01). The islet purity was significantly better in the LAP-1, oUW, and mUW groups than the HBSS (p < 0.001). The islet viability was lowest in the HBSS group immediately after purification (vs. LAP-1, oUW, and mUW, p < 0.05) and further decreased during culture (p < 0.01). Both the number and viability of cultured islets were the highest with LAP-1 solution but without statistical significance between mUW and oUW. Electron microscopic examination showed only slight damage to cell membranes immediately after purification of islets stored in LAP-1 solution and their complete recovery within 1-2 days of culture. These islets also exhibited normal insulin responses to high glucose by static incubation and perifusion assays.
Adolescent↗
Matrix metalloproteinase expression in rat pancreatic islets.
Matrix metalloproteinases (MMPs) are involved in the regulation of extracellular matrix turnover and tissue remodeling, through which they can influence the infiltration of a graft by immune-competent cells. Little is known about their role in islet allograft rejection. Therefore we investigated the expression of several MMPs and of two of their tissue inhibitors (TIMPs) in rat pancreatic islets. MMP and TIMP expression in isolated rat pancreatic islets was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) from total RNA. Several MMPs of different substrate specificities were found to be expressed in rat pancreatic islets, either shortly after islet isolation and in all conditions tested (MMP-9, TIMP-1) or after a lag time (MMP-2, MMP-3, MMP-14, TIMP-2). Fetal calf serum induced MMP-7 expression. The inflammatory cytokine interleukin-1 beta (IL-1 beta) did not induce MMP or TIMP expression. We showed that rat pancreatic islets are well equipped with MMPs and TIMPs, but the functional meaning of this expression remains to be elucidated. On the basis of the known effects on tissue remodeling and cytokine processing, we anticipate that they can influence islet engraftment and viability and participate to islet graft rejection.
Animals↗