The anti-inflammatory and immunological properties of SGLT-2 inhibitors.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are antidiabetic oral drugs that act on proximal renal tubules promoting renal glucose excretion. Although SGLT-2i belong to the class of hypoglycemic agents, in the last years great interest has emerged in studying their pleiotropic effects, beyond their ability to lower glucose levels. PURPOSE: In this review we are describing the anti-inflammatory and immunological properties of SGLT-2i; furthermore, we are addressing how the mechanisms associated with the aforementioned anti-inflammatory properties may contribute to the beneficial effects of SGLT-2i in diabetes. METHODS: A systematic search was undertaken for studies related the properties of SGLT-2i in reducing the inflammatory milieu of acute and chronic disease by acting on the immune system, independently by glycemia. RESULTS: Recently, some data described the anti-inflammatory and immunological properties of SGLT-2 in both pre-clinical and clinical studies. Numerous data confirmed the cardio- and -renal protective effects of SGLT-2i in patients with heart failure and kidney diseases, with or without diabetes. CONCLUSIONS: SGLT-2i are promising drugs with anti-inflammatory and immunological properties. Despite the mechanism of action of SGLT-2i is not fully understood, these drugs demonstrated anti-inflammatory effects, which may help in keeping under control the variety of complications associated with diabetes.

Anti-inflammatory effects of diet and caloric restriction in metabolic syndrome.

BACKGROUND: Weight loss in patients with metabolic syndrome has positive effects on cardiovascular and type 2 diabetes risks, but its effects on peripheral cytokines and lipid profiles in patients are still unclear. AIM: To determine the effects of diet-induced weight loss on metabolic parameters, lipids and cytokine profiles. METHODS: Eighteen adult males with metabolic syndrome (defined according to IDF 2009) and Body Mass Index (BMI) between 25 and 35 kg/m2 were subjected to a balanced hypocaloric diet for 6 months to reach at least a 5% body weight loss. RESULTS: After weight loss, a significant improvement in BMI, waist circumference, insulin, fasting blood glucose and HOMA-IR (homeostasis model assessment of insulin resistance) was observed. The analysis of LDL (low-density lipoprotein cholesterol) and HDL (high-density lipoprotein cholesterol) lipoproteins showed a change in their composition with a massive transfer of triacylglycerols from HDL to LDL. This was associated with a significant reduction in peripheral pro-inflammatory cytokines such as IL-6, TNF-α, IL-8 and MIP-1ß, leading to an overall decreased inflammatory score. An interesting positive correlation was also observed among peripheral cytokines levels after diet and peripheral levels of CETP (cholesteryl ester transfer protein), an enzyme with a key role in lipid change. CONCLUSION: Weight loss through caloric restriction is associated with an improvement in peripheral lipid and cytokine profiles that may play a major role in improving cardiovascular risk.

Blood pressure control in type 2 diabetes mellitus with arterial hypertension. The important ancillary role of SGLT2-inhibitors and GLP1-receptor agonists.

Type 2 diabetes mellitus and arterial hypertension are major cardiovascular risks factors which shares metabolic and haemodynamic abnormalities as well as pathophysiological mechanisms. The simultaneous presence of diabetes and arterial hypertension increases the risk of left ventricular hypertrophy, congestive heart failure, and stroke, as compared to either condition alone. A number of guidelines recommend lifestyle measures such as salt restriction, weight reduction and ideal body weight mainteinance, regular physical activity and smoking cessation, together with moderation of alcohol consumption and high intake of vegetables and fruits, as the basis for reduction of blood pressure and prevention of CV diseases. Despite the availability of multiple drugs effective for hypertension, BP targets are reached in only 50 % of patients, with even fewer individuals with T2DM-achieving goals. It is established that new emerging classes of type 2 diabetes mellitus treatment, SGLT2 inhibitors and GLP1-receptor agonists, are efficacious on glucose control, and safe in reducing HbA1c significantly, without increasing hypoglycemic episodes. Furthermore, in recent years, many CVOT trials have demonstrated, using GLP1-RA or SGLT2-inihibitors compared to placebo (in combination with the usual diabetes medications) important benefits on reducing MACE (cardio-cerebral vascular events) in the diabetic population. In this hypothesis-driven review, we have examined the anti-hypertensive effects of these novel molecules of the two different classes, in the diabetic population, and suggest that they could have an interesting ancillary role in controlling blood pressure in type 2 diabetic patients.

Clinical efficacy and predictors of response to dulaglutide in type-2 diabetes.

Aim of this retrospective multicenter observational study was to evaluate the efficacy and safety of the glucagon-like peptide-1 receptor agonist (GLP-1 RA) dulaglutide in a type-2 diabetic real-world population and to determine the factors predicting the response in terms of glycated haemoglobin (HbA1c) and other relevant clinical outcomes. Data for efficacy outcomes, adverse events and drug discontinuation were collected from records of patients with type-2 diabetes treated with once-a-week 1.5 mg of dulaglutide for 12 months in routine clinical practice. Initial analysis included 782 patients and 626 had complete follow-up at 6- and 12-months. There was a significant reduction of HbA1c at 6 months (-1 ± 0.8 %, p < 0.0001), which remained stable at 12-months follow-up (-1 ± 0.9 %, p < 0.0001). The percentage of subjects with HbA1c≤7.0 % increased significantly from 7.2 % at baseline to 52.7 % at 6 months to 55.8 % at 12 months. Predictors of the achievement of HbA1c≤7.0 % were low baseline HbA1c and short duration of diabetes. The reduction of HbA1c was associated with reductions of BMI, waist circumference, fasting plasma glucose and blood pressures. Neither sex nor age had significant effects on any clinical or laboratory outcome. The effects of dulaglutide on HbA1c, BMI and SBP tended to be greater in patients who shifted from dipeptidyl peptidase-IV inhibitors (-0.8 ± 0.8 %) than other GLP-1 RA, even if an improvement of HbA1c reduction (-0.5 %) was also seen in those shifting from other GLP-1 RA. This study confirms that addition of dulaglutide 1.5 mg once a week in real word settings has beneficial effects on both clinical and laboratory outcomes in patients with uncontrolled type-2 diabetes. Dulaglutide has a greater effect on HbA1c in patients with higher baseline values and helps achieve a target HbA1c≤7.0 %, more consistently in patients with lower baseline HbA1c and shorter diabetes duration.

Noninvasive induction of angiogenesis in tissues by external suction: sequential optimization for use in reconstructive surgery.

In reconstructive surgery, tissues are routinely transferred to repair a defect caused by trauma, cancer, chronic diseases, or congenital malformations; surgical transfer intrinsically impairs metabolic supply to tissues placing a risk of ischemia-related complications such as necrosis, impaired healing, or infection. Pre-surgical induction of angiogenesis in tissues (preconditioning) can limit postsurgical ischemic complications and improve outcomes, but very few preconditioning strategies have successfully been translated to clinical practice due to the invasiveness of most proposed approaches, their suboptimal effects, and their challenging regulatory approval. We optimized a method that adopts noninvasive external suction to precondition tissues through the induction of hypoxia-mediated angiogenesis. Using a sequential approach in a rodent model, we determined the parameters of application (frequency, suction levels, duration, and interfaces) that fine-tune the balance of enhanced angiogenesis, attenuation of hypoxic tissue damage, and length of treatment. The optimized repeated short-intermittent applications of intermediate suction induced a 1.7-fold increase in tissue vascular density after only 5 days of treatment (p < 0.05); foam interfaces showed the same effectiveness and caused less complications. In a second separate experiment, our model showed that the optimized technique significantly improves survival of transferred tissues. Here we demonstrate that noninvasive external suction can successfully, safely, and promptly enhance vascularity of soft tissues: these translational principles can help design effective preconditioning strategies, transform best clinical practice in surgery, and improve patient outcomes.

The purinergic system in allotransplantation.

The purine nucleotide adenosine triphosphate (ATP) is a universal source of energy for any intracellular reaction. Under specific physiological or pathological conditions, ATP can be released into extracellular spaces, where it binds and activates the purinergic receptors system (i.e. P2X, P2Y and P1 receptors). Extracellular ATP (eATP) binds to P2X or P2Y receptors in immune cells, where it mediates proliferation, chemotaxis, cytokine release, antigen presentation and cytotoxicity. eATP is then hydrolyzed by ectonucleotidases into adenosine diphosphate (ADP), which activates P2Y receptors. Ectonucleotidases also hydrolyze ADP to adenosine monophosphate and adenosine, which binds P1 receptors. In contrast to P2X and P2Y receptors, P1 receptors exert mainly an inhibitory effect on the immune response. In transplantation, a prominent role has been demonstrated for the eATP/P2X7R axis; the targeting of this pathway in fact is associated with long-term graft function and reduced graft versus host disease severity in murine models. Novel P2X receptor inhibitors are available for clinical use and are under assessment as immunomodulatory agents. In this review, we will focus on the relevance of the purinergic system and on the potential benefits of targeting this system in allograft rejection and tolerance.

Improved function of circulating angiogenic cells is evident in type 1 diabetic islet-transplanted patients.

Circulating angiogenic cells (CACs) are vascular-committed bone marrow-derived cells that are dysfunctional in type 1 diabetes (T1D). Here we studied whether restoration of normoglycemia following islet transplantation is associated with better CAC function. We carried out a cross-sectional study of 18 T1D patients, 14 insulin-independent islet-transplanted patients (ITA) and 14 healthy controls (C) evaluating in vivo and in vitro CACs viability and function. We found that the percentage of CACs in vivo did not differ among the three groups while the number of CAC colonies obtained from T1D, but not from ITA, was reduced compared to C (C = 7.3 ± 1.9, T1D = 0.9 ± 0.4 and ITA = 4.7 ± 1.9; p < 0.05 T1D vs. all). In vitro CAC migration/differentiation were similar, while in vivo an improved angiogenic ability of ITA compared to T1D was shown (capillary density: C = 93.5 ± 22.1, T1D = 19.2 ± 2.8 and ITA = 44.0 ± 10.5, p < 0.05 T1D vs. all). Increased apoptosis and lesser IL-8 secretion were evident in CACs obtained from T1D compared to C and ITA. in vitro addition of anti-hIL-8 reduced the number of colonies obtained from C. Finally, T1D, but not ITA, had a lower endothelial-dependent dilatation (EDD) compared with C. These data suggest that CAC function is altered in T1D and may be improved after islet transplantation.

Liver focal fatty changes at ultrasound after islet transplantation: an early sign of altered graft function?

AIMS: Few longitudinal imaging studies of liver-engrafted islets after islet transplantation are available for islet-transplant-alone (ITA) and islet-after-kidney (IAK) transplanted patients. Particularly controversial is the link between islet function and the appearance of islet-induced liver focal fatty changes. Aims of this study were to assess liver focal fatty changes at ultrasound after islet transplantation and their relationship with islet function. METHODS: The timing of first ultrasound detection of liver focal fatty changes and the prevalence and duration of these changes were assessed in 30 IAK transplanted patients, in five ITA patients and, retrospectively, in full-, partial- and no-function groups, according to islet function evaluated 1 year after transplantation. Patients with persistent ultrasound detected liver focal fatty changes underwent liver biopsy. Ultrasound positive and negative patients with functioning islets were compared for islet-function and C-peptide-levels during the follow-up. Variations of cholesterol/triglycerides and other metabolic parameters were also recorded at 1 year. RESULTS: Liver focal fatty changes at ultrasound were found in 12 patients (10/30 IAK, 2/5 ITA). First detection was at 6 months in eight cases and at 12 months in four cases. Liver ultrasound changes were of more than 1 year duration in eight cases. Steatosis was found histologically in 8/8 patients. At 12 months, liver ultrasound changes were detected to a greater extent in patients with partial islet function (10/12, eight IAK, two ITA) compared with patients with full islet function. C-peptide-levels were significantly lower in ultrasound-positive than in ultrasound-negative patients. At 18 months, ultrasound- positive patients were more prone to worsening of their function (9/12) compared with ultrasound-negative patients (3/18). No statistically significant differences of cholesterol/triglycerides levels were found in either the total number of patients or the IAK and ITA patients. CONCLUSIONS: Liver focal fatty changes at ultrasound (steatosis) after islet transplantation in IAK and ITA patients may represent an early sign of altered graft function.

Laser capture microdissection as a new tool to assess graft-infiltrating lymphocytes gene profile in islet transplantation.

Innovative tolerogenic protocols in transplantation would take advantage of the development of new tools capable of evaluating the impact of these treatments on the immune system. These assays have potential for clinical application. Currently, many of these studies are based on the analysis of peripheral lymph nodes and blood-derived cells, where the percentage of alloantigen-specific cells can be low or even unpredictable. We combined a laser capture microdissection (LCM) technique with real-time PCR (RT-PCR) to evaluate gene profile of islet-infiltrating lymphocytes. Donor Lewis rats islets were transplanted under the kidney capsule in diabetic Brown Norway rats. Administration of anti-LFA1 mAb or anti-CD28 F(Ab)' was able to prolong islet survival, while the combined treatment resulted in indefinite survival. The analysis of gene expression profile for IL-2, IFN-gamma, and IL-10 production of graft-infiltrating cells revealed high IL-2, IFN-gamma, and IL-10 in untreated rats; on the contrary, the combined treatment selectively abrogated IL-2- and IFN-gamma-producing cells infiltrate. The comparison between cytokine profile in periphery (even during an allogenic extra stimulus) and in the graft revealed the dichotomy between graft and peripheral cytokine assessment. We thus propose that direct analysis of graft-infiltrating cells should be used whenever possible to evaluate the effects of a new immunomodulatory protocol.

The clinical impact of islet transplantation.

Islet cell transplantation has recently emerged as one of the most promising therapeutic approaches to improving glycometabolic control in diabetic patients and, in many cases, achieving insulin independence. Unfortunately, many persistent flaws still prevent islet transplantation from becoming the gold standard treatment for type 1 diabetic patients. We review the state of the art of islet transplantation, outcomes, immunosuppression and--most important--the impact on patients' survival and long-term diabetic complications and eventual alternative options. Finally, we review the many problems in the field and the challenges to islet survival after transplantation. The rate of insulin independence 1 year after islet cell transplantation has significantly improved in recent years (60% at 1 year posttransplantation compared with 15% previously). Recent data indicate that restoration of insulin secretion after islet cell transplantation is associated with an improvement in quality of life, with a reduction in hypoglycemic episodes and potentially with a reduction in long-term diabetic complications. Once clinical islet transplantation has been successfully established, this treatment could even be offered to diabetic patients long before the onset of diabetic complications.

Beta 3 integrins regulate lymphocyte migration and cytokine responses in heart transplant rejection.

Integrin alpha v beta 3 is important for cell survival, signaling and migration, particularly during angiogenesis and tumorigenesis, where it has been proposed as a therapeutic target. alpha v beta 3 is up-regulated following transplantation and beta 3 polymorphisms are associated with increased acute kidney rejection, suggesting that alpha v beta 3 may also play a role in transplant rejection. Here, using a model of allogeneic heart transplantation, we show that allograft survival is prolonged in beta 3 integrin-deficient (beta 3(-/-)) mice. This is associated with Th2-type immune responses and reduced T-cell infiltration into grafts and T cells from beta 3(-/-) mice show impaired adhesion and migration, consistent with a role for alpha v beta 3 in transmigration. These studies provide evidence that targeting beta 3 integrins impairs recruitment of effector cells and alters cytokine production, so prolonging graft survival. We also show that low doses of blocking antibodies against leukocyte function associated antigen-1 (LFA-1)/alpha L beta 2 and very late antigen-4 (VLA-4)/alpha 4 beta 1, when combined with deletion of beta 3, lead to long-term survival of allografts with no evidence of chronic rejection. Hence we provide strong mechanistic evidence supporting previous genetic studies, demonstrate the involvement of beta 3 integrins in both acute and chronic rejection and identify beta 3 as a new target for immunosuppressive therapy.

Cardiovascular benefits of simultaneous pancreas-kidney transplant versus kidney alone transplant in diabetic patients.

UNLABELLED: The aim of our study was to demonstrate the cardiovascular benefits of simultaneous pancreas-kidney transplantation when compared to kidney-alone transplants in diabetic recipients. PATIENTS AND METHODS: A total of 386 renal transplants were performed from 1985 to 2004, including 262 (68%) in diabetic recipients and 124 (32%) in nondiabetics. Among the former group, 200 kidneys were transplanted simultaneously to the pancreatic graft (KP group) and 62 were kidney-alone transplants (KA group). The mean time on dialysis was 31 +/- 20 months (range 0-126 months). The duration of diabetes was 24 +/- 7 years (range 5-51 years). Ninety-nine percent of the patients were on renal replacement therapy (79% on hemodialysis and 20% on peritoneal dialysis). RESULTS: Among 262 patients, 28 (11%) died due to a cardiovascular event, which was higher among KA patients compared with the KP group (P = .004). Overall patient survival was significantly higher in the KP group when compared with the KA group (log-rank: P = .0004). Patient survivals were 80% and 70% versus 70% and 40% at 5 and 10 years in the KP and KA groups, respectively. Kidney graft survivals were 81% and 60% versus 63% and 26% at 5 and 10 years in the KP and KA groups, respectively. Pancreas graft survival was 70% and 50% at 5 and 10 years, respectively. CONCLUSIONS: This clinical evaluation, even if retrospective, confirmed that simultaneous pancreas-kidney transplantation has a protective effect against cardiovascular mortality in diabetic recipients affected by end-stage renal disease.

Multivariate analysis of factors affecting patient and graft survival after renal transplant.

AIM: To evaluate factors affecting patient and kidney survival after renal transplant. PATIENT AND METHODS: Among 361 patients undergoing renal transplant: 52% (n = 189) were simultaneous with pancreas transplant (SPKT group) and 48% (n = 172), a kidney transplant alone (KT group). Out of 361 patients, 75% (n = 270) were diabetics. The patients were 220 (61%) men and 141 (39%) women of mean age 41 +/- 9 years. The mean time of dialysis was 42 +/- 21 months (range 0 to 126), and the mean duration of diabetes 24 +/- 7 years (range 5 to 51). A Cox regression analysis was done. RESULTS: The multivariate analysis revealed that in the final model diabetes and donor age were significant predictors of kidney graft survival; moreover, diabetes and recipient age were predictors of patient survival. Overall patient survival was significantly greater among nondiabetic patients (P = .002) or in diabetic patients who received SPKT, when compared with diabetics in whom only the kidney was transplanted (P = .001). CONCLUSIONS: Diabetes and donor age were independent prognostic factors affecting kidney graft survival after renal transplant, and recipient age and diabetes were prognostic factors affecting patient survival. Combined pancreas and kidney transplantation should be offered to patients with end-stage diabetic nephropathy.

Determination of asymmetric and symmetric dimethylarginines in plasma of hyperhomocysteinemic subjects.

The aim of this study was to investigate the possible relationship among dimethylarginines (asymmetric, ADMA; symmetric, SDMA) and homocysteine (Hcy) levels in subjects affected by chronic, mild to intermediate, hyperhomocysteinemia. ADMA and SDMA were assayed by an optimised HPLC method in 75 patients (Hcy = 20.8 micromol/L, 17.1-30.2; median and percentile range) and, for comparison, in 85 healthy subjects (Hcy = 8.0 micromol/L, 7.0-9.1). In controls, the cut-off values were set at 0.61 micromol/L for ADMA and 0.56 or 0.48 micromol/L for male and female SDMA, respectively. In patients, ADMA and SDMA levels were increased (p < 0.001) with respect to controls, but no correlation with Hcy was observed. Hyperhomocysteinemic subjects showed a different behaviour in respect to ADMA and SDMA levels and this allowed their stratification in 3 subgroups characterized by ADMA and SDMA in the normal range, only SDMA, or both ADMA and SDMA over the cut-off values. A lack of correlation with Hcy was again observed, thus minimizing the direct role of Hcy on ADMA and SDMA metabolism and suggesting the need for further studies on this issue.

Management of papillary microcarcinoma of the thyroid gland.

DESIGN: To investigate the frequency, treatment and clinical behaviour of differentiated microcarcinoma of the thyroid gland (PTMC). PATIENTS AND METHODS: Out of 376 patients submitted to surgical treatment for differentiated thyroid cancer from June 1980 to October 2003, 77 had been identified has having a PTMC (63 females, 14 males; mean age 43+/-13 years). Sixty-seven patients (87%) met the AMES risk definition for low (group I) and 10 (13%) for high-risk (group II) definition. The surgical procedures were lobo-isthmusectomy (n=14) or subtotal thyroidectomy (n=20) and total thyroidectomy (n=43) with node dissection in 15 cases. Follow-up ranging from 9 to 274 months (mean 124+/-84). RESULTS: Overall patient survival rates were 100 and 94% at 20 years in groups I and II, respectively (p=ns). There were no significant differences in surgical complications and in survival in patients submitted to total thyroidectomy when compared to partial thyroid resection. The presence of cervical node metastasis did not affect patient survival (p=0.8). The overall mean survival time was 266 months. CONCLUSIONS: Despite the overall excellent prognosis, PTMC was associated with a 1% disease-related mortality, a 2.5% local recurrence rate, 1% lymph-node recurrence rate, and 1% distant metastasis rate. We recommend total thyroidectomy accompanied by modified neck dissection if enlarged nodes are diagnosed.

Long-term survival after kidney and kidney-pancreas transplantation in diabetic patients.

PURPOSE: To investigate the influence of diabetes mellitus on patient and graft survival among renal versus renal-pancreatic recipients. METHODS: Among 270 renal transplants performed from 1985 to 2002, a total of 204 (75%) were in diabetic patients and 66 (25%) in nondiabetic patients. Among the 204 diabetic patients 161 (60%) kidneys were transplanted simultaneously with a pancreatic graft (SKPT group). The overall group of patient included 164 (61%) men and 106 (39%) women with mean time on dialysis of 31 +/- 21 months (range 0 to 126 months). The mean duration of diabetes was 24 +/- 7 years (range 5 to 51 years). Ninety-nine percent of the patients were on renal replacement therapy (79% hemodialysis and 20% peritoneal dialysis). RESULTS: The overall rejection rate was similar (NS). Both patient and kidney graft survival rates were worse in diabetics. Patient survival was 82% at 5 years among patients undergoing SKPT, 60% in diabetics receiving only a kidney, and 88% in nondiabetic transplanted patients. Kidney graft survival at 5 years was 77% in diabetics receiving SKPT, 68% in diabetics receiving a kidney alone, and 82% in nondiabetic patients. Overall patient survival was significantly greater among nondiabetics (P =.002) or in diabetics who received SKPT compared with diabetics who only had a kidney transplant (P =.001). CONCLUSIONS: This retrospective clinical evaluation confirms that combined pancreas and kidney transplantation should be the first choice to insulin-dependent diabetes mellitus (IDDM) patients with end-stage diabetic nephropathy.

Simultaneous pancreas-kidney transplantation: short- and long-term results.

Simultaneous kidney and pancreas transplantation (SKPT) is the treatment of choice for a majority of type I diabetic patients with end-stage renal disease. With continual refinements in surgical technique and an evolving immunosuppressive arsenal, graft and patient survival have continually improved. The purpose of this study was to evaluate the short- and long-term results of SKPTs performed in 174 recipients from June 1985 to March 2003 including 37 segmental grafts with duct occlusion, 73 whole pancreas transplants with bladder diversion, and 64 whole pancreas grafts with enteric diversion. The series includes 160 cases with systemic drainage and 14 with portal drainage. In the segmental pancreas group, patient survival was 85%, 76%, and 53% with pancreas survival of 67%, 36%, and 15%, and kidney survival of 82%, 63%, and 15%, respectively, at 1, 5, and 10 years. Among the bladder diversion group, patient survival was 94%, 83%, and 73% pancreas survival 72%, 67%, and 65%, and kidney survival 89%, 78%, and 58%, respectively, 1, 5, and 10 years. Among the enter diversion group patient survival was 90% and 90% at 12 and 108 months, pancreas survival 80% and 65%, and kidney survival 85% and 85%, respectively. There were significant differences between curves of survival distribution according to the surgical technique applied for patients (P =.04), pancreas (P =.007), and kidney (P =.005). Based on the results from our study, the short- and long-term prognosis after SKPT is satisfactory, especially compared to the outcomes of long-term dialysis among patients with end-stage renal disease caused by type I diabetes.

[Simultaneous pancreas-kidney transplantation: a single center experience on 148 cases]. / Risultati del trapianto simultaneo di rene e pancreas: esperienza su 148 casi.

AIM: To evaluate the outcome of simultaneous pancreas transplantation (SKPT) focusing on the surgical technique applied. PATIENTS AND METHODS: One hundred forty-eight patients were submitted to SKPT 33 with segmental pancreas with duct occlusion (from 1985 to 1990), 77 with whole pancreas with bladder diversion (from 1990 to 1998) and 38 whole pancreas with enteric diversion (29 with systemic and 9 with portal drainage) (from 1998 to December 2001). RESULTS: Patient survival was 92%, 82%, 63% at 1, 5, and 10 years respectively. Kidney survival was 87%, 75%, and 48% at 1, 5, 10 years. Pancreas graft survival was 71%, 58%, and 46% at 1, 5, 10 years. In the enteric diversion group patient, kidney, pancreas survival at one year was 93%, 92%, and 75%. A positive effect on patient survival was evident in enteric diversion versus duct occlusion group (p = 0.03), but not versus bladder diversion group and on pancreas graft survival in enteric diversion versus duct occlusion group (p < 0.01). CONCLUSIONS: These data suggest that SKPT has become a successful intervention for patients with type I diabetes and end stage renal disease. Reasons for these improvements include improved donor and patient selection criteria, refinements in surgical technique and better immunosuppression.

Secretory defects induced by immunosuppressive agents on human pancreatic beta-cells.

Despite the considerable interest for islet and pancreas transplantation, remarkably little is known about the direct effects of immunosuppressive drugs on human beta-cell function. We measured different insulin secretory parameters and insulin gene expression of human islets cultured for 5 days in the presence of mycophenolate mofetil (MMF), cyclosporin A (CsA), tacrolimus (FK506) or a mixture of 3 cytokines. Basal insulin release after exposure to cytokines and FK506 was significantly higher than in control islets. Responsiveness to an acute glucose stimulus did not differ significantly between control and treated islets. However, absolute incremental insulin responses (delta-AUCs) of islets exposed to cytokines or FK506 were significantly higher compared to islets exposed to CsA or MMF, mainly because of the higher basal release. Indeed, maximal over basal release (stimulation index, SI) tended to be lower in islets exposed to FK506 than in control islets. Insulin gene expression was significantly reduced only in islets exposed to CsA. FK506 was, among those tested, the immunosuppressive drug that most profoundly altered the normal insulin secretory pattern of human beta-cells, whereas CsA was the only inhibiting insulin gene expression. Although the abnormalities induced by the immunosoppressive drugs utilized in this study were modest, these in vitro data are consistent with the reported in vivo diabetogenicity of CsA and FK506 and point to MMF as the ideal immunosuppressive agent from a pancreatic beta-cell point of view.