Michael Eckhard

Progressive Islet Graft Failure Occurs Significantly Earlier in Autoantibody-Positive Than in Autoantibody-Negative IDDM Recipients of Intrahepatic Islet Allografts

Alloimmunity has been uncovered to be a cause of graft loss representing a major barrier for clinical islet transplantation, and several studies are designed to evaluate new strategies for immunosuppression to prevent alloimmunity. In contrast, the significance for autoimmune destruction of transplanted β-cells has remained somewhat controversial. Recently, two case reports based on histological findings have suggested recurrent autoimmune insulitis despite immunosup-pressive therapy both in clinical pancreas and in islet transplantation. In the present study, in 23 islet-grafted patients with IDDM receiving standard immunosuppressive therapy, we demonstrate that progressive impairment of islet graft function occurs significantly earlier in those individuals positive for autoantibodies as a typical stigma of diabetes-associated autoimmunity that is well established in the pre-diabetic periods of IDDM. Intraportal infusion of allo-geneic islets was performed in 23 C-peptide-negative IDDM patients, according to the clinical transplantation categories defined as islet after kidney (IAK) or simultaneous islet and kidney (SIK). Complete islet graft failure was defined as the 1st day of permanent C-peptide negativity in the serum (<0.2 ng/ml) and C-peptide negativity in the urine (<2 μg/dl). The median observation period following islet transplantation was 12 months (range 1–50) with a cumulative follow-up of 336 months. Islet cell antibodies (ICAs) and GAD65 antibodies were monitored before and regularly after islet transplantation. Kaplan-Meier survival analysis and log-rank statistics revealed a significant (P < 0.05) difference in cumulative islet graft survival depending on the presence of islet cell and/or GAD65 antibodies. These results strongly suggest that recurrent autoimmunity directed to transplanted β-cells contributes to islet graft failure despite sustained immunosuppression. For successful clinical islet transplantation in the future, new immunosuppressive therapies are needed to prevent both alloimmunity and autoimmunity.

Isolated Pancreatic Islets in Three-Dimensional Matrices are Responsive to Stimulators and Inhibitors of Angiogenesis

The formation of a new microvasculature is essential for the long-term survival and function of the islet graft. In this study we examined endothelium of isolated pancreatic islets by stimulation with growth factors, different culture conditions, and genetic modification. We also inspected the effect of immunosuppressives used in human transplantation on angiogenesis. Isolated islets were embedded in a three-dimensional fibrin or Matrigel matrix. The effect of hyperglycemia, hypoxia, and the addition of VEGF and bFGF was investigated. We exposed islets from transgenic mice expressing the VEGF gene (RIP1VEGF-A) to high glucose (16.7 mmol/L) medium and tested the immunosuppressive agents rapamycin (100 ng/ml) and FK506 (100 ng/ml). To quantify angiogenesis the percentage of sprouting islets was determined. New endothelial capillary-like structures protruded from isolated pancreatic islets. Addition of VEGF to the islets and transgenic RIP-VEGF islets showed a two- to threefold increase of sprouting islets compared to control. Hypoxic culture conditions stimulated angiogenesis, resulting in a twofold increase of capillary sprouting. Rapamycin and FK506 proved to be potent inhibitors of angiogenesis in this system, because a decrease of sprouting islets of more than 20% by both agents was observed. Isolated pancreatic islets are capable of forming new capillary structures and are susceptible to pro- and antiangiogenic stimuli.

Initiating Insulin Therapy in Type 2 Diabetic Patients Failing on Oral Hypoglycemic Agents: Basal or prandial insulin? The APOLLO trial and beyond

Type 2 diabetes is a chronic disease characterized by coexisting insulin deficiency and insulin resistance, with the resultant hyperglycemia leading to micro- and macrovascular complications. A large number of intervention trials demonstrated that improving glycemic control achieves considerable reductions of such complications (1–7). It has been estimated using the homeostasis multiple assessment (HOMA) that, at the time of diagnosis, ∼50% of pancreatic β-cell function has been lost, with almost 4% further loss of function expected per year thereafter (8,9). Therefore, type 2 diabetes is a chronic progressive disease characterized by worsening hyperglycemia and escalating deterioration in the function of pancreatic β-cells and loss of β-cell mass (10). Because of the progressive nature of the disease, an evolving treatment strategy is therefore necessary to maintain both fasting and postprandial glycemic control. Recently, an American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) Consensus recommended a target of A1C <7% for good glucose control in clinical practice (11). Insulin therapy is required when dietary restrictions and lifestyle modifications combined with oral hypoglycemic agents (OHAs) failed to provide acceptable metabolic control (12). One major lesson learned from the milestone U.K. Prospective Diabetes Study (UKPDS) is the increasing requirement for multiple therapies in patients with type 2 diabetes to achieve blood glucose (BG) target control (13). The augmentation of insulin to OHAs contributed to several beneficial metabolic effects, as recently reviewed (14). However, there is ongoing debate as to whether it is more rewarding to target postprandial BG concentrations with meal-related insulin, or to target fasting BG concentrations with basal insulin. Monnier et al. (15,16) provided data to explain the relative contribution of fasting and postprandial BG to A1C in patients with mild-to-moderate hyperglycemia (A1C <7.3%) than in those with more poorly …

New-Onset Diabetes Mellitus After Renal Transplantation

BACKGROUND New-onset diabetes mellitus after organ transplantation (PTDM) significantly impairs patient and organ survival. Published rates of PTDM range from 2% to 54%, depending on the definition. OBJECTIVES To analyze incidence of PTDM after renal transplantation according to recent guidelines and to evaluate implementation of a prospective standardized screening protocol. PATIENTS AND METHODS Data for all consecutive patients who underwent transplantation from 2000 to 2006 were analyzed retrospectively for PTDM. In a prospective pilot trial all candidates for living related donor transplantation underwent a 75-g oral glucose tolerance test at evaluation prior to renal transplantation and at 3, 6, and 12 months thereafter. RESULTS Data for 181 out of 271 consecutive patients were analyzed. Of these patients, 36 (19.9%) developed PTDM. Age, body mass index, pretransplantation fasting glucose concentration, and number of HLA mismatches were significant predictive risk factors. Posttransplantation diabetes mellitus occurred more frequently in patients receiving a cadaver organ compared with a living donor organ and in those receiving tacrolimus therapy vs cyclosporine therapy. Preliminary results demonstrated a 55.5% incidence of PTDM at 3 months in patients who received a living donor organ, much higher than expected. CONCLUSIONS With an incidence of approximately 20%, PTDM is a frequent complication of transplantation. Prospective screening using oral glucose tolerance testing is a more sensitive method for detection of impaired glucose metabolism and PTDM. Relevance and therapeutic consequences must be determined in large-scale prospective studies.

Circulating cytokines are associated with human islet graft function in type 1 diabetes.

Islet cell transplantation has considerable potential as a cure for type 1 diabetes, but recurrent autoimmunity and allograft rejection in which both cytokines play an important role are major obstacles. Using a new approach considering confounders by regression analysis, we investigated circulating cytokines and their association with graft function in type 1 diabetes patients who underwent either simultaneous islet kidney (SIK) or islet after kidney (IAK) transplantation. After transplantation, interleukin (IL)-10 was lower in SIK recipients with subsequent loss of graft function in comparison to recipients maintaining graft function. Before transplantation, high IL-13 and IL-18 concentrations were prospectively associated for subsequent loss of graft function in IAK recipients, whereas in SIK recipients, high macrophage migration inhibitory factor (MIF) concentrations were associated with subsequent loss of graft function. Circulating cytokines are associated with islet graft function in patients with long-standing type 1 diabetes when considering confounders.

Clinical Islet Transplantation After Allogeneic Orthotopic Liver Transplantation

ISLET transplantation as a treatment for type 1 diabetes mellitus has been applied mostly in patients with endstage diabetic nephropathy, either with previously established kidney allograft (islet after kidney transplant, IAK) or by a simultaneous islet–kidney transplantation (SIK) procedure, in the latter case utilizing pancreas and islets from the same donor. Immunosuppressive protocols for these patients are based on cyclosporine, usually in combination with corticosteroids and azathioprine or mycophenolate mofetil for induction and maintenance immune therapy, and in the majority of cases combined with anti– T-lymphocyte antibodies for a limited perioperative period. A small number of pancreatectomized patients (usually for treatment of upper abdominal malignancy) have received a simultaneous islet-liver transplant in previous studies. In most of these cases, induction/maintenance immunosuppression therapy has been based on tacrolimus (Prograf). In the present case study, for the first time an islet allograft (islet after liver transplantant, IAL) has been performed in a patient with type 1 diabetes who had previously received an orthotopic liver transplant for treatment of cryptogenic liver cirrhosis. Clinical and metabolic data are provided for the 6 month follow-up.

Wenn der Zucker das neue Organ angreift

ZusammenfassungRelativ häufig tritt nach einer Transplantation ein Diabetes mellitus auf. Die Bedeutung dieses Posttransplantationsdiabetes wird oft unterschätzt. Er erhöht sowohl die Mortalität als auch die Rate an Transplantatversagen signifikant. Die Störung des Glukosestoffwechsels wird häufig erst spät entdeckt. Dabei ist ein frühzeitiges, konsequentes Eingreifen nötig, um Komplikationen zu reduzieren. Bereits vor der Aufnahme auf eine Transplantationswarteliste sollte ein oraler Glukosetoleranztest durchgeführt werden. Die Therapie orientiert sich an den Leitlinien für Erwachsene mit Diabetes mellitus Typ 2. Ergänzend stehen transplantationsspezifische Möglichkeiten zur Verfügung, die aber nur in enger Absprache von Hausarzt, Diabetologen und Transplantationsmediziner gewählt werden sollten. Der vorliegende Beitrag erläutert die pathogenetischen Besonderheiten des Posttransplantationsdiabetes sowie das diagnostische und therapeutische Vorgehen.