[Socioeconomic significance of inadequate diabetes management].
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Cost of Illness↗
Biomedical subjects
R G Bretzel
Publications and source records attributed to R G Bretzel.
[Islet cell and pancreas transplantation in diabetes: status 1996].
Replacement of the patient's islets of Langerhans either by pancreas transplantation or by isolated islet transplantation is the only treatment of type I diabetes mellitus to achieve an insulin-independent, constant normoglycemic state. The penalty for this benefit is the need for immunosuppressive treatment in the recipient with all its potential risks. Thus, indications for pancreas or islet transplantations at present exist almost only in patients with end-stage renal disease waiting on dialysis for a kidney graft or in diabetics with already established kidney graft being and going to be obligated to immunosuppression for this reason, respectively. Pancreas transplants alone are primarily performed in only highly selected non-uremic patients with extreme problems of the diabetes. Recent studies demonstrated that pancreas transplantations finally delay the progression of diabetic secondary complications and probably prolong patient's life expectancy. Furthermore, there is no doubt on the dramatic improvement of quality of life. However, pancreas transplantation confers a certain risk and has its complications whereas islet transplantation is a rather minor procedure associated with only small risk, if any. Islet transplantation offers the possibility to alter in vitro the islet immunogenicity and antigenicity, to induce an immunotolerant state or to encapsulate the islets so as to introduce only temporary immunosuppressive treatment of the recipient or to obviate the need for immunosuppression after islet allo- or xenotransplantation. The effectiveness of this concept was demonstrated in animal experiments and may successfully be transferred into the clinical situation. In that case the indications for islet transplantations may be extended to nonuremic type I diabetics including diabetic children. This group of patients is ultimately targetted at by this treatment concept. But, up to now, islet transplantations have been performed only simultaneously to or after kidney transplantations. However, the progress during the last years period has provided evidence that islet transplantation may in principle establish insulin independence also in man albeit prolonged insulin independence has been achieved in only a small number of cases. The state-of-the-art of clinical islet transplantations in type I diabetes mellitus is presented based on a recent analysis of the data of the International Islet Transplant Registry kept in Giessen. Our own experience at the Giessen Transplant Center with transplantations of isolated adult islets of Langerhans in type I diabetic patients is supplementary provided.
Adult↗
[Combined kidney and pancreas transplantation in the late-stage diabetic syndrome].
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Diabetes Mellitus, Type 1↗
Secondary intervention with aminoguanidine retards the progression of diabetic retinopathy in the rat model.
Primary prevention with aminoguanidine-an inhibitor of advanced glycation end product (AGE) formation--has been successfully employed to prevent diabetic retinopathy in the rat. However, it is unknown whether inhibition of AGE formation is still effective in a secondary intervention strategy. The present study addresses this question by comparing secondary intervention with aminoguanidine with syngeneic islet transplantation in the rat model. After 6 months of diabetes, one group was treated with aminoguanidine (50 mg/100 ml drinking water; D-AG) while another group received syngeneic transplantation of collagenase-ficoll isolated islets by intraportal injection (Tx). After an additional 4 months, both groups were compared to a normal (NC 10) and diabetic (DC 10) control group. Retinal autofluorescence was increased 2.5-fold after 6 months and increased 3.7-fold after 10 months of diabetes (p < 0.001). Aminoguanidine and islet Tx retarded the further accumulation of autofluorescence equally (p < 0.001 vs DC 10), although the values were higher than those observed in DC at 6 months (p < 0.001). Diabetes was associated with a 2.7-fold increase in acellular capillaries after 6 months and a 4.1-fold increase after 10 months. Treatment with aminoguanidine or islet Tx reduced but did not completely attenuate the progression of vascular occlusion (p < 0.001 vs DC 10; D-AG vs DC 6, p < 0.05; Tx vs DC 6, p < 0.01). Both treatments reduced endothelial proliferation (22.4% after 10 months; p < 0.001) and completely arrested pericyte dropout (40% after 10 months; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Glucose metabolism and left ventricular dysfunction are normalized by insulin and islet transplantation in mild diabetes in the rat.
The aim of the present experimental study in the rat heart was to assess cardiac performance and metabolism in mild diabetes of 2 months' duration (postprandial blood sugar levels of 307 +/- 101 mg/dl and nearly normal fasting blood glucose of 102 +/- 40 mg/dl) using the working rat heart model at physiological workload with a perfusion time of 60 min. We also compared the effect of two forms of therapy for diabetes, islet transplantation and insulin therapy (s.c.), after 2 months. A 36% reduction in glucose utilization is metabolically characteristic for the diabetic heart, mainly caused by a 55% reduced glucose uptake (P < 0.001), but also by a nearly twofold increased lactate and pyruvate production (P < 0.001). This reduced carbohydrate metabolism is accompanied by a 37% reduction of oxygen uptake (P < 0.001) as well as a significant reduction in myocardial ATP and CP levels (P < 0.001), resulting in a significantly reduced cardiac output (P < 0.001). Moreover, the balance of energy reveals that the diabetic heart obtains 46% of its energy requirements for 1 h from endogenous glycogen, whereas the control heart obtains 91% of its energy needs (i.e. preferentially) from exogenous glucose (only 9% from endogenous glycogen). Both investigated therapeutic interventions led to a complete reversibility of the hemodynamic and metabolic alterations, indicating that the cause of diabetic cardiomyopathy in this model of mild and short-term diabetes is due to a defect in cardiac carbohydrate metabolism, which is correctable by insulin administration.
Adenosine Triphosphate↗
The influence of thioctic acid on metabolism and function of the diabetic heart.
Streptozotocin-diabetes as a model for insulin-deficient Type 1 diabetes leads to cardiomyopathy, characterized by a 50% reduced glucose uptake (P < 0.001) and increased lactate and pyruvate levels (P < 0.001), i.e. a reduced glucose utilization by the heart. As thioctic acid (TA) has favourable effects on glucose metabolism, the influence of this drug at two different doses (0.1 mg/ml and 0.5 mg/ml, added to the perfusion medium) was investigated in the heart after 2 weeks of diabetes, using the working rat heart model at physiological workload about 45 min. TA at high doses led to a normalization of glucose uptake (P < 0.001) and glucose utilization, and consequently to a normalization of oxygen uptake (P < 0.001), myocardial ATP levels (P < 0.001) as well as cardiac output (P < 0.05). Whereas a low dose of TA resulted in a normalization of lactate and pyruvate production (P < 0.001), neither a normalization of glucose utilization nor of cardiac output was achieved by this low dosage. Additionally, TA improved at both doses utilization of endogenous glycogen in the diabetic heart (P < 0.001), the latter here already delivering 45% of the utilized glucose. TA acts especially by increasing glucose uptake, glycogen breakdown and glucose oxidation. Thus, metabolic and hemodynamic sequelae of insulin-deficiency in the heart can be corrected by TA. Due to its anti-diabetic effects on cardiac metabolism, TA could be considered an adjuvant therapy in diabetic cardiomyopathy.
Adenosine Triphosphate↗
Improvement of cardiac performance and metabolism in long-term diabetes mellitus after treatment with insulin [see comment].
Rat hearts induced diabetic by administration of streptozotocin were investigated after 8 months using the isolated perfused working rat heart model at a physiological workload of approximately 45 min. They are hemodynamically characterized by a significantly reduced cardiac output (p < 0.001) and metabolically by a 49% reduction in glucose utilization (p < 0.001), mainly caused by reduced glucose uptake (p < 0.001) and an increased lactate and pyruvate production (p < 0.001), associated with a reduction of oxygen consumption by 44% (p < 0.001). Both lead to reduced ATP and CP myocardial tissue levels (p < 0.001). Similar results with respect to cardiac performance and metabolism are observed already after 2 months of diabetes. Treating these rats after 2 months of diabetes with insulin for 6 months, cardiac output (ns), cardiac metabolism (ns), oxygen uptake (ns) as well as ATP and CP levels (ns) are restored, indicating that normalization of cardiac function in this model depends mainly on the restored cardiac metabolism. These findings were associated with changes in the angioarchitecture as demonstrated.
Adenosine Triphosphate↗
Islet isolation from the pancreas of large mammals and humans: 10 years of experience.
Despite experience, that has been obtained in the field of islet isolation in large mammals for about the past 20 years, allo- and autotransplantation of both human and porcine islets are still not routine procedures. The reasons for islet isolation and purification associated problems, which prevent a continuous isolation success and regular islet transplantation, can be categorized to variables related to 1) pancreas donor; 2) pancreas procurement; 3) isolation-techniques and 4) purification techniques. The development of porcine and human islet isolation was carried out by the authors since 1986. During this period several techniques for the isolation and purification of human and porcine islets were compared with regard to their influence on islet isolation outcome, integrity of islet morphology, islet in-vitro and in-vivo function: sequential vs continuous digestion-filtration, counterflow elutriation vs neutral density separation, conventional density gradient centrifugation vs Cobe cell separation and discontinuous vs continuous gradient purification. Furthermore, we analysed the influence of donor factors and variables related to organ procurement on islet isolation success. From this experience we concluded that successful porcine islet isolation is possible if islets of adult donors are isolated utilizing the continuous digestion-filtration following distension with UW-solution prior to a neutral density gradient purification on a Cobe. Human islets can be successfully isolated by digestion-filtration and purified utilizing a continuous Ficoll-sodium-diatrizoate gradient on a Cobe when intact pancreata are harvested after a secondary pancreatic warm ischemia time < 20 min from adult donors > 30 years.
Adult↗
Body mass index of pancreatic donors: a decisive factor for human islet isolation.
Despite improvements in islet isolation techniques, islet transplantation remains unpredictable as a method for reliably rendering human type I diabetic recipients normoglycemic. Advances in immunosuppression to prevent primary nonfunction, to promote engraftment and to prevent rejection should improve success rates. However, factors influencing the isolation process remain incompletely defined. During our experience, the donor's nutritional status as well as other donor characteristics were noted to be associated with islet isolation success. Thus, in this study, we tried to clarify whether the body mass index of the human pancreatic donor affects islet isolation yield and viability. In lean donors we found significantly lower islet yields in comparison with normal and obese donors and a significantly lower islet viability compared to obese donors. Obese donor islets had a significantly higher insulin secretory capacity than lean and normal donor islets. In summary, islet yield and viability were improved selecting pancreata from obese donors associated with a BMI > 24 for islet preparation. We hypothesize that, on the one hand, the increased distribution of fat in pancreata of obese donors possibly can facilitate the release of islets during the collagenase digestion, and, on the other hand, pancreata of obese donors contain more islets than pancreata of lean donors. These data underline the decisive influence of the pancreas donor's body mass index on successful human islet isolation. The body mass index should be noted as a potential predictor of success of islet preparations.
Body Mass Index↗
Activation of human complement by collagenase and ficoll.
Collagenase and ficoll are standard chemicals used for isolation and purification of pancreatic islets. The capacity of these substances to activate human complement was tested by incubation for 45 min at 37 degrees C with fresh or liquid nitrogen-stored human plasma from normal blood donors. Complement-split products were then determined by sensitive enzyme immunoassays from QUIDEL. Collagenase activates both the classical and the alternative pathway, whereas Ficoll activates the alternative pathway only. When present in islet preparations used for islet transplantation, these substances may induce local inflammatory reactions compromising islet viability and engraftment.
Cell Separation↗
Comparison of the survival of fresh or cultured pancreatic islets, pseudoislets and single cells following allotransplantation beneath the kidney capsule in non-immunosuppressed diabetic rats.
The purpose of the present study was to examine the effect of culture pretreatment and islet structure on transplantation survival time. Donors for islet isolation were highly inbred male Lewis rats (RT 1(1)). Production of single cells was performed by using EDTA and Trypsin. Pseudo-islets were produced by culturing single cell suspensions at 37 degrees C for 12-14 days. Recipients were BDE rats (RT 1u), made diabetic by streptozotocin injection. 1000-1200 islets (or corresponding amount of single cells or pseudoislets) were transplanted to the subcapsular renal space. Five groups were transplanted. Group 1 (n = 5) received freshly isolated islets of Langerhans. Group 2 (n = 7) received single cells, produced from freshly isolated islets. In group III (n = 7) pseudoislets were transplanted. The animals of group IV received 37 degrees C cultured islets (12-14 days), while group V received single cells consisting of 12-14 day cultured islets at 37 degrees C. The median survival times were: gr. I 7 d.; gr. II 5 d.; gr. III 120 d.; gr. IV 11 d.; gr. V 9 d.. Group III showed a prolongation of allograft survival that was statistically significant compared to all other groups. 4 from 7 animals showed a long-term acceptance. It can be concluded that neither culturing islets at 37 degrees C nor producing single cells achieves long-term acceptance. Transplanting pseudoislets resulted in a long-term acceptance of allograft, without immunosuppression of the host. Three factors may be responsible for this success: Firstly, a reduced number of class-II-antigen positive cells, secondly, metabolic state of rest, and thirdly, the transplantation site.
Animals↗
Pancreatic islet xenografts at two different transplantation sites (renal subcapsular versus intraportal): comparison of graft survival and morphology.
Our primary objective in this study was to determine the effect of two different transplantation sites (renal capsule vs. portal vein) on islet xenograft survival and graft morphology. 59 chemically induced diabetic C57BL/6J mice were transplanted either intraportally (n = 30) or under the left renal capsule (n = 29) receiving 300-350 either freshly isolated or culture pretreated (37 degrees C or 22 degrees C) Lewis rat islets without any immunosuppressive therapy. Histology was performed by immunohistochemical staining to examine the morphologic pattern after rejection or after post-transplant normoglycemia for more than 120 days. Life table analysis revealed a significant (p < 0.001) prolongation of xenograft survival using the renal capsule as transplantation site. 75% graft rejection occurred 56 days after transplantation when the renal capsule was used, compared to 19.5 days intraportal. The intriguing finding was that graft morphology was different depending on the transplantation site. After transplantation under the renal capsule we observed predominantly a more periinsular infiltration with focal aggregates of mononuclear cells at the periphery of the graft. This pattern was more consistent with a non-destructive type of insulitis. In contrast, we found direct infiltration of the transplanted islets following intraportal transplantation reflecting a more destructive type of insulitis. In summary, we could demonstrate a significant prolongation of islet xenograft survival by using the renal capsule as transplantation site in contrast to intraportal transplantation. The morphological pattern possibly indicates two different mechanisms of rejection depending on the transplantation site.
Animals↗
The influence of donor specific vertebral body derived bone marrow cell infusion on canine islet allograft survival without irradiation conditioning of the recipient.
In recent studies in rodents, it was shown, that donor specific tolerance towards islet allografts without irradiation therapy of the recipient is induced by bone marrow cell infusion in combination with temporary immunosuppression. In the present study, the effect of donor specific bone marrow cell (DBMC) infusion at the time of intrahepatic islet allotransplantation without irradiation conditioning of the recipient was investigated in the canine model, paralleling ongoing clinical trials. It was observed, that unfractionated bone marrow cells given simultaneous to islet allografts led to higher frequencies of rejection periods and decreased islet allograft survival, when administered to recipients immunosuppressed with Cyclosporine A only. In contrast, an additional short inductive treatment of the recipient with an anti-dog-T-lymphocyte monoclonal antibody (5G2) abrogated the enhanced immunogenicity of the unfractionated bone marrow preparation, prolonging islet allograft survival with no rejection episodes observed during the immunosuppressive treatment with Cyclosporine. The composition of bone marrow cells might have contributed to the higher immunogenicity, since the percentage of MHC-class II antigen bearing cells is similar to man, but significantly higher than compared to rodents. It is therefore suggested, that further studies should encompass both timing of bone marrow cell infusion, appropriate immunosuppression and strategies to functionally inactivate mature MHC-class-II positive cells prior to DBMC infusion.
Animals↗
Different toxic effects of hydrogen peroxide, nitric oxide, and superoxide on human, pig, and rat islets of Langerhans.
Susceptibility of islet cells to damage by hydrogen peroxide, superoxide, and nitric oxide was determined on islets isolated from humans, pigs, and rats. Islets were incubated for 20 hr at 37 degrees C with different concentrations of hydrogen peroxide, hypoxanthine/xanthine oxidase, or nitroprusside sodium, respectively. Islet cell damage was then measured as trypan blue-uptake. Rat islets showed a higher sensitivity than human or pig islets to damage by reactive oxygen species or nitric oxide. These results indicate that pig islets may be a more suitable model than rat islets to study inflammatory islet cell damage in diabetes and clinical islet transplantation.
Animals↗
Islet transplantation in immunoseparating membranes for treatment of insulin-dependent diabetes mellitus.
Despite remarkable progress in treatment life expectancy of insulin-dependent diabetics is limited by the onset of life threatening complications. These could be avoided by an optimized glucose hemeostasis only as it has been shown by experimental islet transplantation. Successful transplantation of islets encapsulated in immunoseparating membranes (bioartificial pancreas) would circumvent problems of islet availability and rejection. In this article macro- and microencapsulation as the two major principles are evaluated. Present limitations are discussed under technical and immunological aspects and directions for future research are addressed. Progress in the development of immunoseparating membranes and devices for treatment of insulin-dependend diabetes and finally their clinical introduction will permit the application of this technology in other endocrine deficiency syndromes.
Animals↗
Evaluation of the effect of microencapsulation and immuno-modulation on islet immunogenicity in vitro.
The complexity of the transplantation model in microencapsulated islet transplantation suggests the use of an in vitro model for the analysis of the effect of encapsulation and graft pretreatment on islet immunogenicity. In this study, the mixed lymphocyte islet culture is applied to islets encapsulated in barium alginate beads, showing a significant reduction of the cellular response compared with non-encapsulated islets. Moreover, the effect of low-temperature culture as the immuno modulatory principle is shown on encapsulated and non-encapsulated islets. The data suggest that encapsulation reduces but not totally impedes the immunological interaction between the encapsulated tissue and the surrounding immune cells and that the stimulatory potency of the encapsulated islet may be modified by immuno-altering pretreatment.
Adjuvants, Immunologic↗
Islet cell transplantation in diabetes mellitus--from bench to bedside.
Replacement of the patient's islets of Langerhans either by pancreas transplantation or by isolated islet transplantation is the only treatment of type I diabetes mellitus to achieve an insulin-independent, constant normoglycemic state. The expense for this benefit is the need for immunosuppressive treatment of the recipient with all its potential risks. Thus, indications for pancreas or islet transplantations at present exist almost exclusively in patients with end-stage renal disease who are waiting on dialysis for a kidney graft or in diabetics with an established kidney graft obliged to be immunosuppressed. Islet transplants possess significantly potential advantages over whole-gland transplants: it is a simple procedure with only small risk, if any; it offers the potential advantages of pre-transplant reduction of immunogenicity thus possibly obviating the need for continuous life-long recipient immunosuppression and it offers the future feasibility of transplanting heterologous (pig) islets. The effectiveness of this concept was demonstrated in animal experiments and may be successfully transferred into the clinical situation. In this case, the indications for islet transplantation may be extended to non-uremic type I diabetics including diabetic children. This group of patients is the ultimate target group for this most direct and appealing concept of treating type I diabetes. As of 1994, more than 200 adult islet allografts were reported to the International Islet Transplant Registry (ITR) at the Justus-Liebig-University, Giessen, Germany. A detailed analysis of 75 well-documented cases grafted between 1990 and 1993 revealed a one-year survival rate of the patients and islets of 95% and 28% (in terms of significant basal C-peptide secretion), respectively, and insulin independence was achieved in 11% of the cases after simultaneous islet-kidney (SIK) or islet-after-kidney (IAK) transplants. At present, there is no clinical data available and the follow-up studies of the posttransplant period are too short to draw any conclusions concerning the effects of islet transplants on diabetic secondary complications. Moreover, islet transplantation is still a clinical investigational procedure. Obviously, a number of fundamental steps will have to be taken before the appealing concept of transplanting adult pancreatic islets can attain clinical importance in the treatment of type I diabetic subjects. Islet cell transplantation has come the long way from animal experiments to successful clinical application, but, more research at the bench has to be performed before islet cell transplants will be successfully performed in non-uremic, non-kidney transplanted type I diabetic patients.
Animals↗
The effects of glucagon-like peptide-I (GLP-I) on hormone secretion from isolated human pancreatic islets.
Glucagon-like peptide-I (GLP-I) is a potent incretin hormone that is now considered as a new therapeutic tool in the treatment of diabetes mellitus. In this study we characterized the effects of GLP-I on peptide hormone release from isolated human pancreatic islets. GLP-I stimulated insulin release in the presence of 10 mM glucose (2.8 mM glucose, 100%; 10 mM glucose, 166%; 10 mM glucose + 10 nM GLP-I, 222%) but had only a weak insulinotropic effect (128%) at 2.8 mM glucose. Glucagon release was inhibited by 10 mM glucose (2.8 mM glucose, 100%; 10 mM glucose, 72%) and by 10 nM GLP-I at 2.8 mM glucose (67%). Somatostatin secretion was increased by 10 mM glucose (2.8 mM glucose, 100%; 10 mM glucose, 166%). GLP-I stimulated somatostatin release in the presence of 2.8 mM glucose (172%). Pancreatic polypeptide (PP) secretion was enhanced by 10 mM glucose (2.8 mM glucose, 100%; 10 mM glucose, 236%). GLP-I induced PP release only in the presence of 2.8 mM glucose (184%).
Culture Techniques↗