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E Salzsieder

Publications and source records attributed to E Salzsieder.

At least 19 recordsLinked to original sources
PubMed2004

Fas ligand down-regulates cytokine-induced Fas receptor expression on insulinoma (NIT-1), but not islet cells, from autoimmune nonobese diabetic mice.

In the pathogenesis of autoimmune type 1 diabetes, the apoptosis receptor Fas appears de novo on the surface of insulin-producing beta-cells. Fas expression is thought to be induced by proinflammatory cytokines, such as IL-1beta, interferon-gamma (IFNgamma), and TNFalpha, released by islet-infiltrating mononuclear cells. To determine whether beta-cells can modulate their sensitivity to apoptosis at the level of Fas, we investigated the effect of Fas ligand (FasL) on surface expression of Fas in NIT-1 insulinoma cells from nonobese diabetic (NOD) mice prone to autoimmune diabetes and islet cells from NOD and nonautoimmune BALB/c mice. In NIT-1 insulinoma cells, Fas expression induced by the cytokine combination IL-1beta and IFNgamma was reduced in the presence of FasL, whereas in islet cells Fas expression was unaffected by FasL. The effect of FasL on NIT-1 cells was evident during and after the induction of Fas expression by IL-1beta and IFNgamma. Thus, FasL down-regulates cytokine-induced Fas expression in NOD mouse-derived NIT-1 cells, but not in NOD or BALB/c mouse islets. The ability of NIT-1 cells to down-regulate Fas receptor in response to ligation is similar to that of a variety of tumor cells, which may use this mechanism to escape destruction by cytotoxic T cells. Islets apparently cannot protect themselves against FasL-induced apoptosis by down-regulating the Fas receptor. Understanding how NIT-1 insulinoma cells down-regulate Fas receptor in response to ligation by FasL has therapeutic implications for protecting normal beta-cells in autoimmune type 1 diabetes.

Animals↗
PubMed2003

Surface and intracellular Fas expression associated with cytokine-induced apoptosis in rodent islet and insulinoma cells.

During the process of insulitis in the pathogenesis of type I (insulin-dependent) diabetes mellitus, proinflammatory cytokines induce expression of the death receptor Fas on the surface of pancreatic beta-cells and thereby contribute to the enhanced susceptibility of beta-cells for apoptosis. The aim of this study was to compare cell-surface and intracellular Fas expression associated with cytokine-induced apoptosis in commonly used beta-cell models such as isolated islets and insulinoma lines derived from mouse and rat. The cell line NIT-1 responded to the interleukin (IL)-1beta+interferon (IFN)-gamma stimulus with translocation of Fas to the cell surface. Likewise, islet cells from non-obese diabetic (NOD) mice and BB/OK rats expressed increasing amounts of the Fas receptor on their surfaces after exposure to IL-1beta in combination with IFN-gamma and tumour necrosis factor-alpha. Moreover, islets obtained from BB/OK rats at an age near the onset of diabetes had an increased surface expression of Fas compared with young rats. In contrast, western blot analysis of cell lysates from cytokine-exposed islets and insulinoma cells revealed total Fas expression levels comparable to those of untreated controls. In conclusion, islets from BB/OK rats and NOD mice, in addition to NIT-1 insulinoma cells, responded to cytokine exposure with surface expression of the Fas receptor, whereas in cell lysates the levels of expression of Fas were found to be independent of cytokine exposure. Taken together, the findings indicate that cytokine-treated beta-cells might possess two pools of Fas protein, one of which is inducible by cytokines and accounts for surface Fas expression, whereas the other is constitutively expressed in cytoplasmic compartments. The underlying mechanisms, including possible interactions between these two sources of cellular Fas expression, need to be investigated in future studies.

Animals↗
PubMed2002

Cell surface trafficking of Fas in NIT-1 cells and dissection of surface and total Fas expression.

The appearance of Fas receptor at the surface of pancreatic beta-cells affected by progressive insulitis strongly suggests that Fas-mediated beta-cell apoptosis plays an important role in the pathogenesis of type 1 diabetes. In support of this concept, the present study has shown that islet cells from NOD mice and the beta-cell line NIT-1 respond to the proinflammatory cytokines IL-1beta and IFN-gamma with Fas surface expression in a dose- and time-dependent manner. Moreover, the prevention of cytokine-induced surface Fas expression by actinomycin D, cycloheximide, and brefeldin A demonstrated that trafficking of Fas to the beta-cell surface requires RNA and protein synthesis and, in addition is critically dependent on intracellular protein transport. Compared with total cellular Fas protein, the amount of Fas at the cell surface was relatively small and indicated that Fas is preferentially expressed in cytoplasmic compartments of NIT-1 cells. It is concluded that inflammatory insults specifically induce translocation of Fas to the beta-cell surface and that interference with cell surface Fas expression is a new strategy to improve beta-cell survival in inflamed islets.

Animals↗
PubMed2000

Immunoadsorption of immunoglobulins alters intracytoplasmic type 1 and type 2 T cell cytokine production in patients with refractory autoimmune diseases.

Intracellular cytokine staining and flow cytometry were used to investigate whether immunoadsorption (IA) of immunoglobulins alters intracytoplasmic cytokine production in CD4+ and CD8+ T cells from the blood of patients with refractory rheumatoid arthritis (n = 7), membrane proliferative glomerulonephritis (n = 1), and Goodpasture's syndrome (n = 1). Four patients (Group 1) showed severely depressed production of TNF-alpha, IL-2, IFN-gamma, and IL-4 by CD4+ and CD8+ T cells and responded to 3 IA sessions with significant increases in CD4+TNF-alpha+, CD4+IL-2+, and CD8+IL-2+ T cells. Also, a tendency toward increased percentage levels of CD4+ T cells producing IFN-gamma or IL-4 and of CD8+ T cells producing either TNF-alpha or IFN-gamma was seen, but due to the small number of patients investigated, these differences did not attain statistic significance. Group 2 (n = 5) showed unimpaired intracellular cytokine levels and responded to IA with a heterogeneous pattern of changes in TNF-alpha, IL-2, IFN-gamma, and IL-4 production, but these alterations were smaller than those in Group 1. The present findings indicate that the extracorporeal removal of immunoglobulins by anti-IgG or protein A adsorber columns has an impact on T cell immunity and suggest that modulating effects on cellular immune system function are involved in the mode of action of IA.

Adult↗
PubMed1998

Mixed graphical models for simultaneous model identification and control applied to the glucose-insulin metabolism.

In this paper a method for model identification of biological systems described by stochastic linear differential equations using a new computational technique for statistical Bayesian inference, namely mixed graphical models in the sense of Lauritzen and Wermuth, is presented. The model is identified in terms of biological model parameters and noise parameters. This non-linear estimation problem is solved by means of an exact inference algorithm. The parameter estimates are given as a-posteriori distributions which can be interpreted as fuzzy possibility distributions. For model-based simulations of the underlying biological system the model parameters are represented as uncertain parameters with the distributions obtained from the estimation procedure. We apply the presented methods to a model for the glucose-insulin metabolism: the Karlsburg model for type I diabetes.

Bayes Theorem↗
PubMed1994

KADIS: model-aided education in type I diabetes. Karlsburg Diabetes Management System.

Education and training in self-management of blood glucose control has become a permanent task for all people involved in the care of diabetic patients. Since this may be facilitated by applying state-of-the-art information technology, we have developed the decision support system KADIS (Karlsburg Diabetes Management System). It comprises computer-aided tools for (1) the evaluation (selection, aggregation, storage, statistics, graphics) of therapeutic data, e.g. from patients' logbooks, and (2) the simulation of daily profiles of glycaemia and insulinaemia on the basis of a mathematical model of the glucose-insulin regulatory system, parameters of which can be adapted to the characteristics of individual patients. The latter tool allows the patient to predict his response to any modification in the therapeutic regime and to learn how variations in timing, formulation and doses of insulin, in carbohydrate equivalents and absorption characteristics of meals, and in exercise may influence the daily pattern in glycaemia. This procedure has been well accepted as an educational tool by those patients who were 'self-managing' their metabolic control.

Computer Graphics↗
PubMed1993

Primary health care of diabetic patients in a specialized outpatient setting: a DIABCARE-based analysis.

To assure health care quality requires a tool for establishing the feedback between parameters of patient management and related standards. To assess the current situation and to evaluate the DIABCARE system as a potential monitoring instrument, a retrospective study was performed in 85 randomly assigned insulin-treated patients (72% type 2) who were regularly attending the diabetes outpatient unit (total of 3,595 patients) in a township of approximately 90,000 inhabitants. 1,195 records of sequential medical visits during the years 1987 and 1990 were analyzed. -Selected results (averages in 1987 vs. 1990): (1) Visits per year 6.9 vs 7.1; (2) intensified insulin treatment in 14 vs. 27% of all patients, they were on 4.0 vs. 4.5 injections per day applying doses of 0.8 vs. 0.6 IU kg-1 d-1; (3) glycaemic control: random blood glucose 6.0 vs. 5.8 mmol/l on conventional and 6.4 vs. 5.7 mmol/l on intensified regimes, HbA1 regular measurements in 2 vs. 21% of the patients; (4) body mass index 26.4 vs. 26.6 (conventional) and 24.7 vs. 25.9 (intensified) kg/(m)2; (5) retinopathy prevalence 30 vs. 29%, in 4 vs. 29% of the patients no information; (6) nephropathy prevalence 7 vs. 11%, in 75 vs. 68% of the patients no information; (7) foot complications prevalence 6 vs. 9%, in 91 vs. 84% of the patients no pathological findings. -The DIABCARE monitor proved appropriate but too laborious. The general level of care showed a tendency towards improvement between the two investigated periods but dit not yet meet the standards which must be attained to attain the St. Vincent Declaration.

Adult↗
PubMed1993

Diabetes prevalence from health insurance data: evaluation of estimates by comparison with a population-based diabetes register.

UNLABELLED: At present in Germany, data on the prevalence of diabetes can only be obtained by modelling health insurance data. The National Diabetes Register of the former (East) German Democratic Republic which, between 1960 and 1990, monitored approximately 98% of all diabetic subjects, provides a tool for evaluating epidemiological estimates from other data sources. Therefore, the following data bases were compared for the year 1988: (1) a 5% random-sample (n = 6478) of all subjects insured at a local statutory health insurance company in the city of Dormund; (2) related data from the population-based diabetes register of former East-Berlin and (3) of the former German Democratic Republic. All data were standardized by sex and age according to the 1988 population statistics of the Federal Republic of (West) Germany thus resulting in the apparent diabetes prevalence of the Western part of Germany at that time. RESULTS: total prevalence rates were (1) 4.8%, (2) 4.9%, and (3) 4.4% (p < 0.05). The percentages of insulin-treated patients were (1) 18%, (2) 19%, and (3) 16%, respectively. 54% (1), 37% (p < 0.05) (2), and 42% (p < 0.05) (3), of the patients received oral antidiabetic drugs. It is concluded that the three samples are comparable and that the diabetes prevalence rates as estimated from health insurance data and from the two population-based registers give corresponding conclusions. Sample-based health insurance data may provide a useful and reliable tool for epidemiological studies on diabetes mellitus.

Adult↗
PubMed1992

Artificial connection between glucose sensing and insulin delivery: implications of peritoneal administration.

The replacement of insulinogenic function in insulin-dependent diabetes has to restore the feedback between intracorporal glucose and insulin. This has been accomplished by the following approaches: (a) the so-called open-loop insulin treatment by means of injections or pumps, employing laboratory or other extracorporal analytical devices and closing the feedback at large intervals only; (b) transplantation of insulin producing tissue and the bioartificial pancreas, employing the natural beta-cell both for glucose sensing and insulin delivery; (c) implanted artificial drug delivery systems providing chemical feedback between intracorporal glucose and insulin release from a nonrefillable reservoir of limited capacity; (d) the intracorporal or paracorporal artificial beta-cell comprising a glucose sensor (electrochemical or other type) that permanently delivers the signal to the computer-controlled insulin pump. This artificial device works on the basis of an algorithm of glucose-dependent insulin provision, compensating for the lack of other regulators, for the site of insulin administration, which is usually posthepatic, and for the kinetic properties of sensing system, e.g., a subcutaneous inserted amperometric electrode. Present experimental studies show that the pharmacodynamics of peritoneally applied insulin may be implemented into a mathematical model of the overall glucose-insulin system. They include absorption nearly as fast as after intravenous application, predominant portal inflow and approximately 30% hepatic removal. Feedback-controlled peritoneal insulin administration by means of an artificial beta-cell working on peripheral-venous blood glucose monitoring results in normal glycemic profiles under basal conditions and during oral glucose loads, if the pharmacodynamic properties of the peritoneal route are implemented into the insulin dosage algorithm.

Algorithms↗
PubMed1990

KADIS--a computer-aided decision support system for improving the management of type-I diabetes.

Despite the introduction of new therapeutic aids such as insulin pumps and injectors, blood glucose test tapes, particular insulin formulations, and the physiological basis-bolus principle of insulin dosage regimes, the metabolic care of most insulin-dependent patients is still insufficient. One potential tool of further improving the results in diabetes treatment consists in the application of computer-aided procedures to estimate individually optimal regimes. Employing a validated mathematical model of the glucose/insulin metabolic control system and individual sets of data from patients' self-monitoring, a software package was developed on a micro-computer which allowed both the retrospective analysis of data resulting from the therapeutic process, and the prospective simulation of the outcome of alterations in the regime in terms of glycaemia and insulinaemia. The two parts of the programme provide either for the patient or for the physician an interactive mode of working with the computer. The system is now being validated by means of a long-term follow-up study in type-I diabetic patients. It may be used mainly in diabetic outpatient centers and as a tool of educating, training, and motivating patients.

Computer Simulation↗
PubMed1990

A model-based system for the individual prediction of metabolic responses to improve therapy in type I diabetes.

Despite recent achievements such as home glucose monitoring and intensified injection regimens or insulin pumps, the metabolic care in diabetic patients is still mostly insufficient. One approach of further improving the management is the application of computer-aided procedures to estimate individually the optimal regimes. To accomplish this, a model-based strategy was developed which permits the prospective assessment of the metabolic outcome. This strategy comprises the following components: (1) a validated model of the physiological glucose-insulin regulatory system; (2) a procedure for identifying the metabolic situation of a given patient in terms of the model parameters; (3) methods of estimating the pharmacokinetics of insulin and its effect on glycemia, the absorption profiles of ingested glucose equivalents, and the effect of exercise as expressed in equivalents of insulin action; (4) computer procedures of prospective simulation of glycemic profiles around the day under the influence of selected or proposed therapeutic regimes. The entire method has been validated in C-peptide negative type I diabetic patients by comparing experimental results with theoretical predictions from model-based simulations over up to one year. This model-based simulation may be applied by ambulatory patients together with their physicians as a decision-support system in selecting appropriate individually suited regimes.

Blood Glucose↗
PubMed1986

[Status and perspectives of automated insulin therapy].

The aim of the optimization of insulin supply in insulin-dependent diabetes mellitus is by means of restoration of blood glucose regulation resembling the physiological control to contribute to the secondary prevention of the late diabetes-specific complications. An individually different permanent supply of a basic insulin dose, the adapted application of additional doses during the meals and the avoidance of an induced hyperinsulinism are to be achieved. Several apparative or biomaterial-depending techniques of an optimized insulin supply are still at the stage of technological research and of animal experiments: bioartificial (hybrid) pancreas and implantable therapeutic systems. Artificial beta-cells (feedback controlled insulin infusion systems) are hitherto commercially available only as bedside apparatuses and for this reason above all suitable for purposes of research; portable and in a few cases implantable insulin pumps (not automatically glucose-dependent controlled) are at present subject of long-term, controlled clinical-ambulatory studies on the borderline to highly specialized therapy. From experience in the use of these methods results the strategy of an "intensified conventional" insulin therapy which may be recommended for wide-spread application.

Blood Glucose↗
PubMed1985

Alterations in alanine metabolism in diabetic dogs during short-term treatment with an artificial B cell.

The flux rates of plasma glucose and alanine were studied isotopically (6-3H-glucose and U-14C-alanine simultaneously) in resting chronically diabetic dogs during short-term treatment with an artificial B cell where the insulin was infused into a peripheral vein. Despite perfect blood glucose control and normal glucose flux rates, the concentration and rates of appearance and disappearance of alanine were significantly elevated in the diabetic animals before, during and after an exogenous glucose load. The incorporation of the carbon moiety of alanine into circulating glucose was also increased, but diminished to a near-normal extent when exogenous glucose was given. The plasma clearance rates for alanine in the diabetic dogs were normal throughout the study. It is concluded that normal blood glucose control in diabetes does not necessarily mean normalization of the entire metabolic network. On the basis of peripheral hyperinsulinaemia alanine formation from glucose and branched chain amino acids is elevated in muscle. This may explain increased flux of alanine despite normal blood glucose control.

Alanine↗
PubMed1985

In vivo comparison of different algorithms for the artificial beta-cell.

Using an extracorporeal artificial beta-cell in chronically diabetic dogs, the effects of four different mathematical models of glucose-controlled insulin dosage were compared: the Biostator algorithm (quadratic equation), Toronto algorithm (hyperbolic tangent function), Karlsburg algorithm (modified first-order derivative controller), and Ilmenau algorithm (second-order linear difference equation). The constants of all formulas implemented for the artificial beta-cell were obtained by regression analysis of paired blood glucose and plasma insulin data from normal control animals. Thus, they were biologically equivalent for all formulas. The patterns of blood glucose, insulin doses, and plasma insulin before, during, and after an intravenous glucose infusion test performed during the glucose-controlled insulin infusion showed no significant differences between the experimental groups subjected to the different algorithms. However, in no case were really normal blood glucose response curves restored by the artificial beta-cell. This might be due, first, to the fact that the algorithm parameters were not adapted to the actual individual insulin responsiveness, second, to the unphysiological peripheral venous route of insulin administration, and, third, to the lack of appropriate adaptation of the animals to normoglycemia.

Animals↗
PubMed1984

Estimation of individually adapted control parameters for an artificial beta cell.

For optimum long-term glycemic regulation using a miniaturized artificial beta cell it is indispensible to estimate control parameters suited to the individual requirements of each diabetic patient. To solve this problem, a strategy has been developed which is based on engineering optimum-control theory with a model involving glucose and insulin interactions. The model considers physiologically relevant unit processes like endogenous glucose production, insulin-independent glucose uptake from its apparent distribution space, insulin-dependent glucose utilization, glucose-dependent insulin supply, and insulin catabolism. The assumed model structure is validated by results obtained in experimentally diabetic dogs using partition analysis. The individual parameter values of the model are obtained by a digital computer procedure based on a simple test which involves a bolus injection of glucose + insulin when a constant basal insulin dose is being administered in the diabetic in whom normoglycemia was re-established before the test. The method presented is recommended for future use in all cases where an optimized insulin regimen is to be worked out.

Animals↗
PubMed1984

Modelling the glucose-insulin system as a basis for the artificial beta cell.

The control constants for glucose-dependent insulin dosage in diabetic dogs were determined from test results in the opened system on the basis of a global blood glucose plasma-insulin control model. The controlled plant of the model consisted of the glucose and insulin subsystems; the entire insulin providing process was considered to be the controlling element, and the glucose-dependent insulin dose estimation, the controller. The constants obtained were employed in the extracorporeal artificial beta cell. The structure of the model and the numerical values of its state variables were verified by the prediction of blood glucose responses to intravenous glucose loads and by the correspondence between glucose balances and insulin doses as calculates and those as observed in diabetic animals. The application of the optimum control constant estimates in feedback-controlled insulin infusions provides improved blood glucose patterns but unchanged needs for insulin in comparison to the application of standard control parameters.

Animals↗