Klaus-dieter Kohnert - Academia.edu (original) (raw)

Papers by Klaus-dieter Kohnert

Research paper thumbnail of Associations of blood glucose dynamics with antihyperglycemic treatment and glycemic variability in type 1 and type 2 diabetes

Journal of Endocrinological Investigation, May 8, 2017

correlated with increasing glucose variability and glucose exposure. Statistically, significant c... more correlated with increasing glucose variability and glucose exposure. Statistically, significant correlations existed between higher MSE complexity indices and better glycemic control. In multivariate regression analysis, the antidiabetic therapy was the most powerful predictor of the MSE (β = −0.940 ± 0.242, R 2 = 0.306, p < 0.001), whereas the potential confounders failed to contribute. Conclusions The loss of dynamical complexity in glucose homeostasis correlates more closely with therapy modalities and glucose variability than with clinical measures of glycemia. Thus, targeting the glucoregulatory system by adequate therapeutic interventions may protect against progressive worsening of diabetes control.

Research paper thumbnail of Glycemic Variability Correlates Strongly With Postprandialβ-Cell Dysfunction in a Segment of Type 2 Diabetic Patients Using Oral Hypoglycemic Agents

Diabetes Care, Feb 24, 2009

OBJECTIVE-Glucose fluctuations trigger activation of oxidative stress, a main mechanism leading t... more OBJECTIVE-Glucose fluctuations trigger activation of oxidative stress, a main mechanism leading to secondary diabetes complications. We evaluated the relationship between glycemic variability and ␤-cell dysfunction. RESEARCH DESIGN AND METHODS-We conducted a cross-sectional study in 59 patients with type 2 diabetes (aged 64.2 Ϯ 8.6 years, A1C 6.5 Ϯ 1.0%, and BMI 29.8 Ϯ 3.8 kg/m 2 [mean Ϯ SD]) using either oral hypoglycemic agents (OHAs) (n ϭ 34) or diet alone (nonusers). As a measure of glycemic variability, the mean amplitude of glycemic excursions (MAGE) was computed from continuous glucose monitoring data recorded over 3 consecutive days. The relationships between MAGE, ␤-cell function, and clinical parameters were assessed by including postprandial ␤-cell function (PBCF) and basal ␤-cell function (BBCF) obtained by a model-based method from plasma C-peptide and plasma glucose during a mixed-meal test as well as homeostasis model assessment of insulin sensitivity, clinical factors, carbohydrate intake, and type of OHA. RESULTS-MAGE was nonlinearly correlated with PBCF (r ϭ 0.54, P Ͻ 0.001) and with BBCF (r ϭ 0.31, P ϭ 0.025) in OHA users but failed to correlate with these parameters in nonusers (PBCF P ϭ 0.21 and BBCF P ϭ 0.07). The stepwise multiple regression analysis demonstrated that PBCF and OHA combination treatment were independent contributors to MAGE (R 2 ϭ 0.50, P Ͻ 0.010), whereas insulin sensitivity, carbohydrate intake, and nonglycemic parameters failed to contribute. CONCLUSIONS-PBCF appears to be an important target to reduce glucose fluctuations in OHA-treated type 2 diabetes.

Research paper thumbnail of Decreased intracellular phosphate in vascular smooth muscle cells from SHR and decreased ATPase activities

Research paper thumbnail of Discordant results in the assay of cytoplasmic islet cell autoantibodies with ELISA and immunohistochemical techniques

PubMed, Jul 1, 1995

We evaluated 6 batches of a solid phase enzyme-linked immunosorbent assay (ELISA) Isletest-ICA ki... more We evaluated 6 batches of a solid phase enzyme-linked immunosorbent assay (ELISA) Isletest-ICA kit commercially available for the determination of autoantibodies to pancreatic islet cells, and compared the results with those obtained by a standardized immunohistochemical method. Following the immunohistochemical determination of autoantibodies to pancreatic islet cells, sera from patients with insulin-dependent diabetes mellitus, both positive and negative for autoantibodies to pancreatic islet cells, were randomly selected and analysed by ELISA. Sera from healthy control subjects, as well as standards recommended by the International Diabetes Workshop (IDW) ICA (Autoantibodies to Pancreatic Islet Cells) Proficiency Program, were included. Of the sera testing positive for autoantibodies to pancreatic islet cells in the immunohistochemical assay, only 14 +/- 5% were found to give a positive reaction in the ELISA. Among the sera from healthy control subjects and pancreatic islet cell autoantibody-negative insulin-dependent diabetes mellitus patients, 25 +/- 7% and 1 +/- 1%, respectively, yielded false-positive readings for autoantibodies to pancreatic islet cells. These results clearly show that the ELISA test presently available does not reliably detect autoantibodies to pancreatic islet cells, even qualitatively. Thus, it cannot be used for screening subjects at risk of developing diabetes.

Research paper thumbnail of Islet graft-induced changes of ß-hydroxybutyrate dehydrogenase and glucose-6-phosphatase activity in liver cells of diabetic recipient rats

Experimental and Toxicologic Pathology, May 1, 2000

ABSTRACT

Research paper thumbnail of Model-based Decision Support System to Improve Diabetes Care and Management

IFAC Proceedings Volumes, 2009

The model-based Karlsburg Diabetes Management System (KADIS ®) has been developed as a decision s... more The model-based Karlsburg Diabetes Management System (KADIS ®) has been developed as a decision support for physicians in their efforts to optimize metabolic control in diabetes care. For this purpose, KADIS ® was evaluated under different conditions by conducting open-label mono and polycentric trials, a case-control study and, last but not least, an observational study in routine diabetes outpatient care. The trial outcomes clearly show that the recommendations provided to the physicians by KADIS ® lead to significant improvement of metabolic control. It is concluded that this model-based decision support system provides an excellent tool to effectively guide physicians in decision making to achieve optimal metabolic control for their patients.

Research paper thumbnail of Mathematical Modelling of Competitive Labelled-Ligand Assay Systems. Theoretical Re-Evaluation of Optimum Assay Conditions and Precision Data for Some Experimentally Established Radioimmunoassay Systems

Clinical Chemistry and Laboratory Medicine, 1991

A mathematical theory of competitive labelled-ligand assays was developed with the intention of t... more A mathematical theory of competitive labelled-ligand assays was developed with the intention of theoretically re-evaluating the optimal assay conditions and precision data of assay Systems established by experiment. Our theory is based upon the assumptions of a simple bimolecular reaction mechanism, homogeneous reactants, äs well äs kinetically indistinguishable labelled and non-labelled ligands. The general case of two-step (non-equilibrium) assay was considered including the one-step (equilibrium) assay äs a special case. The solution of the System of corresponding kinetic differential equations was used to mathematically construct Standard curves. Furthermore, intraassay precision profiles and indices äs well äs detection limits were calculated considering solely the pipetting error, , äs a source of experimental error. A procedure was outlined to mathematically determine the optimal incubation conditions for any assay System targeted to a given analyte concentration, P, at which the Standard deviation of assay results is to be minimized. Estimates of both the content of binding sites and the equilibrium constant, K, of the specific binding agent are necessary, and these can be derived from Scatchard plots. For six RIA Systems, of which three were one-step and three were two-step assays, experimental assay conditions and precision data were compared with theoretical predictions. Experimentally determined antibody binding site concentrations agreed fairly well with those independently evaluated by mathematical optimization. Mean precision indices, defined äs constituting an average over the complete precision profile, were fotind to be within the theoretically predicted ränge, i. e. two-to threefold the pipetting error. Detection limits (Standard deviation near concentration 0) differed from theoretical values at most by a factor of two in the case of two-step assays and were nearly identical with theoretical values for one-step assays. Generally, they were Of the order of , approaching a lower limit by the order of , when P falls to the order of K. Comparing the advantages of the one-step and two-step technique of competitive labelled ligand assays, the following results were obtained: The one-step method provides a möre fävoürable pfecision profile, especially a better detection limit, and a higher specificity of analyte recogiütion. The quantity of reagents needed (specific binding agent äs well äs labelled ligand) is three to four times lower than in the two^step method. On the other hand, the higher amount of reagents employed for the two-step technique resülts in ä considefably higher measuring signal, which is important where activity of the labelled ligand is low. We conclude that mathematical modelling of labelled-ligand assays should be useful in re-evaluating assay conditions and precision data obtained by experiment. Furthermore, it permits some general assertions concenüng the principal limits of assay precision äs well äs the advantages and disadvantages pf different assay protocols. n o uc on named labelled-ligand assays, have found wide appli-Since the introduction of their basic analytical prin-cation in clinical chemistry and biochemistry. To ciple in 1959 (1), radioiiiimunoassays (RIA), enzyme quantify a certain analyte in a biological fluid, comimmunoassays and other related methods, generally petitive or non-competitive (sandwich) immunoassays

Research paper thumbnail of Inhibition of Glucagon Release of Isolated Islets of Langerhans by Monoclonal Antibodies*

Experimental and Clinical Endocrinology & Diabetes, Jul 16, 2009

The presence of islet cell cytoplasmic antibodies (ICA) and islet cell surface antibodies (ICSA) ... more The presence of islet cell cytoplasmic antibodies (ICA) and islet cell surface antibodies (ICSA) at the time of diagnosis of type 1 (insulin-dependent) diabetes mellitus has been taken as evidence that autoimmune mechanisms are involved in the pathogenesis of the disease. The demonstration that ICSA in the presence of complement are preferentially lytic for beta-cells may be important in defining the role of these autoantibodies in the pathogenesis of type 1 diabetes. Because of the polyclonality of the immune response, the ICA and ICSA molecules of diabetic patient vary enormously in their binding parameters. For this reason we have generated monoclonal antibodies (MC-Ab) to islet cell antigens. In this study we investigate the effect of the two MC-Ab K28 A1 and K28 D6 resulted from the same fusion of the P3-X63-Ag8 murine myeloma cell line with the spleen cells of a Balb/c mouse immunized with rat islet cells on the hormone release of isolated rat islet in co-culture with the antibody-secreting hybridomas. The MC-Ab K28 D6 binds to both islet cell cytoplasmic and surface antigens, the K28 A1 is only reactive with cytoplasmic antigens. Surprisingly, in contrast to the monoclonal antibody K28 A1, K28 D6 enhanced the glucagon content and diminished the insulin secretion of the islets. Either the K28 D6 is directed to an epitope occurring on the beta- as well as alpha-cells or the antibody-mediated inhibition of the glucagon release results in a significantly reduced insulin secretion.

Research paper thumbnail of Glucose transporter isoform (GLUT) 2 expression in beta-cells of long-term syngeneic islet grafts

Acta Diabetologica, Dec 15, 1997

Syngeneic islets were transplanted into the liver of streptozotocin (STZ)-induced diabetic LEW.1W... more Syngeneic islets were transplanted into the liver of streptozotocin (STZ)-induced diabetic LEW.1W rats, and the expression of the glucose transporter isoform GLUT 2, an essential component of the glucose-sensing mechanism of the pancreatic beta-cell, was determined in the grafted islet tissue. Graft-bearing liver was obtained 12, 36, and 60 weeks after transplantation, and tissue sections were immunoperoxidase stained for GLUT 2 and major islet peptides. Islet cell aggregates of different sizes were found in the portal tract and in juxtaposition to the hepatocytes. At all time points, beta-cells in the grafts displayed GLUT 2 expression comparable to that of islets in nondiabetic rats. Islet cells containing immunoreactive insulin and islet amyloid polypeptide were plentiful, while those staining positive for glucagon and somatostatin were scarce in these grafts. The results show that beta-cells in islets engrafted in the liver, although initially exposed to chronic hyperglycemia, have the capability of stably expressing GLUT 2 over long-term periods.

Research paper thumbnail of Relationships between Glucose Variability and Conventional Measures of Glycemic Control in Continuously Monitored Patients with Type 2 Diabetes

Hormone and Metabolic Research, Feb 1, 2009

Given the importance of glucose variability in the development of diabetic complications, the pre... more Given the importance of glucose variability in the development of diabetic complications, the present study used continuous glucose monitoring (CGM) to determine various indices of glucose variability and to investigate their relationships with conventional measures of chronic sustained hyperglycemia. We examined 53 women and 61 men, aged 36-79 years afflicted with type 2 diabetes for 1-24 years. The following indices of glycemic variability were computed from CGM data sets: mean amplitude of glycemic excursions (MAGE), CGM glucose range, interquartile range (IQR), SD-score, and average daily risk range (ADRR). CGM measurements and self-monitored blood glucose (SMBG) records were used to calculate mean CGM sensor glucose and mean SMBG, respectively. In simple correlation analysis, the indices of glucose variability showed weak correlations with HbA1c: MAGE (r=0.27, p &amp;amp;amp;amp;lt;0.01), CGM glucose range (r=0.21, p &amp;amp;amp;amp;lt;0.05), IQR (r=0.31, p &amp;amp;amp;amp;lt;0.01), SD-score (r=0.34, p&amp;amp;amp;amp;lt;0.001), and ADRR (r=0.24, p&amp;amp;amp;amp;lt;0.05). These indices were found to differ at identical HbA1c among several patients, as reflected by diurnal excursions of different frequency and magnitude. With the exception of ADRR, stronger correlations were found between mean SMBG and the other variability indices (r=0.51-0.63, p&amp;amp;amp;amp;lt;0.01 for all). CGM provides various indices of glycemic variability not captured by conventional measures of glycemic control. Detection of the location and the magnitude of glucose fluctuations by CGM should aid in optimal treatment of glycemic disorders in type 2 diabetes.

Research paper thumbnail of Q-Score: development of a new metric for continuous glucose monitoring that enables stratification of antihyperglycaemic therapies

BMC Endocrine Disorders, May 1, 2015

Background: Continuous glucose monitoring (CGM) has revolutionised diabetes management. CGM enabl... more Background: Continuous glucose monitoring (CGM) has revolutionised diabetes management. CGM enables complete visualisation of the glucose profile, and the uncovering of metabolic 'weak points'. A standardised procedure to evaluate the complex data acquired by CGM, and to create patient-tailored recommendations has not yet been developed. We aimed to develop a new patient-tailored approach for the routine clinical evaluation of CGM profiles. We developed a metric allowing screening for profiles that require therapeutic action and a method to identify the individual CGM parameters with improvement potential. Methods: Fifteen parameters frequently used to assess CGM profiles were calculated for 1,562 historic CGM profiles from subjects with type 1 or type 2 diabetes. Factor analysis and varimax rotation was performed to identify factors that accounted for the quality of the profiles. Results: We identified five primary factors that determined CGM profiles (central tendency, hyperglycaemia, hypoglycaemia, intra-and inter-daily variations). One parameter from each factor was selected for constructing the formula for the screening metric, (the 'Q-Score'). To derive Q-Score classifications, three diabetes specialists independently categorised 766 CGM profiles into groups of 'very good', 'good', 'satisfactory', 'fair', and 'poor' metabolic control. The Q-Score was then calculated for all profiles, and limits were defined based on the categorised groups (<4.0, very good; 4.0-5.9, good; 6.0-8.4, satisfactory; 8.5-11.9, fair; and ≥12.0, poor). Q-Scores increased significantly (P <0.01) with increasing antihyperglycaemic therapy complexity. Accordingly, the percentage of fair and poor profiles was higher in insulin-treated compared with diet-treated subjects (58.4% vs. 9.3%). In total, 90% of profiles categorised as fair or poor had at least three parameters that could potentially be optimised. The improvement potential of those parameters can be categorised as 'low', 'moderate' and 'high'. Conclusions: The Q-Score is a new metric suitable to screen for CGM profiles that require therapeutic action. Moreover, because single components of the Q-Score formula respond to individual weak points in glycaemic control, parameters with improvement potential can be identified and used as targets for optimising patienttailored therapies.

Research paper thumbnail of Utility of different glycemic control metrics for optimizing management of diabetes

World Journal of Diabetes, 2015

Research paper thumbnail of Ketosis, Serum Carnitine and its Precursor Amino Acids in Normal and Diabetic Ethiopians

Experimental and Clinical Endocrinology & Diabetes, Jul 16, 2009

In a hospital-based study in northwestern Ethiopia some clinical and biochemical features of diab... more In a hospital-based study in northwestern Ethiopia some clinical and biochemical features of diabetes mellitus have been assessed to contribute to the problem of classification of diabetes in a tropical country. Diabetes requiring primary insulin treatment is presented by unequivocally elevated blood glucose levels and the classic symptoms of the disease. Newly discovered cases and readmitted rural diabetics show significantly lower body mass indices and 31% have been classified as underweight. The overall frequency of ketonuria at (re)admission was 45% together with moderately elevated or high 3-hydroxybutyrate serum concentrations. The hormonal status is characterized by a reduced beta-cell function. Serum concentrations of all carnitine fractions are lower in both normal and diabetic Ethiopians when compared with Caucasoids. Carnitine precursor amino acids are normal and the complete amino acid spectrum reveales no clear-cut pattern related to protein-energy malnutrition.

Research paper thumbnail of Advances in Understanding Glucose Variability and the Role of Continuous Glucose Monitoring

European Endocrinology, 2010

Evidence from several large randomised clinical trials has linked glycated haemoglobin (HbA 1c) t... more Evidence from several large randomised clinical trials has linked glycated haemoglobin (HbA 1c) to vascular diabetes complications. 1,2 Consequently, current diabetes management relies mainly on HbA 1c to assess quality of treatment and to adjust therapy. Optimal glycaemic Recent data have suggested that glucose variability may add to or modify the risk of diabetes complications. Glycated haemoglobin (HbA 1c), an integrated measure of sustained chronic hyperglycaemia, fails to reflect glucose variability and the risks associated with extreme glucose swings. Thus, whether glucose variability should become an integral part of assessing glucose control in clinical practice remains unknown. Since the establishment of continuous glucose monitoring (CGM) systems, various indices of glucose variability and quality of glycaemic control such as the mean amplitude of glycaemic excursions (MAGE) and the Glycaemic Risk Assessment Diabetes Equation (GRADE) can now be precisely computed from CGM data sets. Analysis of CGM data, including the impact of glucose variability and its temporal aspects, has clinical importance and should be incorporated into use in clinical trials and the design of optimal antidiabetes therapies.

Research paper thumbnail of The metabolic syndrome in patients with type 1 diabetes mellitus. Associations with cardiovascular risk factors and cardiovascular morbidity

Herz, Aug 1, 2004

Type 1 diabetes is known to be associated with increased cardiovascular disease in the presence o... more Type 1 diabetes is known to be associated with increased cardiovascular disease in the presence of nephropathy and hypertension. It was the aim of the present study to elucidate whether or not clinical findings of metabolic syndrome (MS) are further increasing cardiovascular morbidity among type 1 diabetics. In the present cross-sectional study, 1,241 type 1 diabetics were included. These patients attended the Diabetes Clinic Karlsburg, Germany, from February 1, 2002 to December 31, 2003. The presence of the following findings was taken into consideration as clinical features of MS in type 1 diabetes: fasting triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), body mass index (BMI), daily insulin requirement/kg body weight (b.w.), increased blood pressure &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 130/85 mmHg, including overt arterial hypertension. In each of the five categories the highest quintile in each sample was assessed: TG 2.9 +/- 3.6 mmol/l, HDL-C 1.48 +/- 0.46 mmol/l, BMI 29.1 +/- 4.98 kg/m(2) height, insulin requirement 0.71 +/- 0.23 IU/kg b.w., systolic blood pressure 130 +/- 12.3 mmHg. MS was defined as the presence of at least three categories. Among 1,241 type 1 diabetics (651 men, 590 women), 226 patients (129 men, 97 women) fulfilled the criteria of MS. The risk of MS was assessed by multiple regression analysis. Risk variables were: age, diabetes duration, sex, glycated hemoglobin (HbA(1c)), actual smoking, neuropathy, albumin excretion rate (AER), regular alcohol consumption, retinopathy, peripheral vascular disease (PVD), coronary heart disease (CHD), TGs, HDL-C, low-density lipoprotein cholesterol (LDL-C), cholesterol, blood pressure increase, BMI, increased insulin requirement, and foot syndrome. After adjusting for age, the variables were separately included into the mathematical model. The risk of MS was assessed after excluding the variables defining MS. Type 1 diabetics with MS were characterized by higher age (46 vs. 36 years; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01), and longer diabetes duration (19 vs. 16 years; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). The risk of MS was independently associated (odds ratios) with higher age (40-59 years; 4.21; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01), increased HbA(1c) (1.41; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01), PVD (2.28; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01), CHD (2.19; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01), and the foot syndrome (4.17; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). There were no significant associations of MS with type 2 diabetes heredity (first and second degree). Patients with type 1 diabetes and the presence of findings of MS are suffering from increased cardiovascular morbidity. The risk of MS increases with the age and HbA(1c). Life style factors such as weight gain and muscular inactivity seem to have an influence on the pathogenesis of MS in type 1 diabetes, thereby increasing cardiovascular morbidity.

Research paper thumbnail of Autoantibodies to Insulin and to Proinsulin in Type 1 Diabetic Patients and in At-Risk Probands Differentiate Only Little between Both Antigens

Hormone and Metabolic Research, Feb 1, 1995

To answer the question whether insulin or proinsulin would be the true antigen for both insulin a... more To answer the question whether insulin or proinsulin would be the true antigen for both insulin and proinsulin autoantibodies, displacement experiments of 125I-insulin and -proinsulin binding with both unlabeled antigens were performed in sera of four groups of antibody-positive probands: first-degree relatives of Type 1 diabetic patients, pre-Type 1 diabetic persons, recent-onset Type 1 diabetic patients, insulin-treated Type 1 diabetic patients. In subjects who were primarily screened to constitute these groups, prevalences of insulin and proinsulin autoantibodies were nearly identical. In antibody-positive sera, 125I-insulin and -proinsulin binding values in general were closely correlated to each other with regression coefficients near 1.0. In all groups of probands, mean values of 125I-insulin and -proinsulin binding did not significantly differ. With the exception of a few sera, insulin and proinsulin antibodies differentiated only little between both antigens. Epitopes of the insulin molecule are therefore preferred. Nevertheless, insulin and proinsulin autoantibodies are not completely identical nor are insulin autoantibodies merely a subgroup of proinsulin autoantibodies: In each group, in the mean, insulin antibodies as well as proinsulin antibodies reacted somewhat (but significantly) stronger with their respective antigen. In some cases a distinct (relative) specificity for either antigen of insulin and proinsulin autoantibodies were observed, the latter being still present after some months of insulin treatment. In conclusion, despite detectable differences in antigen specificity, insulin and proinsulin autoantibodies seem to be equally potent markers of Type 1 diabetes mellitus.

Research paper thumbnail of Outpatient Assessment of Karlsburg Diabetes Management System–Based Decision Support

Diabetes Care, Jul 1, 2007

OBJECTIVE-We sought to assess the benefit of the Karlsburg Diabetes Management System (KADIS) in ... more OBJECTIVE-We sought to assess the benefit of the Karlsburg Diabetes Management System (KADIS) in conjunction with the continuous glucose monitoring system (CGMS) in an outpatient setting. RESEARCH DESIGN AND METHODS-A multicentric trial was performed in insulin-treated outpatients (n ϭ 49), aged 21-70 years, with a mean diabetes duration of 14.2 years. Subjects were recruited from five outpatient centers and randomized for CGMS-or CGMS/ KADIS-based decision support and followed up for 3 months. After two CGMS monitorings, the outcome parameters A1C (%), mean sensor glucose of the CGMS profile (MSG) (mmol/l), and duration of hyperglycemia (h/day) were evaluated. RESULTS-In contrast with the CGMS group (0.27 Ϯ 0.67%), mean change in A1C decreased in the CGMS/KADIS group during the follow-up (Ϫ0.34 Ϯ 0.49%; P Ͻ 0.01). MSG levels were not affected in the CGMS group (7.75 Ϯ 1.33 vs. 8.45 Ϯ 2.46 mmol/l) but declined in the CGMS/KADIS group (8.43 Ϯ 1.33 vs. 7.59 Ϯ 1.47 mmol/l; P Ͻ 0.05). Net KADIS effect (Ϫ0.60 [95% CI Ϫ0.96 to Ϫ 0.25%]; P Ͻ 0.01) was associated with reduced duration of hyperglycemia (4.6 vs. 1.0 h/day; P Ͻ 0.01) without increasing hypoglycemia. Multiple regression revealed that the A1C outcome was dependent on KADIS-based decision support. Age, sex, physician's specialty, diabetes type, and BMI had no measurable effect. CONCLUSIONS-If physicians were supported by CGMS/KADIS in therapeutic decisions, they achieved better glycemic control for their patients compared with support by CGMS alone. KADIS is a suitable decision support tool for physicians in outpatient diabetes care and has the potential to improve evidence-based management of diabetes.

Research paper thumbnail of Chronic hyperglycemia but not glucose variability determines HbA1c levels in well-controlled patients with type 2 diabetes

Diabetes Research and Clinical Practice, Sep 1, 2007

To determine the relationships between HbA1c, characteristics of hyperglycemia and glycemic varia... more To determine the relationships between HbA1c, characteristics of hyperglycemia and glycemic variability in well-controlled type 2 diabetes (HbA1c < 7.0%), we studied 63 primary-care patients (36 men and 27 women), aged 34-75 years, with type 2 diabetes for 2-32 years using a continuous glucose monitoring system (CGMS) and standardized meal test (MMT). Duration of hyperglycemia (>8.0 mmol/l), standard deviation score (S.D.-score) and mean amplitude of glycemic excursions (MAGE) were analyzed from CGMS data and postprandial glucose during MMT (PPG MMT). Patients were hyperglycemic for 5.7 h/day (median), experienced 4.1 hyperglycemic episodes/day, and 78% exceeded PPG levels of 8.0 mmol/l. HbA1c, though associated with the extent of hyperglycemia (r = 0.40, p < 0.001), failed to correlate with S.D.-score and MAGE. Multiple regression analysis demonstrated that HbA1c was predicted only by fasting glucose (R 2 = 0.24, p < 0.001) but neither by PPG MMT , duration of hyperglycemia, S.D.-score nor MAGE. CGMS and meal test provide the tools for complete characterization of glycemia in type 2 diabetes. In well-controlled type 2 diabetes, HbA1c correlates with chronic hyperglycemia but not with glucose variability. Our data suggest that chronic sustained hyperglycemia and glucose fluctuations are two independent components of dysglycemia in diabetes.

Research paper thumbnail of Einfluss einer chronischen Behandlung mit Leukozyten Dialysat (DLE) auf den glukoseintoleranten Stoffwechsel und die Entwicklung von strukturellen Veränderungen in pankreatischen Inseln von Zucker Ratten (fa/fa)

Diabetologie Und Stoffwechsel, 2006

Research paper thumbnail of Fraktionierung handelsüblichen insulins. Gewinnung und eigenschaften einer hochmolekularen, insulin-ähnlichen komponente

FEBS Letters, May 20, 1971

A component with high molecular weight is prepared from commercial bovine insulin by gel filtrati... more A component with high molecular weight is prepared from commercial bovine insulin by gel filtration on Sephadex G 50. The substance has little biological and immunological activity in comparison to insulin. The activity is not changed by incubation with trypsin. It associates in 1 M CH&OOH and possesses a molecular weight of 28,500 as shown by ultracentrifugation. The ability of the component to precipitate with bovine insulin antibodies demonstrates that it contains immunologically active insulin-like proteins and is not a homogenous substance.

Research paper thumbnail of Associations of blood glucose dynamics with antihyperglycemic treatment and glycemic variability in type 1 and type 2 diabetes

Journal of Endocrinological Investigation, May 8, 2017

correlated with increasing glucose variability and glucose exposure. Statistically, significant c... more correlated with increasing glucose variability and glucose exposure. Statistically, significant correlations existed between higher MSE complexity indices and better glycemic control. In multivariate regression analysis, the antidiabetic therapy was the most powerful predictor of the MSE (β = −0.940 ± 0.242, R 2 = 0.306, p < 0.001), whereas the potential confounders failed to contribute. Conclusions The loss of dynamical complexity in glucose homeostasis correlates more closely with therapy modalities and glucose variability than with clinical measures of glycemia. Thus, targeting the glucoregulatory system by adequate therapeutic interventions may protect against progressive worsening of diabetes control.

Research paper thumbnail of Glycemic Variability Correlates Strongly With Postprandialβ-Cell Dysfunction in a Segment of Type 2 Diabetic Patients Using Oral Hypoglycemic Agents

Diabetes Care, Feb 24, 2009

OBJECTIVE-Glucose fluctuations trigger activation of oxidative stress, a main mechanism leading t... more OBJECTIVE-Glucose fluctuations trigger activation of oxidative stress, a main mechanism leading to secondary diabetes complications. We evaluated the relationship between glycemic variability and ␤-cell dysfunction. RESEARCH DESIGN AND METHODS-We conducted a cross-sectional study in 59 patients with type 2 diabetes (aged 64.2 Ϯ 8.6 years, A1C 6.5 Ϯ 1.0%, and BMI 29.8 Ϯ 3.8 kg/m 2 [mean Ϯ SD]) using either oral hypoglycemic agents (OHAs) (n ϭ 34) or diet alone (nonusers). As a measure of glycemic variability, the mean amplitude of glycemic excursions (MAGE) was computed from continuous glucose monitoring data recorded over 3 consecutive days. The relationships between MAGE, ␤-cell function, and clinical parameters were assessed by including postprandial ␤-cell function (PBCF) and basal ␤-cell function (BBCF) obtained by a model-based method from plasma C-peptide and plasma glucose during a mixed-meal test as well as homeostasis model assessment of insulin sensitivity, clinical factors, carbohydrate intake, and type of OHA. RESULTS-MAGE was nonlinearly correlated with PBCF (r ϭ 0.54, P Ͻ 0.001) and with BBCF (r ϭ 0.31, P ϭ 0.025) in OHA users but failed to correlate with these parameters in nonusers (PBCF P ϭ 0.21 and BBCF P ϭ 0.07). The stepwise multiple regression analysis demonstrated that PBCF and OHA combination treatment were independent contributors to MAGE (R 2 ϭ 0.50, P Ͻ 0.010), whereas insulin sensitivity, carbohydrate intake, and nonglycemic parameters failed to contribute. CONCLUSIONS-PBCF appears to be an important target to reduce glucose fluctuations in OHA-treated type 2 diabetes.

Research paper thumbnail of Decreased intracellular phosphate in vascular smooth muscle cells from SHR and decreased ATPase activities

Research paper thumbnail of Discordant results in the assay of cytoplasmic islet cell autoantibodies with ELISA and immunohistochemical techniques

PubMed, Jul 1, 1995

We evaluated 6 batches of a solid phase enzyme-linked immunosorbent assay (ELISA) Isletest-ICA ki... more We evaluated 6 batches of a solid phase enzyme-linked immunosorbent assay (ELISA) Isletest-ICA kit commercially available for the determination of autoantibodies to pancreatic islet cells, and compared the results with those obtained by a standardized immunohistochemical method. Following the immunohistochemical determination of autoantibodies to pancreatic islet cells, sera from patients with insulin-dependent diabetes mellitus, both positive and negative for autoantibodies to pancreatic islet cells, were randomly selected and analysed by ELISA. Sera from healthy control subjects, as well as standards recommended by the International Diabetes Workshop (IDW) ICA (Autoantibodies to Pancreatic Islet Cells) Proficiency Program, were included. Of the sera testing positive for autoantibodies to pancreatic islet cells in the immunohistochemical assay, only 14 +/- 5% were found to give a positive reaction in the ELISA. Among the sera from healthy control subjects and pancreatic islet cell autoantibody-negative insulin-dependent diabetes mellitus patients, 25 +/- 7% and 1 +/- 1%, respectively, yielded false-positive readings for autoantibodies to pancreatic islet cells. These results clearly show that the ELISA test presently available does not reliably detect autoantibodies to pancreatic islet cells, even qualitatively. Thus, it cannot be used for screening subjects at risk of developing diabetes.

Research paper thumbnail of Islet graft-induced changes of ß-hydroxybutyrate dehydrogenase and glucose-6-phosphatase activity in liver cells of diabetic recipient rats

Experimental and Toxicologic Pathology, May 1, 2000

ABSTRACT

Research paper thumbnail of Model-based Decision Support System to Improve Diabetes Care and Management

IFAC Proceedings Volumes, 2009

The model-based Karlsburg Diabetes Management System (KADIS ®) has been developed as a decision s... more The model-based Karlsburg Diabetes Management System (KADIS ®) has been developed as a decision support for physicians in their efforts to optimize metabolic control in diabetes care. For this purpose, KADIS ® was evaluated under different conditions by conducting open-label mono and polycentric trials, a case-control study and, last but not least, an observational study in routine diabetes outpatient care. The trial outcomes clearly show that the recommendations provided to the physicians by KADIS ® lead to significant improvement of metabolic control. It is concluded that this model-based decision support system provides an excellent tool to effectively guide physicians in decision making to achieve optimal metabolic control for their patients.

Research paper thumbnail of Mathematical Modelling of Competitive Labelled-Ligand Assay Systems. Theoretical Re-Evaluation of Optimum Assay Conditions and Precision Data for Some Experimentally Established Radioimmunoassay Systems

Clinical Chemistry and Laboratory Medicine, 1991

A mathematical theory of competitive labelled-ligand assays was developed with the intention of t... more A mathematical theory of competitive labelled-ligand assays was developed with the intention of theoretically re-evaluating the optimal assay conditions and precision data of assay Systems established by experiment. Our theory is based upon the assumptions of a simple bimolecular reaction mechanism, homogeneous reactants, äs well äs kinetically indistinguishable labelled and non-labelled ligands. The general case of two-step (non-equilibrium) assay was considered including the one-step (equilibrium) assay äs a special case. The solution of the System of corresponding kinetic differential equations was used to mathematically construct Standard curves. Furthermore, intraassay precision profiles and indices äs well äs detection limits were calculated considering solely the pipetting error, , äs a source of experimental error. A procedure was outlined to mathematically determine the optimal incubation conditions for any assay System targeted to a given analyte concentration, P, at which the Standard deviation of assay results is to be minimized. Estimates of both the content of binding sites and the equilibrium constant, K, of the specific binding agent are necessary, and these can be derived from Scatchard plots. For six RIA Systems, of which three were one-step and three were two-step assays, experimental assay conditions and precision data were compared with theoretical predictions. Experimentally determined antibody binding site concentrations agreed fairly well with those independently evaluated by mathematical optimization. Mean precision indices, defined äs constituting an average over the complete precision profile, were fotind to be within the theoretically predicted ränge, i. e. two-to threefold the pipetting error. Detection limits (Standard deviation near concentration 0) differed from theoretical values at most by a factor of two in the case of two-step assays and were nearly identical with theoretical values for one-step assays. Generally, they were Of the order of , approaching a lower limit by the order of , when P falls to the order of K. Comparing the advantages of the one-step and two-step technique of competitive labelled ligand assays, the following results were obtained: The one-step method provides a möre fävoürable pfecision profile, especially a better detection limit, and a higher specificity of analyte recogiütion. The quantity of reagents needed (specific binding agent äs well äs labelled ligand) is three to four times lower than in the two^step method. On the other hand, the higher amount of reagents employed for the two-step technique resülts in ä considefably higher measuring signal, which is important where activity of the labelled ligand is low. We conclude that mathematical modelling of labelled-ligand assays should be useful in re-evaluating assay conditions and precision data obtained by experiment. Furthermore, it permits some general assertions concenüng the principal limits of assay precision äs well äs the advantages and disadvantages pf different assay protocols. n o uc on named labelled-ligand assays, have found wide appli-Since the introduction of their basic analytical prin-cation in clinical chemistry and biochemistry. To ciple in 1959 (1), radioiiiimunoassays (RIA), enzyme quantify a certain analyte in a biological fluid, comimmunoassays and other related methods, generally petitive or non-competitive (sandwich) immunoassays

Research paper thumbnail of Inhibition of Glucagon Release of Isolated Islets of Langerhans by Monoclonal Antibodies*

Experimental and Clinical Endocrinology & Diabetes, Jul 16, 2009

The presence of islet cell cytoplasmic antibodies (ICA) and islet cell surface antibodies (ICSA) ... more The presence of islet cell cytoplasmic antibodies (ICA) and islet cell surface antibodies (ICSA) at the time of diagnosis of type 1 (insulin-dependent) diabetes mellitus has been taken as evidence that autoimmune mechanisms are involved in the pathogenesis of the disease. The demonstration that ICSA in the presence of complement are preferentially lytic for beta-cells may be important in defining the role of these autoantibodies in the pathogenesis of type 1 diabetes. Because of the polyclonality of the immune response, the ICA and ICSA molecules of diabetic patient vary enormously in their binding parameters. For this reason we have generated monoclonal antibodies (MC-Ab) to islet cell antigens. In this study we investigate the effect of the two MC-Ab K28 A1 and K28 D6 resulted from the same fusion of the P3-X63-Ag8 murine myeloma cell line with the spleen cells of a Balb/c mouse immunized with rat islet cells on the hormone release of isolated rat islet in co-culture with the antibody-secreting hybridomas. The MC-Ab K28 D6 binds to both islet cell cytoplasmic and surface antigens, the K28 A1 is only reactive with cytoplasmic antigens. Surprisingly, in contrast to the monoclonal antibody K28 A1, K28 D6 enhanced the glucagon content and diminished the insulin secretion of the islets. Either the K28 D6 is directed to an epitope occurring on the beta- as well as alpha-cells or the antibody-mediated inhibition of the glucagon release results in a significantly reduced insulin secretion.

Research paper thumbnail of Glucose transporter isoform (GLUT) 2 expression in beta-cells of long-term syngeneic islet grafts

Acta Diabetologica, Dec 15, 1997

Syngeneic islets were transplanted into the liver of streptozotocin (STZ)-induced diabetic LEW.1W... more Syngeneic islets were transplanted into the liver of streptozotocin (STZ)-induced diabetic LEW.1W rats, and the expression of the glucose transporter isoform GLUT 2, an essential component of the glucose-sensing mechanism of the pancreatic beta-cell, was determined in the grafted islet tissue. Graft-bearing liver was obtained 12, 36, and 60 weeks after transplantation, and tissue sections were immunoperoxidase stained for GLUT 2 and major islet peptides. Islet cell aggregates of different sizes were found in the portal tract and in juxtaposition to the hepatocytes. At all time points, beta-cells in the grafts displayed GLUT 2 expression comparable to that of islets in nondiabetic rats. Islet cells containing immunoreactive insulin and islet amyloid polypeptide were plentiful, while those staining positive for glucagon and somatostatin were scarce in these grafts. The results show that beta-cells in islets engrafted in the liver, although initially exposed to chronic hyperglycemia, have the capability of stably expressing GLUT 2 over long-term periods.

Research paper thumbnail of Relationships between Glucose Variability and Conventional Measures of Glycemic Control in Continuously Monitored Patients with Type 2 Diabetes

Hormone and Metabolic Research, Feb 1, 2009

Given the importance of glucose variability in the development of diabetic complications, the pre... more Given the importance of glucose variability in the development of diabetic complications, the present study used continuous glucose monitoring (CGM) to determine various indices of glucose variability and to investigate their relationships with conventional measures of chronic sustained hyperglycemia. We examined 53 women and 61 men, aged 36-79 years afflicted with type 2 diabetes for 1-24 years. The following indices of glycemic variability were computed from CGM data sets: mean amplitude of glycemic excursions (MAGE), CGM glucose range, interquartile range (IQR), SD-score, and average daily risk range (ADRR). CGM measurements and self-monitored blood glucose (SMBG) records were used to calculate mean CGM sensor glucose and mean SMBG, respectively. In simple correlation analysis, the indices of glucose variability showed weak correlations with HbA1c: MAGE (r=0.27, p &amp;amp;amp;amp;lt;0.01), CGM glucose range (r=0.21, p &amp;amp;amp;amp;lt;0.05), IQR (r=0.31, p &amp;amp;amp;amp;lt;0.01), SD-score (r=0.34, p&amp;amp;amp;amp;lt;0.001), and ADRR (r=0.24, p&amp;amp;amp;amp;lt;0.05). These indices were found to differ at identical HbA1c among several patients, as reflected by diurnal excursions of different frequency and magnitude. With the exception of ADRR, stronger correlations were found between mean SMBG and the other variability indices (r=0.51-0.63, p&amp;amp;amp;amp;lt;0.01 for all). CGM provides various indices of glycemic variability not captured by conventional measures of glycemic control. Detection of the location and the magnitude of glucose fluctuations by CGM should aid in optimal treatment of glycemic disorders in type 2 diabetes.

Research paper thumbnail of Q-Score: development of a new metric for continuous glucose monitoring that enables stratification of antihyperglycaemic therapies

BMC Endocrine Disorders, May 1, 2015

Background: Continuous glucose monitoring (CGM) has revolutionised diabetes management. CGM enabl... more Background: Continuous glucose monitoring (CGM) has revolutionised diabetes management. CGM enables complete visualisation of the glucose profile, and the uncovering of metabolic 'weak points'. A standardised procedure to evaluate the complex data acquired by CGM, and to create patient-tailored recommendations has not yet been developed. We aimed to develop a new patient-tailored approach for the routine clinical evaluation of CGM profiles. We developed a metric allowing screening for profiles that require therapeutic action and a method to identify the individual CGM parameters with improvement potential. Methods: Fifteen parameters frequently used to assess CGM profiles were calculated for 1,562 historic CGM profiles from subjects with type 1 or type 2 diabetes. Factor analysis and varimax rotation was performed to identify factors that accounted for the quality of the profiles. Results: We identified five primary factors that determined CGM profiles (central tendency, hyperglycaemia, hypoglycaemia, intra-and inter-daily variations). One parameter from each factor was selected for constructing the formula for the screening metric, (the 'Q-Score'). To derive Q-Score classifications, three diabetes specialists independently categorised 766 CGM profiles into groups of 'very good', 'good', 'satisfactory', 'fair', and 'poor' metabolic control. The Q-Score was then calculated for all profiles, and limits were defined based on the categorised groups (<4.0, very good; 4.0-5.9, good; 6.0-8.4, satisfactory; 8.5-11.9, fair; and ≥12.0, poor). Q-Scores increased significantly (P <0.01) with increasing antihyperglycaemic therapy complexity. Accordingly, the percentage of fair and poor profiles was higher in insulin-treated compared with diet-treated subjects (58.4% vs. 9.3%). In total, 90% of profiles categorised as fair or poor had at least three parameters that could potentially be optimised. The improvement potential of those parameters can be categorised as 'low', 'moderate' and 'high'. Conclusions: The Q-Score is a new metric suitable to screen for CGM profiles that require therapeutic action. Moreover, because single components of the Q-Score formula respond to individual weak points in glycaemic control, parameters with improvement potential can be identified and used as targets for optimising patienttailored therapies.

Research paper thumbnail of Utility of different glycemic control metrics for optimizing management of diabetes

World Journal of Diabetes, 2015

Research paper thumbnail of Ketosis, Serum Carnitine and its Precursor Amino Acids in Normal and Diabetic Ethiopians

Experimental and Clinical Endocrinology & Diabetes, Jul 16, 2009

In a hospital-based study in northwestern Ethiopia some clinical and biochemical features of diab... more In a hospital-based study in northwestern Ethiopia some clinical and biochemical features of diabetes mellitus have been assessed to contribute to the problem of classification of diabetes in a tropical country. Diabetes requiring primary insulin treatment is presented by unequivocally elevated blood glucose levels and the classic symptoms of the disease. Newly discovered cases and readmitted rural diabetics show significantly lower body mass indices and 31% have been classified as underweight. The overall frequency of ketonuria at (re)admission was 45% together with moderately elevated or high 3-hydroxybutyrate serum concentrations. The hormonal status is characterized by a reduced beta-cell function. Serum concentrations of all carnitine fractions are lower in both normal and diabetic Ethiopians when compared with Caucasoids. Carnitine precursor amino acids are normal and the complete amino acid spectrum reveales no clear-cut pattern related to protein-energy malnutrition.

Research paper thumbnail of Advances in Understanding Glucose Variability and the Role of Continuous Glucose Monitoring

European Endocrinology, 2010

Evidence from several large randomised clinical trials has linked glycated haemoglobin (HbA 1c) t... more Evidence from several large randomised clinical trials has linked glycated haemoglobin (HbA 1c) to vascular diabetes complications. 1,2 Consequently, current diabetes management relies mainly on HbA 1c to assess quality of treatment and to adjust therapy. Optimal glycaemic Recent data have suggested that glucose variability may add to or modify the risk of diabetes complications. Glycated haemoglobin (HbA 1c), an integrated measure of sustained chronic hyperglycaemia, fails to reflect glucose variability and the risks associated with extreme glucose swings. Thus, whether glucose variability should become an integral part of assessing glucose control in clinical practice remains unknown. Since the establishment of continuous glucose monitoring (CGM) systems, various indices of glucose variability and quality of glycaemic control such as the mean amplitude of glycaemic excursions (MAGE) and the Glycaemic Risk Assessment Diabetes Equation (GRADE) can now be precisely computed from CGM data sets. Analysis of CGM data, including the impact of glucose variability and its temporal aspects, has clinical importance and should be incorporated into use in clinical trials and the design of optimal antidiabetes therapies.

Research paper thumbnail of The metabolic syndrome in patients with type 1 diabetes mellitus. Associations with cardiovascular risk factors and cardiovascular morbidity

Herz, Aug 1, 2004

Type 1 diabetes is known to be associated with increased cardiovascular disease in the presence o... more Type 1 diabetes is known to be associated with increased cardiovascular disease in the presence of nephropathy and hypertension. It was the aim of the present study to elucidate whether or not clinical findings of metabolic syndrome (MS) are further increasing cardiovascular morbidity among type 1 diabetics. In the present cross-sectional study, 1,241 type 1 diabetics were included. These patients attended the Diabetes Clinic Karlsburg, Germany, from February 1, 2002 to December 31, 2003. The presence of the following findings was taken into consideration as clinical features of MS in type 1 diabetes: fasting triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), body mass index (BMI), daily insulin requirement/kg body weight (b.w.), increased blood pressure &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 130/85 mmHg, including overt arterial hypertension. In each of the five categories the highest quintile in each sample was assessed: TG 2.9 +/- 3.6 mmol/l, HDL-C 1.48 +/- 0.46 mmol/l, BMI 29.1 +/- 4.98 kg/m(2) height, insulin requirement 0.71 +/- 0.23 IU/kg b.w., systolic blood pressure 130 +/- 12.3 mmHg. MS was defined as the presence of at least three categories. Among 1,241 type 1 diabetics (651 men, 590 women), 226 patients (129 men, 97 women) fulfilled the criteria of MS. The risk of MS was assessed by multiple regression analysis. Risk variables were: age, diabetes duration, sex, glycated hemoglobin (HbA(1c)), actual smoking, neuropathy, albumin excretion rate (AER), regular alcohol consumption, retinopathy, peripheral vascular disease (PVD), coronary heart disease (CHD), TGs, HDL-C, low-density lipoprotein cholesterol (LDL-C), cholesterol, blood pressure increase, BMI, increased insulin requirement, and foot syndrome. After adjusting for age, the variables were separately included into the mathematical model. The risk of MS was assessed after excluding the variables defining MS. Type 1 diabetics with MS were characterized by higher age (46 vs. 36 years; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01), and longer diabetes duration (19 vs. 16 years; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). The risk of MS was independently associated (odds ratios) with higher age (40-59 years; 4.21; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01), increased HbA(1c) (1.41; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01), PVD (2.28; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01), CHD (2.19; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01), and the foot syndrome (4.17; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). There were no significant associations of MS with type 2 diabetes heredity (first and second degree). Patients with type 1 diabetes and the presence of findings of MS are suffering from increased cardiovascular morbidity. The risk of MS increases with the age and HbA(1c). Life style factors such as weight gain and muscular inactivity seem to have an influence on the pathogenesis of MS in type 1 diabetes, thereby increasing cardiovascular morbidity.

Research paper thumbnail of Autoantibodies to Insulin and to Proinsulin in Type 1 Diabetic Patients and in At-Risk Probands Differentiate Only Little between Both Antigens

Hormone and Metabolic Research, Feb 1, 1995

To answer the question whether insulin or proinsulin would be the true antigen for both insulin a... more To answer the question whether insulin or proinsulin would be the true antigen for both insulin and proinsulin autoantibodies, displacement experiments of 125I-insulin and -proinsulin binding with both unlabeled antigens were performed in sera of four groups of antibody-positive probands: first-degree relatives of Type 1 diabetic patients, pre-Type 1 diabetic persons, recent-onset Type 1 diabetic patients, insulin-treated Type 1 diabetic patients. In subjects who were primarily screened to constitute these groups, prevalences of insulin and proinsulin autoantibodies were nearly identical. In antibody-positive sera, 125I-insulin and -proinsulin binding values in general were closely correlated to each other with regression coefficients near 1.0. In all groups of probands, mean values of 125I-insulin and -proinsulin binding did not significantly differ. With the exception of a few sera, insulin and proinsulin antibodies differentiated only little between both antigens. Epitopes of the insulin molecule are therefore preferred. Nevertheless, insulin and proinsulin autoantibodies are not completely identical nor are insulin autoantibodies merely a subgroup of proinsulin autoantibodies: In each group, in the mean, insulin antibodies as well as proinsulin antibodies reacted somewhat (but significantly) stronger with their respective antigen. In some cases a distinct (relative) specificity for either antigen of insulin and proinsulin autoantibodies were observed, the latter being still present after some months of insulin treatment. In conclusion, despite detectable differences in antigen specificity, insulin and proinsulin autoantibodies seem to be equally potent markers of Type 1 diabetes mellitus.

Research paper thumbnail of Outpatient Assessment of Karlsburg Diabetes Management System–Based Decision Support

Diabetes Care, Jul 1, 2007

OBJECTIVE-We sought to assess the benefit of the Karlsburg Diabetes Management System (KADIS) in ... more OBJECTIVE-We sought to assess the benefit of the Karlsburg Diabetes Management System (KADIS) in conjunction with the continuous glucose monitoring system (CGMS) in an outpatient setting. RESEARCH DESIGN AND METHODS-A multicentric trial was performed in insulin-treated outpatients (n ϭ 49), aged 21-70 years, with a mean diabetes duration of 14.2 years. Subjects were recruited from five outpatient centers and randomized for CGMS-or CGMS/ KADIS-based decision support and followed up for 3 months. After two CGMS monitorings, the outcome parameters A1C (%), mean sensor glucose of the CGMS profile (MSG) (mmol/l), and duration of hyperglycemia (h/day) were evaluated. RESULTS-In contrast with the CGMS group (0.27 Ϯ 0.67%), mean change in A1C decreased in the CGMS/KADIS group during the follow-up (Ϫ0.34 Ϯ 0.49%; P Ͻ 0.01). MSG levels were not affected in the CGMS group (7.75 Ϯ 1.33 vs. 8.45 Ϯ 2.46 mmol/l) but declined in the CGMS/KADIS group (8.43 Ϯ 1.33 vs. 7.59 Ϯ 1.47 mmol/l; P Ͻ 0.05). Net KADIS effect (Ϫ0.60 [95% CI Ϫ0.96 to Ϫ 0.25%]; P Ͻ 0.01) was associated with reduced duration of hyperglycemia (4.6 vs. 1.0 h/day; P Ͻ 0.01) without increasing hypoglycemia. Multiple regression revealed that the A1C outcome was dependent on KADIS-based decision support. Age, sex, physician's specialty, diabetes type, and BMI had no measurable effect. CONCLUSIONS-If physicians were supported by CGMS/KADIS in therapeutic decisions, they achieved better glycemic control for their patients compared with support by CGMS alone. KADIS is a suitable decision support tool for physicians in outpatient diabetes care and has the potential to improve evidence-based management of diabetes.

Research paper thumbnail of Chronic hyperglycemia but not glucose variability determines HbA1c levels in well-controlled patients with type 2 diabetes

Diabetes Research and Clinical Practice, Sep 1, 2007

To determine the relationships between HbA1c, characteristics of hyperglycemia and glycemic varia... more To determine the relationships between HbA1c, characteristics of hyperglycemia and glycemic variability in well-controlled type 2 diabetes (HbA1c < 7.0%), we studied 63 primary-care patients (36 men and 27 women), aged 34-75 years, with type 2 diabetes for 2-32 years using a continuous glucose monitoring system (CGMS) and standardized meal test (MMT). Duration of hyperglycemia (>8.0 mmol/l), standard deviation score (S.D.-score) and mean amplitude of glycemic excursions (MAGE) were analyzed from CGMS data and postprandial glucose during MMT (PPG MMT). Patients were hyperglycemic for 5.7 h/day (median), experienced 4.1 hyperglycemic episodes/day, and 78% exceeded PPG levels of 8.0 mmol/l. HbA1c, though associated with the extent of hyperglycemia (r = 0.40, p < 0.001), failed to correlate with S.D.-score and MAGE. Multiple regression analysis demonstrated that HbA1c was predicted only by fasting glucose (R 2 = 0.24, p < 0.001) but neither by PPG MMT , duration of hyperglycemia, S.D.-score nor MAGE. CGMS and meal test provide the tools for complete characterization of glycemia in type 2 diabetes. In well-controlled type 2 diabetes, HbA1c correlates with chronic hyperglycemia but not with glucose variability. Our data suggest that chronic sustained hyperglycemia and glucose fluctuations are two independent components of dysglycemia in diabetes.

Research paper thumbnail of Einfluss einer chronischen Behandlung mit Leukozyten Dialysat (DLE) auf den glukoseintoleranten Stoffwechsel und die Entwicklung von strukturellen Veränderungen in pankreatischen Inseln von Zucker Ratten (fa/fa)

Diabetologie Und Stoffwechsel, 2006

Research paper thumbnail of Fraktionierung handelsüblichen insulins. Gewinnung und eigenschaften einer hochmolekularen, insulin-ähnlichen komponente

FEBS Letters, May 20, 1971

A component with high molecular weight is prepared from commercial bovine insulin by gel filtrati... more A component with high molecular weight is prepared from commercial bovine insulin by gel filtration on Sephadex G 50. The substance has little biological and immunological activity in comparison to insulin. The activity is not changed by incubation with trypsin. It associates in 1 M CH&OOH and possesses a molecular weight of 28,500 as shown by ultracentrifugation. The ability of the component to precipitate with bovine insulin antibodies demonstrates that it contains immunologically active insulin-like proteins and is not a homogenous substance.