Q-Score Complements the Time in Range in the Evaluation of Short-Term Glycemic Control.

BACKGROUND AND AIMS: The Q-Score is a single-number composite metric that is constructed based on the following components: central glycemic tendency, hyperglycemia, hypoglycemia, and intra- and interday variability. Herein, we refined the Q-Score for the screening and analysis of short-term glycemic control using continuous glucose monitoring (CGM) profiles. METHODS: Continuous glucose monitoring profiles were obtained from noninterventional, retrospective cross-sectional studies. The upper limit of the Q-Score component hyperglycemia' that is, the time above target range (TAR), was adjusted from 8.9 to 10 mmol/L (n = 1562 three-day-sensor profiles). A total of 302 people with diabetes mellitus treated with intermittent CGM for ≥14 days were enrolled. The time to stability was determined via correlation-based analysis. RESULTS: There was a strong correlation between the Q-Scores of the two TARs, that is, 8.9 and 10 mmol/L (Q-ScoreTAR10 = -0.03 + 1.00 Q-ScoreTAR8.9, r = .997, p < .001). The times to stability of the Q-Score and TIR were 10 and 12 days, respectively. The Q-Score was correlated with fructosamine concentrations, the glucose management indicator (GMI), the time in range (TIR), and the glycemic risk index (GRI) (r = .698, .887, -.874, and .941), respectively. The number of Q-Score components above the target increased as the TIR decreased, from two (1.7 ± 0.9) in CGM profiles with a TIR between 70% and 80% to four (3.9 ± 0.5) in the majority of the CGM profiles with a TIR below 50%. A conversion matrix between the Q-Score and glycemic indices was developed. CONCLUSIONS: The Q-Score is a tool for assessing short-term glycemic control. The Q-Score can be translated into clinician opinion using the GRI.

Patient-Tailored Decision Support System Improves Short- and Long-Term Glycemic Control in Type 2 Diabetes.

BACKGROUND: The increasing prevalence of type 2 diabetes mellitus (T2D) and specialist shortage has caused a healthcare gap that can be bridged by a decision support system (DSS). We investigated whether a diabetes DSS can improve long- and/or short-term glycemic control. METHODS: This is a retrospective observational cohort study of the Diabetiva program, which offered a patient-tailored DSS using Karlsburger Diabetes-Management System (KADIS) once a year. Glycemic control was analyzed at baseline and after 12 months in 452 individuals with T2D. Time in range (TIR; glucose 3.9-10 mmol/L) and Q-Score, a composite metric developed for analysis of continuous glucose profiles, were short-term and HbA1c long-term measures of glycemic control. Glucose variability (GV) was also measured. RESULTS: At baseline, one-third of patients had good short- and long-term glycemic control. Q-Score identified insufficient short-term glycemic control in 17.9% of patients with HbA1c <6.5%, mainly due to hypoglycemia. GV and hyperglycemia were responsible in patients with HbA1c >7.5% and >8%, respectively. Application of DSS at baseline improved short- and long-term glycemic control, as shown by the reduced Q-Score, GV, and HbA1c after 12 months. Multiple regression demonstrated that the total effect on GV resulted from the single effects of all influential parameters. CONCLUSIONS: DSS can improve short- and long-term glycemic control in individuals with T2D without increasing hypoglycemia. The Q-Score allows identification of individuals with insufficient glycemic control. An effective strategy for therapy optimization could be the selection of individuals with T2D most at need using the Q-Score, followed by offering patient-tailored DSS.

Applications of Variability Analysis Techniques for Continuous Glucose Monitoring Derived Time Series in Diabetic Patients.

Methods from non-linear dynamics have enhanced understanding of functional dysregulation in various diseases but received less attention in diabetes. This retrospective cross-sectional study evaluates and compares relationships between indices of non-linear dynamics and traditional glycemic variability, and their potential application in diabetes control. Continuous glucose monitoring provided data for 177 subjects with type 1 (n = 22), type 2 diabetes (n = 143), and 12 non-diabetic subjects. Each time series comprised 576 glucose values. We calculated Poincaré plot measures (SD1, SD2), shape (SFE) and area of the fitting ellipse (AFE), multiscale entropy (MSE) index, and detrended fluctuation exponents (α1, α2). The glycemic variability metrics were the coefficient of variation (%CV) and standard deviation. Time of glucose readings in the target range (TIR) defined the quality of glycemic control. The Poincaré plot indices and α exponents were higher (p < 0.05) in type 1 than in the type 2 diabetes; SD1 (mmol/l): 1.64 ± 0.39 vs. 0.94 ± 0.35, SD2 (mmol/l): 4.06 ± 0.99 vs. 2.12 ± 1.04, AFE (mmol2/l2): 21.71 ± 9.82 vs. 7.25 ± 5.92, and α1: 1.94 ± 0.12 vs. 1.75 ± 0.12, α2: 1.38 ± 0.11 vs. 1.30 ± 0.15. The MSE index decreased consistently from the non-diabetic to the type 1 diabetic group (5.31 ± 1.10 vs. 3.29 ± 0.83, p < 0.001); higher indices correlated with lower %CV values (r = -0.313, p < 0.001). In a subgroup of type 1 diabetes patients, insulin pump therapy significantly decreased SD1 (-0.85 mmol/l), SD2 (-1.90 mmol/l), and AFE (-16.59 mmol2/l2), concomitantly with %CV (-15.60). The MSE index declined from 3.09 ± 0.94 to 1.93 ± 0.40 (p = 0.001), whereas the exponents α1 and α2 did not. On multivariate regression analyses, SD1, SD2, SFE, and AFE emerged as dominant predictors of TIR (ß = -0.78, -1.00, -0.29, and -0.58) but %CV as a minor one, though α1 and MSE failed. In the regression models, including SFE, AFE, and α2 (ß = -0.32), %CV was not a significant predictor. Poincaré plot descriptors provide additional information to conventional variability metrics and may complement assessment of glycemia, but complexity measures produce mixed results.

Characterization of the Human Pancreas Side Population as a Potential Reservoir of Adult Stem Cells.

OBJECTIVES: The side population (SP) contains cells with stem cell/progenitor properties. Previously, we observed that the mouse pancreas SP expanded after pancreatic injury. We aimed to characterize the SP in human pancreas as a potential source of stem cells. METHODS: Human organ donor pancreata were fractionated into islets and exocrine tissue, enriched by tissue culture and dispersed into single cells. Cells were phenotyped by flow cytometry, and the SP was defined by efflux of fluorescent dye Hoechst 33342 visualized by ultraviolet excitation. Cells were flow sorted, and their colony-forming potential measured on feeder cells in culture. RESULTS: An SP was identified in islet and exocrine cells from human organ donors: 2 with type 1 diabetes, 3 with type 2 diabetes, and 28 without diabetes. Phenotyping revealed that exocrine SP cells had an epithelial origin, were enriched for carbohydrate antigen 19-9 ductal cells expressing stem cell markers CD133 and CD26, and had greater colony-forming potential than non-SP cells. The exocrine SP was increased in a young adult with type 1 diabetes and ongoing islet autoimmunity. CONCLUSIONS: The pancreatic exocrine SP is a potential reservoir of adult stem/progenitor cells, consistent with previous evidence that such cells are duct-derived and express CD133.

Localization of dipeptidyl peptidase-4 (CD26) to human pancreatic ducts and islet alpha cells.

AIM: DPP-4/CD26 degrades the incretins GLP-1 and GIP. The localization of DPP-4 within the human pancreas is not well documented but is likely to be relevant for understanding incretin function. We aimed to define the cellular localization of DPP-4 in the human pancreas from cadaveric organ donors with and without diabetes. METHODS: Pancreas was snap-frozen and immunoreactive DPP-4 detected in cryosections using the APAAP technique. For co-localization studies, pancreas sections were double-stained for DPP-4 and proinsulin or glucagon and scanned by confocal microscopy. Pancreata were digested and cells in islets and in islet-depleted, duct-enriched digests analyzed for expression of DPP-4 and other markers by flow cytometry. RESULTS: DPP-4 was expressed by pancreatic duct and islet cells. In pancreata from donors without diabetes or with type 2 diabetes, DPP-4-positive cells in islets had the same location and morphology as glucagon-positive cells, and the expression of DPP-4 and glucagon overlapped. In donors with type 1 diabetes, the majority of residual cells in islets were DPP-4-positive. CONCLUSION: In the human pancreas, DPP-4 expression is localized to duct and alpha cells. This finding is consistent with the view that DPP-4 regulates exposure to incretins of duct cells directly and of beta cells indirectly in a paracrine manner.

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

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 patient-tailored therapies.

Declining ß-cell function is associated with the lack of long-range negative correlation in glucose dynamics and increased glycemic variability: A retrospective analysis in patients with type 2 diabetes.

OBJECTIVE: To determine whether characteristics of glucose dynamics are reflections of ß-cell function or rather of inadequate diabetes control. MATERIALS/METHODS: We analyzed historical liquid meal tolerance test (LMTT) and continuous glucose monitoring (CGM) data, which had been obtained from 56 non-insulin treated type 2 diabetic outpatients during withdrawal of antidiabetic drugs. Computed CGM parameters included detrended fluctuation analysis (DFA)-based indices, autocorrelation function exponent, mean amplitude of glycemic excursions (MAGE), glucose SD, and measures of glycemic exposure. The LMTT-based disposition index (LMTT-DI) calculated from the ratio of the area-under-the-insulin-curve to the area-under-the-glucose-curve and Matsuda index was used to assess relationships among ß-cell function, glucose profile complexity, autocorrelation function, and glycemic variability. RESULTS: The LMTT-DI was inverse linearly correlated with the short-range α1 and long-range scaling exponent α2 (r = -0.275 and -0.441, respectively, p < 0.01) such that lower glucose complexity was associated with better preserved insulin reserve, but it did not correlate with the autocorrelation decay exponent γ. By contrast, the LMTT-DI was strongly correlated with MAGE and SD (r = 0.625 and 0.646, both p < 0.001), demonstrating a curvilinear relationship between ß-cell function and glycemic variability. On stepwise regression analyses, the LMTT-DI emerged as an independent contributor, explaining 20, 38, and 47% (all p < 0.001) of the variance in the long-range DFA scaling exponent, MAGE, and hemoglobin A1C, respectively, whereas insulin sensitivity failed to contribute independently. CONCLUSIONS: Loss of complexity and increased variability in glucose profiles are associated with declining ß-cell reserve and worsening glycemic control.

Antigen-based vaccination and prevention of type 1 diabetes.

Insulin-dependent or type 1 diabetes (T1D) is a paradigm for prevention of autoimmune disease: Pancreatic ß-cell autoantigens are defined, at-risk individuals can be identified before the onset of symptoms, and autoimmune diabetes is preventable in rodent models. Intervention in asymptomatic individuals before or after the onset of subclinical islet autoimmunity places a premium on safety, a requirement met only by lifestyle-dietary approaches or autoantigen-based vaccination to induce protective immune tolerance. Insulin is the key driver of autoimmune ß-cell destruction in the nonobese diabetic (NOD) mouse model of T1D and is an early autoimmune target in children at risk for T1D. In the NOD mouse, mucosal administration of insulin induces regulatory T cells that protect against diabetes. The promise of autoantigen-specific vaccination in humans has yet to be realized, but recent trials of oral and nasal insulin vaccination in at-risk humans provide grounds for cautious optimism.

Evaluation of the mean absolute glucose change as a measure of glycemic variability using continuous glucose monitoring data.

BACKGROUND: The mean absolute glucose (MAG) change, originally developed to assess associations between glycemic variability (GV) and intensive care unit mortality, has not yet been validated. We used continuous glucose monitoring (CGM) datasets from patients with diabetes to assess the validity of MAG and to quantify associations with established measures of GV. SUBJECTS AND METHODS: Validation was based on retrospective analysis of 72-h CGM data collected during clinical studies involving 815 outpatients (48 with type 1 diabetes and 767 with type 2 diabetes). Measures of GV included SD around the sensor glucose, interquartile range, mean amplitude of glycemic excursions, and the continuous overlapping net glycemic action indices at 1, 3, and 6 h. MAG was calculated using 5-min, 60-min, and seven-point glucose profile sampling intervals; correlations among the variability measures and effects of sampling frequency were assessed. RESULTS: Strong linear correlations between MAG change and classical markers of GV were documented (r=0.587-0.809, P<0.001 for all), whereas correlations with both glycosylated hemoglobin and mean sensor glucose were found to be weak (r=0.246 and r=0.378, respectively). The magnitude of MAG change decreased in a nonlinear fashion (P<0.001), as intervals between glucose measurements increased. MAG change, as calculated from 5-min sensor glucose readings, did reflect relatively small differences in glucose fluctuations associated with glycemic treatment modality. CONCLUSIONS: MAG change represents a valid GV index if closely spaced sensor glucose measurements are used, but does not provide any advantage over variability indices already used for assessing diabetes control.

The Karlsburg Diabetes Management System: translation from research to eHealth application.

BACKGROUND: Several telemedicine-based eHealth programs exist, but patient-focused personalized decision support (PDS) is usually lacking. We evaluated the acceptance, efficiency, and cost-effectiveness of telemedicine-assisted PDS in routine outpatient diabetes care. METHODS: Data are derived from the Diabetiva® program of the German health insurance company BKK TAUNUS. Diabetiva offers telemedicine-based outpatient health care in combination with PDS generated by the Karlsburg Diabetes Management System, KADIS®. This retrospective analysis is based on data from the first year of running KADIS-based PDS in routine diabetes care. Participants were insured persons diagnosed with diabetes and cardiovascular diseases. For final analysis, patients were grouped retrospectively as users or nonusers according to physician acceptance or not (based on questionnaires) of the KADIS-based PDS. RESULTS: A total of 538 patients participated for more than one year in the Diabetiva program. Of these patients, 289 had complete data sets (two continuous glucose monitoring measurements, two or more hemoglobin A1c (HbA1c) values, and a signed questionnaire) and were included in the final data analysis. Of the physicians, 74% accepted KADIS-based PDS, a rate that was clearly related to HbA1c at the beginning of the observation. If KADIS-based PDS was accepted, HbA1c decreased by 0.4% (7.1% to 6.7%). In contrast, rejection of KADIS-based PDS resulted in an HbA1c increase of 0.5% (6.8% to 7.3%). The insurance company revealed an annual cost reduction of about 900 € per participant in the Diabetiva program. CONCLUSIONS: KADIS-based PDS in combination with telemedicine has high potential to improve the outcome of routine outpatient diabetes care.

Translation of personalized decision support into routine diabetes care.

OBJECTIVE: The aim of this study was to evaluate the impact of personalized decision support (PDS) on metabolic control in people with diabetes and cardiovascular disease. RESEARCH DESIGN AND METHODS: The German health insurance fund BKK TAUNUS offers to its insured people with diabetes and cardiovascular disease the possibility to participate in the Diabetiva® program, which includes PDS. Personalized decision support is generated by the expert system KADIS® using self-control data and continuous glucose monitoring (CGM) as its data source. The physician of the participating person receives the PDS once a year, decides about use or nonuse, and reports his/her decision in a questionnaire. Metabolic control of participants treated by use or nonuse of PDS for one year and receiving CGM twice was analyzed in a retrospective observational study. The primary outcome was hemoglobin A1c (HbA1c); secondary outcomes were mean sensor glucose (MSG), glucose variability, and hypoglycemia. RESULTS: A total of 323 subjects received CGM twice, 289 had complete data sets, 97% (280/289) were type 2 diabetes patients, and 74% (214/289) were treated using PDS, resulting in a decrease in HbA1c [7.10±1.06 to 6.73±0.82%; p<.01; change in HbA1ct0-t12 months -0.37 (95% confidence interval -0.46 to -0.28)] and MSG (7.7±1.6 versus 7.4±1.2 mmol/liter; p=.003) within one year. Glucose variability was also reduced, as indicated by lower high blood glucose index (p=.001), Glycemic Risk Assessment Diabetes Equation (p=.009), and time of hyper-glycemia (p=.003). Low blood glucose index and time spent in hypoglycemia were not affected. In contrast, nonuse of PDS (75/289) resulted in increased HbA1c (p<.001). Diabetiva outcome was strongly related to baseline HbA1c (HbA1ct0; p<.01) and use of PDS (p<.01). Acceptance of PDS was dependent on HbA1ct0 (p=.049). CONCLUSIONS: Personalized decision support has potential to improve metabolic outcome in routine diabetes care.

Morphology of pancreatic islets: a time course of pre-diabetes in Zucker fatty rats.

The Zucker fatty rat (fa/fa; ZR) is considered as a model for pre-diabetes, as characterised by a genetic defect in the leptin receptor, which results in hyperphagia, insulin resistance, hyperinsulinaemia, hyperlipoproteinaemia, and obesity. These animals become glucose intolerant but do not develop type 2 diabetes. As a consequence of increased adiposity and insulin resistance, the endocrine pancreas of ZR undergoes adaptive and compensatory changes. Measurements of the time course of the pathological changes by the histological analysis of the pancreatic islet in combination with metabolic parameters are an effective way to reveal disease progression. A loss in glucose tolerance occurs in ZR by 10 weeks of age and progressively worsens by 19 weeks of age. This process is accompanied by impaired islet histology, changes of beta-cell mass, and impaired islet function. The early expression of insulin resistance and glucose intolerance in ZR results in morphological and functional changes of pancreatic islets despite their capability to maintain normoglycaemia.

Glycemic variability correlates strongly with postprandial beta-cell dysfunction in a segment of type 2 diabetic patients using oral hypoglycemic agents.

OBJECTIVE: Glucose fluctuations trigger activation of oxidative stress, a main mechanism leading to secondary diabetes complications. We evaluated the relationship between glycemic variability and beta-cell dysfunction. RESEARCH DESIGN AND METHODS: We conducted a cross-sectional study in 59 patients with type 2 diabetes (aged 64.2 +/- 8.6 years, A1C 6.5 +/- 1.0%, and BMI 29.8 +/- 3.8 kg/m(2)[mean +/- SD]) using either oral hypoglycemic agents (OHAs) (n = 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, beta-cell function, and clinical parameters were assessed by including postprandial beta-cell function (PBCF) and basal beta-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 = 0.54, P < 0.001) and with BBCF (r = 0.31, P = 0.025) in OHA users but failed to correlate with these parameters in nonusers (PBCF P = 0.21 and BBCF P = 0.07). The stepwise multiple regression analysis demonstrated that PBCF and OHA combination treatment were independent contributors to MAGE (R(2) = 0.50, P < 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.

Dominance of cytokine- over FasL-induced impairment of the mitochondrial transmembrane potential (Deltapsim) in the pancreatic beta-cell line NIT-1.

Mitochondria of pancreatic beta-cells are potential targets of intrinsic and extrinsic apoptotic pathways in the autoimmune pathogenesis of type 1 diabetes. We aimed to investigate whether cytokine- and FasLigand (FasL)-induced apoptosis is associated with impaired mitochondrial transmembrane potential (Deltapsim) in the pancreatic beta-cell line NIT-1. NIT-1 cells were exposed to the interleukin-1beta/interferon-gamma (IL-1beta/IFN-gamma) cytokine combination to induce apoptosis in vitro. Low concentrations of cytokines resulted in Deltapsim impairment, and increasing concentrations had only a minor additional effect. Treatment with the inducible nitric oxide synthase (iNOS) inhibitor Nw-nitro-L-arginine methyl ester hydrochloride (L-NAME) prevented cytokine-mediated Deltapsim impairment, implying that cytokines affect Deltapsim via nitric oxide. The broad-spectrum caspase inhibitor Z-VAD(Ome)-FMK (ZVAD) revealed dichotomic actions. In the presence of ZVAD, cytokine-induced nitrite generation was increased but cell death and Deltapsim impairment were reduced. Deltapsim impairment was also reduced by inhibitors of caspases 1, 6 and 8. Induction of Fas by IL-1beta/IFN-gamma coupled with activation by Super-FasL augmented cytokine-induced cell death. We observed a clear dominance of cytokine- over FasL-induced effects on Deltapsim. Our findings show that IL-1beta/IFN-gamma cytokines have a strong effect to impair Deltaym and prime beta-cells for apoptosis via the intrinsic pathway mediated by iNOS and caspases. Furthermore, at least in NIT-1 cells, the extrinsic FasL/Fas pathway has only a minor additive effect on cytokine-induced Deltapsim impairment.

Outpatient assessment of Karlsburg Diabetes Management System-based decision support.

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 = 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 +/- 0.67%), mean change in A1C decreased in the CGMS/KADIS group during the follow-up (-0.34 +/- 0.49%; P < 0.01). MSG levels were not affected in the CGMS group (7.75 +/- 1.33 vs. 8.45 +/- 2.46 mmol/l) but declined in the CGMS/KADIS group (8.43 +/- 1.33 vs. 7.59 +/- 1.47 mmol/l; P < 0.05). Net KADIS effect (-0.60 [95% CI -0.96 to - 0.25%]; P < 0.01) was associated with reduced duration of hyperglycemia (4.6 vs. 1.0 h/day; P < 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.

Chronic hyperglycemia but not glucose variability determines HbA1c levels in well-controlled patients with type 2 diabetes.

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 5.7h/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.

Telemedicine-based KADIS combined with CGMS has high potential for improving outpatient diabetes care.

BACKGROUND: The Karlsburg Diabetes Management System (KADIS) was developed over almost two decades by modeling physiological glucose-insulin interactions. When combined with the telemedicine-based communication system TeleDIAB and a continuous glucose monitoring system (CGMS), KADIS has the potential to provide effective, evidence-based support to doctors in their daily efforts to optimize glycemic control. METHODS: To demonstrate the feasibility of improving diabetes control with the KADIS system, an experimental version of a telemedicine-based diabetes care network was established, and an international, multicenter, pilot study of 44 insulin-treated patients with type 1 and 2 diabetes was performed. Patients were recruited from five outpatient settings where they were treated by general practitioners or diabetologists. Each patient underwent CGMS monitoring under daily life conditions by a mobile monitoring team of the Karlsburg diabetes center at baseline and 3 months following participation in the KADIS advisory system and telemedicine-based diabetes care network. The current metabolic status of each patient was estimated in the form of an individualized "metabolic fingerprint." The fingerprint characterized glycemic status by KADIS-supported visualization of relationships between the monitored glucose profile and causal endogenous and exogenous factors and enabled evidence-based identification of "weak points" in glycemic control. Using KADIS-based simulations, physician recommendations were generated in the form of patient-centered decision support that enabled elimination of weak points. The analytical outcome was provided in a KADIS report that could be accessed at any time through TeleDIAB. The outcome of KADIS-based support was evaluated by comparing glycosylated hemoglobin (HbA1c) levels and 24-hour glucose profiles before and after the intervention. RESULTS: Application of KADIS-based decision support reduced HbA1c by 0.62% within 3 months. The reduction was strongly related to the level of baseline HbA1c, diabetes type, and outpatient treatment setting. The greatest benefit was obtained in the group with baseline HbA1c levels >9% (1.22% reduction), and the smallest benefit was obtained in the group with baseline HbA1c levels of 6-7% (0.13% reduction). KADIS was more beneficial for patients with type 1 diabetes (0.79% vs 0.48% reduction) and patients treated by general practitioners (1.02% vs 0.26% reduction). Changes in HbA1c levels were paralleled by changes in mean daily 24-hour glucose profiles and fluctuations in daily glucose. CONCLUSION: Application of KADIS in combination with CGMS and the telemedicine-based communication system TeleDIAB successfully improved outpatient diabetes care and management.

Cytokines activate caspase-3 in insulinoma cells of diabetes-prone NOD mice directly and via upregulation of Fas.

In type 1 diabetes, autoimmune inflammation of pancreatic islets of Langerhans ('insulitis') results in destruction of insulin-producing beta cells. Cytokines released from islet-infiltrating mononuclear cells are known to be cytotoxic both directly and by upregulating Fas for FasL-induced apoptosis. To investigate the role of caspase-3, a major effector of apoptosis in beta-cell death, we asked whether cytokine- and/or FasL-induced apoptosis was associated with increased activity of caspase-3 in NIT-1 insulinoma cells and islets of autoimmune diabetes-prone NOD mice. Measurement of caspase-3 activity using a fluorogenic cleavage assay was validated in NOD mouse thymocytes undergoing dexamethasone (Dex)-induced apoptosis. For cytokine-induced apoptosis, NIT-1 cells or islets were exposed to IL-1 beta and IFN-gamma for 24 h. Caspase-3-like activity was increased 2.1+/-0.7 and 2.4+/-0.9-fold in lysates of cytokine-treated NIT-1 cells and NOD mouse islets, respectively. However, NIT-1 cells exhibited 2.1% (4.7 pg active caspase-3/microg protein) and islets 0.8% (1.9 pg active caspase-3/microg protein) of the active caspase-3 content observed in Dex-treated thymocytes (225.1 pg active caspase-3/microg protein). After 24 h cytokine-exposure, the percentage of Fas-positive NIT-1 cells increased from 1.4+/-1.1 to 29.7+/-11.6%. Addition of FasL for a further 3 h increased caspase-3-like activity an additional 1.8-fold in cytokine-treated NIT-1 cells. In summary, exposure of NOD mouse insulinoma cells or islets to IL-1 beta and IFN-gamma for 24 h induced caspase-3-like activity that, in the case of insulinoma cells at least, can be further enhanced by interaction of cytokine-induced Fas receptor with FasL. Compared to thymocytes, insulinoma cells and islets from NOD mice were characterised by low basal and cytokine-induced caspase-3 activity.

IL-1beta, IFN-gamma and TNF-alpha increase vulnerability of pancreatic beta cells to autoimmune destruction.

In the pathogenesis of type-1 diabetes insulin-producing beta-cells are destroyed by cellular autoimmune processes. The locality of beta-cell destruction is the inflamed pancreatic islet. During insulitis cytokines released from islet-infiltrating mononuclear cells affect beta-cells at several levels. We investigated whether cytokine-induced beta-cell destruction is associated with changes in the expression of the surface receptors intercellular adhesion molecule (ICAM)-1 and Fas. Islets from diabetes-prone and congenic diabetes-resistant BB rats were exposed to interleukin (IL)-1beta alone or in combination with interferon (IFN)-gamma plus tumour necrosis factor (TNF)-alpha. Cytokines decreased islet insulin content, suppressed glucose stimulated insulin secretion and generated enhanced amounts of nitric oxide and DNA-strand breaks. While no membrane alterations of IL-1beta treated islets cells were detectable, the cytokine combination caused damage of cell membranes. Independent of diabetes susceptibility IL-1beta treated islet beta-cells expressed a significantly increased amount of ICAM-1 on their surfaces which was not further increased by IFN-gamma+TNF-alpha. However, IL-1beta induced Fas expression was significantly enhanced only on beta-cells from diabetes-prone BB rats. From these results we suggest that IL-1beta mediates the major stimulus for ICAM-1 induction which is possibly a necessary but not sufficient step in the process of beta-cell destruction. Obviously, the additional enhancement of Fas expression on the surface of beta-cells is important for destruction. The combined action of all three cytokines induced the expression of Fas on the beta-cell surface independent of diabetes susceptibility, indicating that such a strong stimulus in vitro may induce processes different from the precise mechanisms of beta-cell destruction in vivo.

Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide.

Insulin is a major target of the autoimmune response associated with destruction of pancreatic beta cells in type 1 diabetes. A peptide that spans the junction of the insulin B chain and the connecting (C) peptide in proinsulin has been reported to stimulate T cells from humans at risk for type 1 diabetes and autoimmune diabetes-prone NOD mice. Here we show that proinsulin B24-C36 peptide binds to I-A(g7), the MHC class II molecule of the NOD mouse, and, after intranasal administration, induces regulatory CD4(+) T cells that, in the absence of CD8(+) T cells, block the adoptive transfer of diabetes. Curiously, however, intranasal B24-C36 did not inhibit development of spontaneous diabetes in treated mice. We then determined that B24-C36, and its core sequence B25-C34, bind to K(d), the NOD mouse MHC class I molecule, and elicit CD8(+) CTLs. When the CD8(+) T lymphocyte epitope was truncated at the C34 valine anchor residue for binding to K(d), the residual CD4(+) T cell epitope, B24-C32/33, significantly inhibited diabetes development after a single intranasal dose. This study identifies a novel CTL epitope in proinsulin and demonstrates that the therapeutic potential of a "tolerogenic" autoantigen peptide can be compromised by the presence of an integral CTL epitope.