Cornelia Haug

System Accuracy Evaluation of 27 Blood Glucose Monitoring Systems According to DIN EN ISO 15197

BACKGROUND Blood glucose (BG) monitoring systems enable diabetes patients to effectively control and adjust their therapy. BG monitoring systems with a Conformité Européenne (CE) label should meet the standard DIN EN ISO 15197:2003: > or =95% of the BG results shall fall within +/-15 mg/dL of the reference method at BG concentrations <75 mg/dL and within +/-20% at BG concentrations > or =75 mg/dL. We intended to verify if BG monitoring systems with a CE label fulfill these minimum accuracy requirements. METHODS We evaluated 27 BG monitoring systems from 18 manufacturers for system accuracy according to DIN EN ISO 15197:2003. Twenty-four systems were compared with the glucose oxidase reaction (YSI 2300 glucose analyzer [YSI Life Sciences, Yellow Springs, OH]) and three systems with the hexokinase reaction (Hitachi 917 [Roche Diagnostics GmbH, Mannheim, Germany]). Duplicate measurements of 100 blood samples with a defined distribution of BG concentrations from 20 mg/dL to 600 mg/dL from > or =100 subjects were included in the evaluation. RESULTS Sixteen of the 27 BG monitoring systems fulfilled the minimum accuracy requirements of the standard, i.e., > or =95% of their results showed the minimum acceptable accuracy. Overall, the mean percentage of results showing the minimum acceptable accuracy was 95.2 +/- 5.2%, ranging from 80.0% to 100.0%. CONCLUSIONS More than 40% of the evaluated BG monitoring systems did not fulfill the minimum accuracy requirements of DIN EN ISO 15197:2003. As inaccurate BG monitoring systems bear the risk of false treatment decisions by the diabetes patient and subsequent possible severe health injury, manufacturers should regularly and effectively check the quality of BG meters and BG test strips.

System Accuracy Evaluation of 43 Blood Glucose Monitoring Systems for Self-Monitoring of Blood Glucose according to DIN EN ISO 15197

Background: The accuracy of systems for self-monitoring of blood glucose is important, as reliable measurement results are a prerequisite for therapeutic decisions. Methods: This system accuracy evaluation study was performed according to DIN EN ISO 15197:2003 for 43 Conformité Européenne (CE)-labeled blood glucose (BG) monitoring systems. Measurement results of each system were compared with results of the designated comparison method (manufacturers measurement procedure): glucose oxidase method (YSI 2300 glucose analyzer) or hexokinase method (Hitachi 917/ cobas 501). Results: Complete assessment according to the International Organization for Standardization (ISO) standard was performed for 34 out of 43 systems, and 27 (79.4%) meet the requirements of the standard, i.e., ≥95% of their results showed at least the minimum acceptable accuracy. For 9 of the 43 systems, complete accuracy assessment was not performed due to an oxygen sensitivity (manufacturers labeling). The bias (according to Bland and Altman) of all 43 evaluated systems ranged from −14.1% to +12.4%. Conclusions: From the 34 systems completely assessed, 7 systems did not fulfill the minimal accuracy requirements of the ISO standard. The CE mark apparently does not guarantee that all BG systems provide accuracy according to the standard. Because inaccurate systems bear the risk of false therapeutic decisions, regular and standardized evaluation of BG meters and test strips should be requested in order to ensure adherence to quality standards.

Oxidized Low-Density Lipoproteins Stimulate Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Release by Coronary Smooth Muscle Cells

Objective—Matrix metalloproteinases (MMPs) seem to play a prominent role in atherogenesis. Extracellular MMP inducer (EMMPRIN), a cell surface glycoprotein which stimulates MMP synthesis, has recently been detected in human atheroma. We have investigated the influence of oxidized low-density lipoproteins (oxLDLs) on EMMPRIN expression in human coronary artery smooth muscle cells (HCA-SMCs). Methods and Results—OxLDL induced a significant increase of EMMPRIN release into HCA-SMC supernatants and a concomitant decrease of cell-associated EMMPRIN. These effects were antagonized by antioxidants as well as by EDTA and the MMP inhibitor GM6001. Western blot analysis demonstrated that MMP-1 and MMP-2 induce the cleavage of the extracellular domain from cell-associated EMMPRIN. MMP-1 and MMP-2 synthesis was upregulated by oxLDL, and, in addition, we have shown that soluble EMMPRIN, isolated from macrophage supernatants, increased MMP-1 and MMP-2 synthesis in HCA-SMC. Conclusion—Our data suggest that oxLDLs stimulate the release of soluble EMMPRIN, at least in part, by MMP-dependent shedding from the cell surface. Additionally, oxLDLs might induce a circular upregulation of matrix degradation because, in turn, soluble EMMPRIN stimulates MMP synthesis in HCA-SMC.

Lot-to-Lot Variability of Test Strips and Accuracy Assessment of Systems for Self-Monitoring of Blood Glucose according to ISO 15197

Background: Accurate and reliable blood glucose (BG) measurements require that different test strip lots of the same BG monitoring system provide comparable measurement results. Only a small number of studies addressing this question have been published. Methods: In this study, four test strip lots for each of five different BG systems [Accu-Chek® Aviva (system A), FreeStyle Lite® (system B), GlucoCheck XL (system C), Pura™/mylife™ Pura (system D), and OneTouch® Verio ™ Pro (system E)] were evaluated with procedures according to DIN EN ISO 15197:2003. The BG system measurement results were compared with the manufacturers measurement procedure (glucose oxidase or hexokinase method). Relative bias according to Bland and Altman and system accuracy according to ISO 15197 were analyzed. A BG system consists of the BG meter itself and the test strips. Results: The maximum lot-to-lot difference between any two of the four evaluated test strip lots per BG system was 1.0% for system E, 2.1% for system A, 3.1% for system C, 6.9% for system B, and 13.0% for system D. Only two systems (systems A and B) fulfill the criteria of DIN EN ISO 15197:2003 with each test strip lot. Conclusions: Considerable lot-to-lot variability between test strip lots of the same BG system was found. These variations add to other sources of inaccuracy with the specific BG system. Manufacturers should regularly and effectively check the accuracy of their BG meters and test strips even between different test strip lots to minimize risk of false treatment decisions.

Effect of rosiglitazone treatment on plaque inflammation and collagen content in nondiabetic patients: data from a randomized placebo-controlled trial.

Background—Therapeutic strategies to stabilize advanced arteriosclerotic lesions may prevent plaque rupture and reduce the incidence of acute coronary syndromes. Thiazolidinediones (TZDs), like rosiglitazone, are oral antidiabetic drugs with additional antiinflammatory and potential antiatherogenic properties. In a randomized, placebo-controlled, single-blind trial, we examined the effect of 4 weeks of rosiglitazone therapy on histomorphological characteristics of plaque stability in artery specimen of nondiabetic patients scheduled for elective carotid endarterectomy. Methods and Results—A total of 24 nondiabetic patients with symptomatic carotid artery stenosis were randomly assigned to rosiglitazone (4 mg BID) or placebo in addition to standard therapy. In this population of nondiabetic patients, rosiglitazone treatment did not significantly change fasting blood glucose, fasting insulin, or lipid parameters. In contrast, rosiglitazone significantly reduced CD4-lymphocyte content as well as macrophage HLA-DR expression in the shoulder region, reflecting less inflammatory activation of these cells by lymphocyte interferon-&ggr;. Moreover, rosiglitazone significantly increased plaque collagen content (7.7±1.6% versus 3.7±0.7% of plaque area; P=0.036) compared with placebo, suggesting that TZD treatment may stabilize arteriosclerotic lesions. In addition, rosiglitazone reduced serum levels of 2 inflammatory arteriosclerosis markers: C-reactive protein and serum amyloid A. Conclusions—Four weeks of treatment with rosiglitazone significantly reduces vascular inflammation in nondiabetic patients, leading to a more stable type of arteriosclerotic lesion.

Continuous Glucose Profiles in Healthy Subjects under Everyday Life Conditions and after Different Meals

Background: This study investigated continuous glucose profiles in nondiabetic subjects. Methods: Continuous interstitial glucose measurement was performed under everyday life conditions (2 days) and after ingestion of four meals with standardized carbohydrate content (50 grams), but with different types of carbohydrates and variable protein and fat content. Twenty-four healthy volunteers (12 female, 12 male, age 27.1 ± 3.6 years) participated in the study. Each subject wore two microdialysis devices (SCGM1, Roche Diagnostics) simultaneously. Results: The mean 24-hour interstitial glucose concentration under everyday life conditions was 89.3 ± 6.2 mg/dl (mean ± SD, n = 21), and mean interstitial glucose concentrations at daytime and during the night were 93.0 ± 7.0 and 81.8 ± 6.3 mg/dl, respectively. The highest postprandial glucose concentrations were observed after breakfast: 132.3 ± 16.7 mg/dl (range 101–168 mg/dl); peak concentrations after lunch and dinner were 118.2 ± 13.4 and 123.0 ± 16.9 mg/dl, respectively. Mean time to peak glucose concentration was between 46 and 50 minutes. After ingestion of standardized meals with fast absorption characteristics, peak interstitial glucose concentrations were 133.2 ± 14.4 and 137.2 ± 21.1 mg/dl, respectively. Meals with a higher fiber, protein, and fat content induced a smaller increase and a slower decrease of postprandial glucose concentrations with peak values of 99.2 ± 10.5 and 122.1 ± 20.4 mg/dl, respectively. Conclusions: This study provided continuous glucose profiles in nondiabetic subjects and demonstrated that differences in meal composition are reflected in postprandial interstitial glucose concentrations. Regarding the increasing application of continuous glucose monitoring in diabetic patients, these data suggest that detailed information about the ingested meals is important for adequate interpretation of postprandial glucose profiles.

Performance Evaluation of Three Continuous Glucose Monitoring Systems: Comparison of Six Sensors Per Subject in Parallel

Background: This study is aimed at comparing the performance of three continuous glucose monitoring (CGM) systems following the Clinical and Laboratory Standards Institutes POCT05-A guideline, which provides recommendations for performance evaluation of CGM systems. Methods: A total of 12 subjects with type 1 diabetes were enrolled in this study. Each subject wore six CGM systems in parallel, two sensors of each CGM system [FreeStyle Navigator™ (Navigator), MiniMed Guardian® REAL-Time with Enlite sensor (Guardian), DexCom™ Seven® Plus 3rd generation (Seven Plus)]. Each sensor was used for the lifetime specified by the manufacturer. To follow POCT05-A recommendations, glucose excursions were induced on two separate occasions, and venous and capillary blood glucose (BG) concentrations were obtained every 15 min for five consecutive hours. Capillary BG concentrations were measured at least once per hour during the day and once at night. Parameters investigated were CGM-to-BG differences [mean absolute relative difference (MARD)] and sensor-to-sensor differences [precision absolute relative difference (PARD)]. Results: Compared with capillary BG reference readings, the Navigator showed the lowest MARD, with 12.1% overall and 24.6% in the hypoglycemic range; for the Guardian and the Seven Plus, MARD was 16.2%/34.9% and 16.3%/32.7%, respectively. PARD also was lowest for the Navigator (9.6%/9.8%), followed by the Seven Plus (16.7%/25.5%) and the Guardian (18.1%/20.2%). During induced glucose excursions, MARD between CGM and BG was, again, lowest for the Navigator (14.3%), followed by the Seven Plus (15.8%) and the Guardian (19.2%). Conclusions: In this study, two sensors of each of the three CGM systems were compared in a setting following POCT05-A recommendations. The Navigator CGM system achieved more accurate results than the Guardian or the Seven Plus with respect to MARD and PARD. Performance in the hypoglycemic range was markedly worse for all CGM systems when compared with BG results.

Depending on their concentration oxidized low density lipoproteins stimulate extracellular matrix synthesis or induce apoptosis in human coronary artery smooth muscle cells.

Abstract Various lines of evidence indicate that oxidative stress resulting in lipid peroxidation and protein modification is involved in the pathogenesis of atherosclerosis and coronary heart disease. We have investigated the effect of modified (oxidized) low-density lipoproteins (oxLDL) on collagen and fibronectin synthesis in cultured human coronary artery smooth muscle cells (HCA-SMC). As shown by immunofluorescence microscopy and time-resolved fluorescence immunoassay, oxLDL dose-dependently stimulated collagen type I and fibronectin synthesis in cultured HCA-SMC. The effect on matrix synthesis was biphasic, with a maximum effect at concentrations between 1 and 10 μg/ml oxLDL. Higher oxLDL concentrations (>25 μg/ml) were cytotoxic. Beside oxLDL, malondialdehyde-modified LDL also stimulated extracellular matrix synthesis. In the presence of 100 μg/ml ascorbic acid, 25, 50 and 100 μg/ml oxLDL induced apoptosis within 6–8 hours (demonstrated by TUNEL-reaction, annexin-V binding and APO-2.7-expression). Apoptosis was not induced by normal (unmodified) LDL and malondialdehyde-modified LDL. The radical scavengers and antioxidants TROLOX and probucol and the hydrogen peroxide eliminator catalase significantly reduced oxLDL-induced apoptosis. Our results demonstrate that low concentrations of oxLDL are profibrogenic by stimulating extracellular matrix synthesis, whereas higher oxLDL concentrations induce oxidative stress and apoptosis in coronary artery smooth muscle cells. The profibrogenic effect might be relevant in the formation of atherosclerotic plaques, and the proapoptotic effect might contribute to an increased plaque vulnerability.

Evaluation of the Performance of a Novel System for Continuous Glucose Monitoring

Background: The performance of a continuous glucose monitoring (CGM) system in the early stage of development was assessed in an inpatient setting that simulates daily life conditions of people with diabetes. Performance was evaluated at low glycemic, euglycemic, and high glycemic ranges as well as during phases with rapid glucose excursions. Methods: Each of the 30 participants with type 1 diabetes (15 female, age 47 ± 12 years, hemoglobin A1c 7.7% ± 1.3%) wore two sensors of the prototype system in parallel for 7 days. Capillary blood samples were measured at least 16 times per day (at least 15 times per daytime and at least once per night). On two subsequent study days, glucose excursions were induced. For performance evaluation, the mean absolute relative difference (MARD) between CGM readings and paired capillary blood glucose readings and precision absolute relative difference (PARD), i.e., differences between paired CGM readings were calculated. Results: Overall aggregated MARD was 9.2% and overall aggregated PARD was 7.5%. During induced glucose excursions, MARD was 10.9% and PARD was 7.8%. Lowest MARD (8.5%) and lowest PARD (6.4%) were observed in the high glycemic range (euglycemic range, MARD 9.1% and PARD 7.4%; low glycemic range, MARD 12.3% and PARD 12.4%). Conclusions: The performance of this prototype CGM system was, particularly in the hypoglycemic range and during phases with rapid glucose fluctuations, better than performance data reported for other commercially available systems. In addition, performance of this prototype sensor was noticeably constant over the whole study period. This prototype system is not yet approved, and performance of this CGM system needs to be further assessed in clinical studies.

Clinical Performance of Three Bolus Calculators in Subjects with Type 1 Diabetes Mellitus: A Head-to-Head-to-Head Comparison

BACKGROUND Insulin pump systems now provide automated bolus calculators (ABCs) that electronically calculate insulin boluses to address carbohydrate intake and out-of-range blood glucose (bG) levels. We compared the efficacy of three ABCs (Accu-Chek(®) Combo [Roche Insulin Delivery Systems (IDS), Inc., Fishers, IN, a member of the Roche Group], Animas(®) 2020 [Animas Corp., West Chester, PA, a Johnson and Johnson company], and MiniMed Paradigm Bolus Wizard(®) [Medtronic MiniMed, Northridge, CA]) to safely reduce postprandial hyperglycemia in type 1 diabetes mellitus (T1DM). METHODS T1DM subjects (n = 24) were recruited at a single center for a prospective, triple crossover study. ABCs with the programmed target range (80-140 mg/dL) were used in random order. Postprandial hyperglycemia was induced by reducing the calculated bolus by 25%. Two hours after test meals, the ABCs were allowed to determine whether a correction bolus was needed. Differences between 6-h bG values after test meals that achieved 2-h postprandial hyperglycemia and the mean of the target range (110 mg/dL) were determined. RESULTS The mean difference between 6-h bG levels following test meals and the 110 mg/dL bG target with the MiniMed device (47.4 ± 31.8 mg/dL) was significantly higher than the Animas (17.3 ± 30.9 mg/dL) and Roche IDS (18.8 ± 33.8 mg/dL) devices (P = 0.0022 and P = 0.0049, respectively). The number of meals with 2-h postprandial hyperglycemia and bG levels at 2 h was similar. Roche IDS and Animas devices recommended correction boluses significantly (P = 0.0001 and P = 0.0002, respectively) more frequently than the MiniMed device. ABC use was not associated with severe hypoglycemia. There was no significant difference in the rate of mild hypoglycemia (bG <60 mg/dL not requiring assistance) among the three groups (Roche IDS and Animas, n = 2; MiniMed, n = 0). CONCLUSIONS In this study, the Roche IDS and Animas devices were more efficacious in controlling postprandial hyperglycemia than the MiniMed device. This may be due, in part, to differences in ABC setup protocols and algorithms. Use of ABCs can assist in controlling postprandial glycemia without significant hypoglycemia.