Considerations for an institution for evaluation of diabetes technology devices to improve their quality in the European Union.

All medical devices used for self-monitoring of blood glucose (BG), insulin injection, continuous subcutaneous insulin infusion, and continuous glucose monitoring in the European Union (EU) must have a Communauté Européenne (CE) mark. However, the approval process for obtaining this mark is different from that used by the European Medicines Agency in the EU for drugs or by the Food and Drug Administration in the United States for such medical and in vitro diagnostic devices. The notified bodies involved in the CE mark process perform this evaluation in cooperation with the manufacturers. They have only limited diabetes know-how; they have to handle all kinds of medical devices. There are devices for therapy on the market in the EU (i.e., they have market approval) that do not fulfill quality requirements, as indicated, for example, in the international norm ISO 15197 for BG test systems. Evaluation of the performance of such systems is usually provided by the manufacturers. What is missing in the EU is an independent institution that performs regular and critical evaluation of the quality of devices used for diabetes therapy before and also after their market approval. The work of such an institution would focus on BG test systems (these represent two-thirds of the market of medical devices for diabetes treatment) but would also evaluate the performance of other devices. It has to be clarified what legal framework is required for such an institution and how it can be financed; probably this can be done in a shared manner by the manufacturers of such devices and the health insurance companies. Positive evaluation results should be a prerequisite prior to any reimbursement for such devices.

Advanced glycation end products strongly activate platelets.

BACKGROUND: Diabetes mellitus is characterized by hyperglycemia that plays an important role in the pathogenesis of diabetic complications including cardiovascular diseases. Moreover, hyperglycemia induces increased generation of advanced glycation end products (AGEs). The activation of platelets is associated with the development of cardiovascular diseases. AIM OF THE STUDY: The question whether AGEs acutely induce platelet activation as a response to exogenous stimulus is addressed. MATERIALS AND METHODS: The effect of AGEs derived from food and human serum being purified by lysozyme affinity chromatography was examined by incubating in vitro freshly isolated blood platelets from fasted subjects at various concentrations and different time points. Platelet activation, determined as expression of surface markers CD62 and CD63, and the presence of the receptor for AGEs (RAGE) in platelet membranes was measured by flow cytometric analysis using specific antibodies. RESULTS: Incubation with food-derived as well as serum-derived AGEs stimulated significantly the expression of CD62 up to 7.1-fold and CD63 up to 2.2-fold at the platelet surface membrane as a function of concentration and time. Incubation with thrombin or AGEs significantly increased RAGE expression twofold at the platelet surface membrane. CONCLUSIONS: The increase in surface activation marker and RAGE expression in platelets, resulting from concentrations of AGEs that occur in vivo after a meal or a drink as a source of exogenous AGEs, points to signaling mechanisms for food AGEs that could favor the precipitation of acute postprandial ischemic events.

Skin autofluorescence increases postprandially in human subjects.

BACKGROUND: Skin autofluorescence (SAF) is a property used for the noninvasive assessment of skin advanced glycation end products (AGEs) and concentration of redox-regulated fluorophores. SAF was shown to closely mirror cardiovascular risk and to constitute a more sensitive parameter for diabetes screening than fasting glucose and hemoglobin A1c. It has also been suggested that SAF measurement is independent of fasting status. Our study was designed in order to test whether SAF changes postprandially. METHODS: We have investigated 21 Caucasian subjects (10 healthy subjects, 11 subjects with type 2 diabetes mellitus). SAF was measured in the fasting state, as well as 2 and 4 h following a meal with a medium AGE content. RESULTS: Two hours postprandially, SAF significantly increased by 10.2% in the whole group, by 11.6% in the group of individuals with diabetes, and by 8.7% in healthy subjects (for all measurements P < 0.05 vs. baseline). CONCLUSIONS: SAF increases postprandially in individuals with diabetes mellitus and in healthy subjects. Therefore, we suggest that measurements of SAF should be performed in the fasting state in order to increase sensitivity and specificity of the method for assessing cardiovascular risk and diabetes screening.

Dietary advanced glycation endproducts and oxidative stress: in vivo effects on endothelial function and adipokines.

Advanced glycation endproducts (AGEs) and oxidative stress (OS) contribute to the development and progression of diabetic complications. We have reported that dietary AGEs and OS induce acute endothelial dysfunction in vivo, but little is known about their effects on adipokines. Twenty inpatients with type 2 diabetes mellitus (mean age: 55.9; range: 32-71 years), received a standard diabetes diet for 6 days. On days 4 and 6, the acute effects of a high-AGE (HAGE) or a low-AGE (LAGE) meal (15.100 vs. 2.750 kU AGE) were studied in a randomized, cross-over, investigator-blinded design. Measurements were performed after an overnight fast, at baseline (B) and at 2, 4, and 6 h after the HAGE or LAGE meals. Both meals had the same ingredients and differed only by the cooking method. Two h following HAGE, a significant decrease from baseline occurred in adiponectin (-10%*double dagger vs. +0%) and leptin (-22%*double dagger vs. -13%*), and a significant increase occurred in vascular cell adhesion molecule 1 (+19%*double dagger vs. -5%) and thiobarbituric acid reactive substances (+23%*double dagger vs. +6%). These changes did not occur, or occurred to a lesser extent, following LAGE. At 4 h following HAGE, an increase in methylglyoxal (+20%double dagger vs. -5%) and E-selectin (+54%*double dagger vs. -3%) occurred. Urinary AGEs increased only after HAGE (+51%*double dagger vs. -2%; values presented as HAGE vs. LAGE; *P < 0.05 vs. baseline, double daggerP < 0.05 vs. LAGE). The postprandial excursions in glucose, insulin, and triglycerides were similar between both meals. A meal rich in AGEs induces acute endothelial and adipocyte dysfunction. These effects were prevented by changing the cooking method.

Parameters affecting postprandial blood glucose: effects of blood glucose measurement errors.

BACKGROUND: The Diabetes Error Test Model (DETM) has been developed to characterize the clinical relevance of the large and varying margins of error of parameters affecting postprandial blood glucose (BG) levels, which increase the risk for hypo- or hyperglycemia. METHODS: The DETM is based on a treatment concept aimed at normoglycemia after meals. The model includes as parameters (a) preprandial BG measurement by patient self-monitoring (SMBG), (b) patient estimate of carbohydrate amounts (CARB-P) in food, (c) effect of CARB-P on maximum BG increase, (d) effect of insulin on maximum BG decrease, and (e) insulin dosage. Covering the relevant range of preprandial BG (30-330 mg/dl), the DETM simulates the maximum effect of these parameters and their margins of error on postprandial BG values. RESULTS: According to the DETM, a SMBG error of +20% results in normoglycemia (BG range: 60-160 mg/dl) as the postprandial outcome if preprandial BG values are in the range of 30-130 or 260-330 mg/dl, but can unexpectedly result in hypoglycemia if preprandial BG values are between 131 and 259 mg/dl. If the SMBG error of +20% is combined, e.g., with an error of CARB-P estimate in the food of +20%, hypoglycemia as the postprandial outcome is worsened. If one combines the effects of errors of more than two parameters, even with errors that are so small that they have no clinically relevant dysglycemic effect on postprandial BG per se (e.g., +/-6%), this can result in postprandial hypo- or hyperglycemic values. CONCLUSION: The DETM simulates the effects of errors of parameters affecting postprandial BG within the clinically relevant BG range. The DETM offers the opportunity to evaluate the clinical relevance of these errors and their contribution to the increased risk of meal-related excessive glucose excursions during intensified insulin therapy.

Effects of low- and high-advanced glycation endproduct meals on macro- and microvascular endothelial function and oxidative stress in patients with type 2 diabetes mellitus.

BACKGROUND: An advanced glycation endproducts (AGEs)-rich diet induces significant increases in inflammatory and endothelial dysfunction markers in type 2 diabetes mellitus (T2DM). OBJECTIVE: The aim was to investigate the acute effects of dietary AGEs on vascular function in T2DM patients. DESIGN: Twenty inpatients with T2DM [x (+/-SEM) age: 55.4 +/- 2.2 y; glycated hemoglobin: 8.8 +/- 0.5%] were investigated. In a randomized crossover design, the effects of a low-AGE (LAGE) and high-AGE (HAGE) meal on macrovascular [by flow-mediated dilatation (FMD)] and microvascular (by Laser-Doppler flowmetry) function, serum markers of endothelial dysfunction (E-selectin, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1), oxidative stress, and serum AGE were assessed. The meals had identical ingredients but different AGE amounts (15.100 compared with 2.750 kU AGE for the HAGE and LAGE meals, respectively), which were obtained by varying the cooking temperature and time. The measurements were performed at baseline and 2, 4, and 6 h after each meal. RESULTS: After the HAGE meal, FMD decreased by 36.2%, from 5.77 +/- 0.65% (baseline) to 3.93 +/- 0.48 (2 h), 3.70 +/- 0.42 (4 h), and 4.42 +/- 0.54% (6 h) (P<0.01 for all compared with baseline). After the LAGE meal, FMD decreased by 20.9%, from 6.04 +/- 0.68% (baseline) to 4.75 +/- 0.48% (2 h), 4.69 +/- 0.51% (4 h), and 5.62 +/- 0.63% (6 h), respectively (P<0.01 for all compared with baseline; P<0.001 for all compared with the HAGE meal). This impairment of macrovascular function after the HAGE meal was paralleled by an impairment of microvascular function (-67.2%) and increased concentrations of serum AGE and markers of endothelial dysfunction and oxidative stress. CONCLUSIONS: In patients with T2DM, a HAGE meal induces a more pronounced acute impairment of vascular function than does an otherwise identical LAGE meal. Therefore, chemical modifications of food by means of cooking play a major role in influencing the extent of postprandial vascular dysfunction.

Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes.

OBJECTIVE: Diabetes is characterized by marked postprandial endothelial dysfunction induced by hyperglycemia, hypertriglyceridemia, advanced glycation end products (AGEs), and dicarbonyls (e.g., methylglyoxal [MG]). In vitro hyperglycemia-induced MG formation and endothelial dysfunction could be blocked by benfotiamine, but in vivo effects of benfotiamine on postprandial endothelial dysfunction and MG synthesis have not been investigated in humans until now. RESEARCH DESIGN AND METHODS: Thirteen people with type 2 diabetes were given a heat-processed test meal with a high AGE content (HAGE; 15.100 AGE kU, 580 kcal, 54 g protein, 17 g lipids, and 48 g carbohydrates) before and after a 3-day therapy with benfotiamine (1,050 mg/day). Macrovascular flow-mediated dilatation (FMD) and microvascular reactive hyperemia, along with serum markers of endothelial disfunction (E-selectin, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1), oxidative stress, AGE, and MG were measured during both test meal days after an overnight fast and then at 2, 4, and 6 h postprandially. RESULTS: The HAGE induced a maximum reactive hyperemia decrease of -60.0% after 2 h and a maximum FMD impairment of -35.1% after 4 h, without affecting endothelium-independent vasodilatation. The effects of HAGE on both FMD and reactive hyperemia were completely prevented by benfotiamine. Serum markers of endothelial dysfunction and oxidative stress, as well as AGE, increased after HAGE. These effects were significantly reduced by benfotiamine. CONCLUSIONS: Our study confirms micro- and macrovascular endothelial dysfunction accompanied by increased oxidative stress following a real-life, heat-processed, AGE-rich meal in individuals with type 2 diabetes and suggests benfotiamine as a potential treatment.

Glucose sensors and the alternate site testing-like phenomenon: relationship between rapid blood glucose changes and glucose sensor signals.

In the last few years blood glucose meters have been developed allowing glucose measurements in capillary blood samples collected at sites other than the fingertips. The main reason for establishing this so-called alternate site testing (AST) was to sample blood from locations with reduced pain perception. It is well known that capillary blood glucose is closely correlated to systemic (i.e., arterial) glucose levels and that under steady-state conditions, glucose values measured in blood samples collected from alternate sites are virtually identical to those collected from the fingertip. However, during rapid changes in blood glucose levels, glucose concentrations in capillary blood samples from the fingertips can differ considerably in both domains (time and concentration) from those determined in capillary blood from alternate sites (i.e., the so-called AST phenomenon). Such differences can have serious clinical consequences (e.g., risky delays in hypoglycemia detection). There is evidence that all skin sites exhibiting a reduced blood flow (in comparison with the fingertip) within the superficial skin layers are prone to this AST phenomenon. Nearly all glucose sensors having been developed so far or being currently under development measure glucose levels at alternate sites and also in another compartment [e.g., interstitial fluid (ISF)] than blood. So, in principle they might be prone to an AST-like phenomenon (i.e., rapid changes in systemic blood glucose levels may also result in delayed ISF glucose readings). Our knowledge about the impact of an AST-like phenomenon on the performance of glucose monitoring systems is presently very limited. Glucose kinetics in the different compartments during dynamic systemic blood glucose changes have not been fully elucidated yet. If an AST-like phenomenon plays a role with glucose sensors should therefore be studied. Depending on the measurement technology used for the individual type of glucose monitoring system probably this phenomenon has a variable impact on the results obtained.

Hypoglycemia warning signal and glucose sensors: requirements and concepts.

Hypoglycemia is the most feared side effect of diabetes therapy with blood glucose-lowering agents. The fear of hypoglycemia often contributes to poor metabolic control of patients with diabetes. Therefore, integration of a hypoglycemia warning signal into continuous glucose monitoring systems represents an important additional help for patients with diabetes. The warning signal can be triggered at a preset level based on the current glucose values (as provided with the presently available glucose monitoring systems) or on prospective trend analysis offering the possibility to predict the risk of a hypoglycemic event in an anticipatory manner. Using the approach of a "Finite State Machine," such a more advanced warning system can completely be described as a finite collection of four states and possible transitions in-between. Most of the currently available glucose monitoring systems measure glucose in the interstitial fluid (ISF) of the dermal or subcutaneous tissue but are calibrated to blood glucose levels. This requires a number of factors to be taken into account: precision and accuracy of the glucose measurements, physiological and physical lag time, and calibration of the glucose monitoring system. From our point of view, the analytical performance of the system should be such that the majority of all hypoglycemic episodes are correctly diagnosed (>75%). Inconsistent findings regarding physiological discrepancies between blood and ISF glucose, which usually are described as a physiological lag time, range from some seconds up to 15 min. They can be observed especially during dynamic blood glucose changes (>3 mg/dL/min) and may represent major challenges for the development of a reliable hypoglycemia warning signal. In addition to possible physiological time lags, device-inherent physical lag times must be considered when selecting the threshold for the warning signal. Despite these problems, most probably all patients with diabetes who are treated with blood glucose-lowering agents will benefit from such a system since their safety and quality of life can be greatly improved, including an optimized metabolic control and lowered diabetes-related mortality. The benefit will be greatest for patients with hypoglycemia unawareness or impaired perception of hypoglycemic symptoms. The risks related to the use of a hypoglycemia warning signal seem to be low if certain precautionary measures are taken. In any case, additional clinical-experimental studies in healthy subjects as well as long-term clinical studies in diabetic patients are necessary to further evaluate the efficacy, benefits, and risks of different hypoglycemia warning concepts implemented in the different continuous glucose monitoring systems.

Continuous glucose monitoring: an overview of today's technologies and their clinical applications.

The first glucose sensors that allow continuous glucose monitoring are now available. It is important that physicians understand the special clinical and technical aspects that are key to successful implementation of these sensors--and of other sensors being under clinical development--into the daily practice of patients with diabetes. One important question is whether under all circumstances changes in blood glucose are paralleled by glucose changes in the interstitial fluid, in terms of both absolute values and time. Only if this is the case can measuring glucose in the interstitial fluid be a reliable substitute for measuring blood glucose. Usually, glucose sensor readings of interstitial fluid are transformed by means of a calibration process, so that the readings show actual blood glucose levels and not the interstitial glucose levels. If the calibration factor is inaccurately estimated, this error would be perpetuated with potential clinical implications. Patients with diabetes have to learn the proper use of the individual glucose sensor system, including its calibration and quality control. They also have to be informed about the problems and limitations of each sensor. Continuous monitoring should supply the patients with all information required to optimise their insulin therapy. The relatively high costs of glucose sensor systems should be viewed in the context of the potential optimisation of metabolic control, which should ultimately reduce the costs for the treatment of late complications of diabetes. These reduced costs would clearly far outweigh the costs of self-monitoring and self-control. Clinical trials are necessary to clearly demonstrate the long-term benefits of continuous glucose monitoring. The development of glucose sensors has now reached a stage at which it is important to address such questions appropriately.

Glucose monitoring at the arm: risky delays of hypoglycemia and hyperglycemia detection.

OBJECTIVE: We have examined whether rapid changes in blood glucose (BG) result in clinically relevant differences between capillary BG values measured at the forearm and the fingertip and whether local rubbing of the skin before blood sampling can diminish such differences. RESEARCH DESIGN AND METHODS: Capillary BG samples were collected every 15 min for 3-5 h from the fingertip and the forearm of 17 insulin-treated diabetic patients and analyzed with different glucose monitors (FreeStyle, One Touch Ultra, and Soft-Sense). In a subgroup of patients (n = 8), local rubbing of the forearm skin was performed before blood sampling. A rapid increase in BG was induced by oral administration of glucose, and subsequently, a rapid decrease in glucose was induced by intravenous administration of insulin. RESULTS: In the fasting state, the BG values at the fingertip and at the forearm were similar (7.8 +/- 2.4 vs. 7.2 +/- 2.3 mmol/l, P = 0.06). However, during rapid increase in glucose, BG values at the fingertip were consistently higher than at the forearm (maximal difference 4.6 +/- 1.2 mmol/l, P < 0.001). During rapid decrease in glucose, lower BG values were recorded at the fingertip (maximal difference to forearm 5.0 +/- 1.0 mmol/l, P < 0.001). At the forearm, BG was delayed by a median of 35 min (P < 0.01) in relation to the fingertip. Rubbing of forearm skin decreased the observed differences but with a large intraindividual and interindividual variability. There were no obvious device-specific differences. CONCLUSIONS: To avoid risky delays of hyperglycemia and hypoglycemia detection, BG monitoring at the arm should be limited to situations in which ongoing rapid changes in BG can be excluded.