Background: In recent randomized clinical trials, an unusual reporting pattern of glycemic data and hypoglycemic events potentially related to an internet enabled blood glucose meter (MyGlucoHealth, BGM) was observed. Therefore, this clinical study was conducted to evaluate the system accuracy of the BGM in accordance with the ISO15197:2015 guidelines with additional data collection. Methods: To investigate system accuracy, 10 of 3088 devices and 6 of 23 strip lots, used in the trials, were selected by a randomization procedure and a standard repeatability assessment. YSI 2300 STAT Plus was used as the standard reference method. The samples were distributed as per the ISO15197:2015 recommendations with 20 additional samples in the hypoglycemic range. Each sample was tested with 6 devices and 6 strip lots with double determinations. Results: Overall, 121 subjects with blood glucose values 26-423 mg/dL were analyzed, resulting in 1452 data points. In all, 186/1452 readings (12.8%) did not meet the ISO acceptance criteria. Data evaluated according to the FDA guidelines showed that 336/1452 (23.1%) readings did not meet the acceptance criteria. A clear bias toward elevated values was observed for BG <100 mg/dL (MARD: 11.0%). Conclusions: The results show that the BGM, although approved according to standard regulatory guidelines, did not meet the level of analytical accuracy required for clinical treatment decisions according to ISO 15197:2015 and FDA requirements. In general, caution should be exercised before selection of BGMs for patients and in clinical trials.

Background: In recent clinical trials, use of the MyGlucoHealth blood glucose meter (BGM) and electronic diary was associated with an unusual reporting pattern of glycemic data and hypoglycemic events. Therefore, the performance of representative BGMs used by the patients was investigated to assess repeatability, linearity, and hematocrit interference in accordance with regulatory guidelines. Method: Ten devices and 6 strip lots were selected using standard randomization and repeatability procedures. Venous heparinized blood was drawn from healthy subjects, immediately aliquoted and adjusted to 5 target blood glucose (BG) ranges for the repeatability and 11 BG concentrations for the linearity tests. For the hematocrit interference test, each sample within 5 target BG ranges was split into 5 aliquots and adjusted to hematocrit levels across the acceptance range. YSI 2300 STAT Plus was used as the laboratory reference method in all experiments. Results: Measurement repeatability or precision was acceptable across the target BG ranges for all devices and strip lots with coefficient of variation (CV) between 3.4-9.7% (mean: 5.7%). Linearity was shown by a correlation coefficient of .991; however, a positive bias was seen for BG <100 mg/dL (86% measurements did not meet ISO15197:2015 acceptance criteria). Significant hematocrit interference (up to 20%) was observed for BG >100 mg/dL (ISO15197:2015 acceptance criteria: ±10%), while the results were acceptable for BG <100 mg/dL. Conclusions: The BGM met repeatability requirements but demonstrated a significant measurement bias in the low BG range. In addition, it failed the ISO15197:2015 criteria for hematocrit interference.

Background: Frequent blood glucose readings are the most cumbersome aspect of diabetes treatment for many patients. The noninvasive TensorTip Combo Glucometer (CoG) component employs dedicated mathematical algorithms to analyze the collected signal and to predict tissue glucose at the fingertip. This study presents the performance of the CoG (the invasive and the noninvasive components) during a standardized meal experiment. Methods: Each of the 36 participants (18 females and males each, age: 49 ± 18 years, 14 healthy subjects, 6 type 1 and 16 type 2 patients) received a device for conducting calibration at home. Thereafter, they ingested a standardized meal. Blood glucose was assessed from capillary blood samples by means of the (non)invasive device, YSI Stat 2300 plus, Contour Next at time points –30, 0, 15, 30, 45, 60, 75, 90, 120, 150, and 180 minutes. Statistical analysis was performed by consensus error grid (CEG) and calculation of mean absolute relative difference (MARD) in comparison to YSI. Results: For the noninvasive (NI) CoG technology, 100% of the data pairs were found in CEG zones A (96.6%) and B (3.4%); 100% were seen in zone A for the invasive component and Contour Next. MARD was calculated to be 4.2% for Contour Next, 9.2% for the invasive component, and 14.4% for the NI component. Conclusions: After appropriate individual calibration of the NI technology, both the NI and the invasive CoG components reliably tracked tissue and blood glucose values, respectively. This may enable patients with diabetes to monitor their glucose levels frequently, reliably, and most of all pain-free.

Background: Intact proinsulin is a biomarker for pancreatic ß-cell dysfunction. In large prospective studies in nondiabetic subjects, elevated intact proinsulin predicted development of type 2 diabetes and/or macrovascular events up to 7 years in advance. This study was performed to evaluate a new semiquantitative lateral flow-based point-of-care rapid test (POCT) for elevated intact proinsulin (cutoff: 15 pmol/L). The test requires 10 µL of capillary whole blood, with visual readout after 5 minutes. It is best applied at 2 hours after a glucose challenge or a meal. Methods: POCT results were obtained by health care professionals from 60 patients and healthy subject (33 female, 27 male, 28 type 2 diabetes, age: 53.6 ± 12.3 years). An additional venous blood sample was obtained from all participants for measurement of intact proinsulin by means of a quantitative ELISA reference method (TecoMedical, Sissach, Switzerland). Results: Elevated intact proinsulin levels (>15 pmol/L) were determined by the reference method in 26 participants, of whom 22 were also positive with the POCT (sensitivity: 85%). All 34 subjects with low intact proinsulin levels were tested negative by the POCT (specificity: 100%). Conclusions: The test successfully detected elevated postprandial intact proinsulin levels in 85% of the tested subjects and no false positive test result occurred. This POCT can therefore serve as a simple screening tool for identification of patients with prevalent ß-cell dysfunction, who are at high risk for development of type 2 diabetes and/or macrovascular events within the next 5-7 years.

The new ISO15197:2013 norm, defining more stringent system accuracy quality standards, was published in Europe in May 2013. After enforcement of this new regulation, all new meters for patient self-monitoring of blood glucose (SMBG) need to show deviations from a reference method of less than ±15 mg/dl (±0.83 mmol/l) for values below or equal to 100 mg/dl (5.6 mmol/l) and ±15% for values above 100 mg/dl in 95% of the cases as assessed by a standardized clinical protocol requiring 3 strip lots to be tested. A transition period of 3 years has been granted to all SMBG manufacturers prior to implementing the new accuracy criteria as essential and mandatory part of the conformity process required to obtain the CE mark for new devices. The GlucoMen LX Plus meter (A. Menarini Diagnostics) is a self-testing device that measures glucose and ß-hydroxybutyrate in capillary blood and has already been introduced in Europe in 2011. Previous clinical and laboratory evaluations with this system have shown excellent accuracy and stability against hematocrit interference. The system is employing an amperometric glucose-oxidase-based technology with integrated correction algorithms, and is specifically designed for measurement in whole blood samples Purpose of our clinical study was to identify the number of blood glucose results falling within the range of the new ISO criteria. The study was performed in January/February 2013 at the laboratories that today belong to Pfützner Science & Health Institute, Mainz, Germany, in compliance with the German Medical Device Act and approved by the responsible Ethics Committee and the Federal Institute of Drugs and Medical Devices. The protocol was designed in compliance with the system accuracy procedure set forth in the ISO15197:2013 norm, in particular with respect to glucose ranges and number of devices and tests strip lots (100 subjects, 3 strip lots, 6 meters). The tested materials including the meters, the control solutions, and strip lots 3211269249 (exp 9/30/2013), 3211325249 (exp 11/30/2013), and 3211334249 (exp 11/30/2013) were provided by the manufacturer. A YSI 2300 STAT Plus glucose analyzer (Yellow Springs Instruments, Yellow Springs, OH, USA) served as reference method for this analysis. Statistical analyses were performed as defined in the ISO guidelines. All 3 strip lots were successfully tested demonstrating compliance with the new ISO criteria as shown in Table 1. The combined system accuracy results for the strip lots tested were falling within 97% to 99% of the ISO criteria. Clinical accuracy was evaluated by means of the Parkes’s consensus error grid. The overall vast majority of data pairs (628/630, 99.7%) of all values were within zone A of the CGA indicating “clinical accurate measurements with no effect on clinical action”, and 2/630 (0.3%) were in zone B (“altered clinical action with little or no effect on clinical outcome”). No values were seen in the zones C, D, or E, which represent clinically inacceptable values. In conclusion, all 3 lots of the GlucoMen LX Plus glucose meter system were compliant with ISO1597:2013 accuracy criteria.

Background: Elevated fasting intact proinsulin is a biomarker of late-stage ß-cell-dysfunction associated with clinically relevant insulin resistance. In this pilot investigation, we explored the potential value of measuring intact proinsulin as a functional predictor of ß-cell exhaustion during an oral glucose tolerance test (OGTT). Methods: The study was performed with 31 participants, 11 of whom were healthy subjects (7 female, age: 59 ± 20 years), 10 had impaired glucose tolerance (IGT, 6 female, 62 ± 10 years), and 10 had known type 2 diabetes (T2DM, 5 female, 53 ± 11 years, HbA1c: 7.0 ± 0.6%, disease duration: 8 ± 5 years). During OGTT, blood was drawn after 0 hours, 1 hour, and 2 hours for determination of glucose and intact proinsulin. Five years later, patients were again contacted to assess their diabetes status and the association to the previous OGTT results was analyzed. Results: The OGTT (0 hours/1 hour/2 hours) results were as follows: healthy subjects: glucose: 94 ± 8 mg/dL/140 ± 29 mg/dL/90 ± 24 mg/dL, intact proinsulin: 3 ± 2 pmol/L/10 ± 7 pmol/L/10 ± 5 pmol/L); IGT: glucose: 102 ± 9 mg/dL/158 ± 57 mg/dL/149 ± 34 mg/dL, intact proinsulin: 7 ± 4 pmol/L/23 ± 8 pmol/L/28 ± 6 pmol/L; T2DM: glucose: 121 ± 20 mg/dL/230 ± 51 mg/dL/213 ± 34 mg/dL; intact proinsulin: 7 ± 7 pmol/L/26 ± 9 pmol/L/27 ± 10 pmol/L). Five years later, all of the IGT and 2 of the healthy subjects had developed T2DM and one had devloped IGT. All of them had elevated 2-hour proinsulin values in the initial OGTT, while patients with normal intact proinsulin results did not develop diabetes. Conclusions: Elevated 2-hour intact proinsulin levels during OGTT were predictive for later type 2 diabetes development. Further studies need to confirm our findings in larger populations.

Background:Daily routine for insulin-treated patients with diabetes mellitus requires correct performance of self-monitoring of blood glucose and insulin injections several times a day. Dexterity skills may play an important role in the performance efficacy of these procedures. Methods:We collected data of insulin-treated (>10 years) patients with different age ranges [healthy controls, 14 female/11 male, age (mean ± standard deviation) 55 ± 7 years; type 1 diabetes mellitus (T1DM) patients, 12/13, 45 ± 9 years, disease duration 23.9 ± 6.5 years; T2DM patients, 8/17, 64 ± 6 years, 16.2 ± 6.9 years; T2DM patients (>70 years of age), 9/16, 75 ± 4 years, 19.7 ± 7.0 years]. After assessment of neuropathy (temperature, pain, and vibration perception), the patients participated in two dexterity test batteries [Jebsen-Taylor hand-function test (JHFT) and motoric performance series (MPS)]. Results:Patients with type 2 diabetes showed disturbed vibration perception as compared to the other groups. The dexterity results were influenced by age to a large extent. Older T2DM patients performed worst in the majority of the subtests (e.g., JHFT, writing nondominant hand: Control, 40.8 ± 11.7 s; T1DM, 46.3 ± 50.9 s, not significant versus control; old T2DM, 68.1 ± 29.5 s, p < .05; young T2DM, 52.5 ± 26.2 s, p < .05). Patients with type 1 diabetes showed similar JHFT and MPS results than the 10-year-older control subjects and performed outside of the age-dependent normal reference range. Conclusions:Manual skills and dexterity differed between the groups, and age-corrected reduced skills were common in both T1DM and T2DM patients in this study. Our findings underline the importance of considering dexterity and manual skills when designing medical devices for patients with diabetes mellitus.

Proinsulin, the precursor of insulin during physiological insulin production, has been demonstrated in the past to stimulate PAI-1 secretion and consecutively block fibrinolysis. Therefore, proinsulin is contributing as an independent factor to the increased cardiovascular risk of patients with type 2 diabetes. However, development of insulin resistance in the course of type 2 diabetes leads to increased insulin demands and finally to an impairment of beta-cell function in later disease stages. Appearance of intact proinsulin in the peripheral blood has been shown to be a good laboratory marker for this phenomenon since it indicates an exhaustion of the cleavage capacity of the intracellular processing enzymes. However, the close relation of the two pathophysiological entities also makes it a very specific marker for insulin resistance per se. During the past years, new immunoassays have been developed that are able to distinguish between intact proinsulin and its specific and unspecific cleavage products. Use of these assays in recent epidemiological and intervention studies has helped to get a better understanding about beta-cell dysfunction and its relation to insulin resistance and cardiovascular risk. In a large cross-sectional study with 4270 orally treated patients, elevation of fasting intact proinsulin was very closely related to insulin resistance, as assessed by iv glucose tolerance test in a subgroup, and by HOMA analysis in the entire patient population. Effective treatment of insulin resistance (e.g. with thiazolidindiones) led to a decrease in elevated proinsulin levels and to a decrease of the cardiovascular risk profile, while the levels remained high during sulfonylurea therapy. These results suggest to reconsider intact and total proinsulin as valuable diagnostic tools in diagnosis and treatment of type 2 diabetes. Based on the published data of the new specific immunoassays, patients with elevated intact proinsulin levels (> 10 pmol/L) should be regarded and treated as being insulin-resistant, while elevation of total proinsulin (>45 pmol/l) may help to identify the high cardiovascular risk patients. Both assays can thus be used to assess beta-cell function, to facilitate the selection of the most promising therapy, and may also serve to monitor treatment success in the further course of the disease.

Insulin resistance in patients with type 2 diabetes is associated with an increased risk of cardiovascular events. While this can be partly explained by an impairment of direct insulin action on the endothelial cell, an independent contribution can be assigned also to the secretory dysfunction of the beta-cell. If the demand for insulin triggered by insulin resistance is arriving at a certain threshold, an insufficiency of the cleavage capacity of beta-cell carboxypeptidase H leads to an increased secretion of intact proinsulin in addition to the desired insulin molecule. Proinsulin, however, has been demonstrated to be an independent cardiovascular risk factor by stimulating plasminogen activator inhibitor-1 secretion and blocking fibrinolysis. A recently introduced intact proinsulin assay is able to distinguish between intact proinsulin and its specific and non-specific cleavage products. This assay allows for a pathophysiological staging of type 2 diabetes based on beta-cell secretion. It could be confirmed by a large epidemiological study (IRIS-2, 4,265 patients) that intact proinsulin is a highly specific marker for insulin resistance. It could also be shown in other studies that successful resistance treatment with insulin or glitazones led to a decrease in elevated proinsulin levels and, thus, to a decrease of cardiovascular risk, while the levels remained high during sulfonylurea therapy. Therefore, patients with increased fasting intact proinsulin values should be treated with a therapy focusing on insulin resistance. Assessment of beta-cell function by determination of intact proinsulin may facilitate the selection of the most promising therapy and may also serve to monitor treatment success in the further course of the disease.