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BackgroundGlycated hemoglobin, reported as hemoglobin A1c (HbA1c), is widely used as a measure of long-term glycemic control in patients with diabetes. The accuracy of measurements depends in part on proper storage of the sample prior to analysis.MethodsThree whole blood (WB) samples at three HbA1c levels were collected and stored at −70°C, −20°C, 4°C, room temperature (17–23°C), and 37°C. One aliquot from each temperature was analyzed by each method on days 1, 2, 3, 6, 7, 10, 14, 21, 28, and 57. ResultsThe Primus CLC (385 and 330) (Primus Corp., Kansas City, MO) showed stability of WB at −20°C and 4°C for 57 days, room temperature for 14 days, and 37°C for 1 day. The Tosoh 2.2 Plus (Tosoh Bioscience, Inc., South San Francisco, CA) showed stability at −20°C for 3 days, 4°C for 14 days, room temperature for 3 days, and 37°C for less than 24 h. With the Tosoh G7, results were acceptable at −20°C for 10 days, 4°C for 57 days, room temperature for 7 days, and 37°C for less than 24 h. The Bio-Rad Variant (Bio-Rad Laboratories, Hercules, CA) showed stability at −20°C for 6 days, 4°C for 14 days, room temperature for 3 days, and 37°C for less than 24 h. The Bio-Rad Variant II showed stability at −20°C for 28 days, 4°C for 57 days, room temperature for 7 days, and 37°C for less than 24 h.ConclusionsAll methods either met or exceeded manufacturers′ claims for stability. The CLC 385330, Tosoh G7, and Bio-Rad Variant II high performance liquid chromatography methods showed better stability than the Tosoh 2.2 Plus and Bio-Rad Variant. [ABSTRACT FROM AUTHOR]

Background: The enhanced precision and selectivity of liquid chromatography-tandem mass spectrometry (LC-MS/MS) makes it an attractive alternative to certain clinical immunoassays. Easily transferrable work flows could help facilitate harmonization and ensure high-quality patient care. We aimed to evaluate the interlaboratory comparability of antibody-free multiplexed insulin and C-peptide LC-MS/MS measurements., Methods: The laboratories that comprise the Targeted Mass Spectrometry Assays for Diabetes and Obesity Research (TaMADOR) consortium verified the performance of a validated peptide-based assay (reproducibility, linearity, and lower limit of the measuring interval [LLMI]). An interlaboratory comparison study was then performed using shared calibrators, de-identified leftover laboratory samples, and reference materials., Results: During verification, the measurements were precise (2.7% to 3.7%CV), linear (4 to 15 ng/mL for C-peptide and 2 to 14 ng/mL for insulin), and sensitive (LLMI of 0.04 to 0.10 ng/mL for C-peptide and 0.03 ng/mL for insulin). Median imprecision across the 3 laboratories was 13.4% (inter-quartile range [IQR] 11.6%) for C-peptide and 22.2% (IQR 20.9%) for insulin using individual measurements, and 10.8% (IQR 8.7%) and 15.3% (IQR 14.9%) for C-peptide and insulin, respectively, when replicate measurements were averaged. Method comparison with the University of Missouri reference method for C-peptide demonstrated a robust linear correlation with a slope of 1.044 and r2 = 0.99., Conclusions: Our results suggest that combined LC-MS/MS measurements of C-peptide and insulin are robust and adaptable and that standardization with a reference measurement procedure could allow accurate and precise measurements across sites, which could be important to diabetes research and help patient care in the future., (Published by Oxford University Press on behalf of Association for Diagnostics & Laboratory Medicine 2024.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background and Objectives: Among people with diabetes mellitus, CKD may promote hypoglycemia through altered clearance of glucose-lowering medications, decreased kidney gluconeogenesis, and blunted counter-regulatory response. We conducted a prospective observational study of hypoglycemia among 105 individuals with type 2 diabetes treated with insulin or a sulfonylurea using continuous glucose monitors., Design, Setting, Participants & Measurements: We enrolled 81 participants with CKD, defined as eGFR<60 ml/min per 1.73 m 2 , and 24 control participants with eGFR≥60 ml/min per 1.73 m 2 frequency-matched on age, duration of diabetes, hemoglobin A1c, and glucose-lowering medications. Each participant wore a continuous glucose monitor for two 6-day periods. We examined rates of sustained level 1 hypoglycemia (<70 mg/dl) and level 2 hypoglycemia (<54 mg/dl) among participants with CKD. We then tested differences compared with control participants as well as a second control population ( n =73) using Poisson and linear regression, adjusting for age, sex, and race., Results: Over 890 total days of continuous glucose monitoring, participants with CKD were observed to have 255 episodes of level 1 hypoglycemia, of which 68 episodes reached level 2 hypoglycemia. Median rate of hypoglycemic episodes was 5.3 (interquartile range, 0.0-11.7) per 30 days and mean time spent in hypoglycemia was 28 (SD 37) minutes per day. Hemoglobin A1c and the glucose management indicator were the main clinical correlates of time in hypoglycemia (adjusted differences 6 [95% confidence interval, 2 to 10] and 13 [95% confidence interval, 7 to 20] fewer minutes per day per 1% higher hemoglobin A1c or glucose management indicator, respectively). Compared with control populations, participants with CKD were not observed to have significant differences in time in hypoglycemia (adjusted differences 4 [95% confidence interval, -12 to 20] and -12 [95% confidence interval, -29 to 5] minutes per day)., Conclusions: Among people with type 2 diabetes and moderate to severe CKD, hypoglycemia was common, particularly with tighter glycemic control, but not significantly different from groups with similar clinical characteristics and preserved eGFR., (Copyright © 2019 by the American Society of Nephrology.)

Background: Inaccurate blood glucsoe monitoring systems (BGMSs) can lead to adverse health effects. The Diabetes Technology Society (DTS) Surveillance Program for cleared BGMSs is intended to protect people with diabetes from inaccurate, unreliable BGMS products that are currently on the market in the United States. The Surveillance Program will provide an independent assessment of the analytical performance of cleared BGMSs., Methods: The DTS BGMS Surveillance Program Steering Committee included experts in glucose monitoring, surveillance testing, and regulatory science. Over one year, the committee engaged in meetings and teleconferences aiming to describe how to conduct BGMS surveillance studies in a scientifically sound manner that is in compliance with good clinical practice and all relevant regulations., Results: A clinical surveillance protocol was created that contains performance targets and analytical accuracy-testing studies with marketed BGMS products conducted by qualified clinical and laboratory sites. This protocol entitled "Protocol for the Diabetes Technology Society Blood Glucose Monitor System Surveillance Program" is attached as supplementary material., Conclusion: This program is needed because currently once a BGMS product has been cleared for use by the FDA, no systematic postmarket Surveillance Program exists that can monitor analytical performance and detect potential problems. This protocol will allow identification of inaccurate and unreliable BGMSs currently available on the US market. The DTS Surveillance Program will provide BGMS manufacturers a benchmark to understand the postmarket analytical performance of their products. Furthermore, patients, health care professionals, payers, and regulatory agencies will be able to use the results of the study to make informed decisions to, respectively, select, prescribe, finance, and regulate BGMSs on the market., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DCK has served on advisory panels for Insuline, Lifecare, Novartis, Roche, Sanofi, Tempramed and Voluntis, has received research support from Eli Lilly, Halozyme, Janssen, and Novo Nordisk, and owns stocks/shares in Tempramed. JLP is an independent consultant and president of Joan Lee Parkes Consulting Inc. She has consulted for Diabetes Technology Society and Lifescan in 2014 and 2015. BPK served as an advisor to Astra Zeneca, Becton, Dickinson, and Company and Sanofi-Aventis and has received research support from Animas Inc, BD, Dexcom, Insulet, Roche Diagnostics, Sanofi-Aventis, and Tandem Diabetes Care. Stock ownership: Inspark Technologies, Inc, and TypeZero Technologies. RAV was a consultant for Sanofi, Medtronic, and Bayer at the time of the development of this program. He received an Investigator Initiated Research Grant from Dexcom. Currently, he has no disclosures except that he is an employee of Medtronic. RDB is on the Board of Diabetes Technology Society. JN has received honoraria and travel expenses from IL, BioRad, Fujiribio, Radiometer and Becton Dickinson over the past year related to scientific presentations and professional consulting. SS is an employee of Abbott Diabetes Care. JJS attended an advisory board meeting for Bayer Diabetes Care on April 25, 2015. CL, SB, GAR, AK, RL, MP, KR, DS, ES, RS, and HWV have no relevant disclosures., (© 2015 Diabetes Technology Society.)

Background: The accurate and precise quantification of HbA1c is essential for the diagnosis and routine monitoring of patients with diabetes. We report an evaluation of the Trinity Biotech Premier Hb9210 analyser (Bray, Ireland/Kansas City, MO, USA), a boronate affinity chromatography-based high performance liquid chromatography (HPLC) system for the measurement of glycated haemoglobin., Methods: We evaluated the analytical performance of the Hb9210 as part of a multicentre evaluation. The effect of haemoglobin variants, other potential interferences and the performance in comparison to both the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and National Glycohemoglobin Standardization Program (NGSP) reference systems, was assessed. Most of the centres participating also act as reference laboratories for both the IFCC standardisation network for HbA1c and the NGSP., Results: The combined data from all centres showed total coefficients of variation (CV) of 2.71%, 2.32% and 2.14% at low, medium and high values, respectively, for mmol/mol (SI units) and 1.62%, 1.59% and 1.68% for % (NGSP units), which are well below the recommended upper limits of 3% CV for mmol/mol (SI units) and 2% CV for % (NGSP). The analyser showed a good correlation to HbA1c methods currently used in clinical practice and the IFCC reference method procedure. Haemoglobin variants AC, AS, AE and AD do not affect the measurement of HbA1c. Overall the Hb9210 performs well across the whole analytical range., Conclusions: The Hb9210 performs well and is suitable for clinical application in the analysis of HbA1c.

Development of efficient and safe intervention strategies for preserving and/or restoring endogenous insulin production in type 1 diabetes has encountered a wide range of challenges, including lack of standardized trial protocols and of consensus on appropriate efficacy endpoints. For the greatest part, difficulties resided in choosing the most suitable assay(s) and parameter(s) to assess the beta-cell function. It is now an accepted approach to evaluate endogenous insulin secretion by measuring C-peptide levels (with highly sensitive and normalized measurement methods) in response to a physiologic stimulus (liquid mixed-meal) under standardized conditions. Preventive interventions mandate the identification of well-defined, reliable and validated mechanistic or immunological markers of efficacy that would correlate with (and predict) the clinical outcome. This has not been consistently achieved to date. However, it has been generally agreed that for preventive studies performed very early in the disease course (in subjects without signs of autoimmunity against beta-cells) development of two or more islet related autoantibodies could be employed as biomarkers of disease and thereafter, diagnostic criteria of diabetes serve as suitable endpoints.This report summarizes the conclusions of the D-Cure workshop of international experts held in Barcelona in April 2007 and the current recommendations and updates in the field.

Background: The American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD)/International Diabetes Federation (IDF)/IFCC Consensus Statement on the worldwide standardization of HbA(1c) states that "... [HbA(1c)] results are to be reported world-wide in IFCC units ... and derived NGSP units ... , using the IFCC-NGSP master equation.", Methods: We describe statistical methods to evaluate and monitor the relationships as expressed in master equations (MEs) between the IFCC Reference Measurement procedure (IFCC-RM) and designated comparison methods (DCMs) [US National Glycohemoglobin Standardization Program (NGSP), Japanese Diabetes Society/Japanese Society for Clinical Chemistry (JDS/JSCC), and Mono-S in Sweden]. We applied these statistics, including uncertainty calculations, to 12 studies in which networks of reference laboratories participated, operating the IFCC-RM and DCMs., Results: For NGSP and Mono-S, slope, intercept, and derived percentage HbA(1c) at the therapeutic target show compliance with the respective MEs in all 12 studies. For JDS/JSCC, a slight deviation is seen in slope and derived percentage HbA(1c) in 2 of the 12 studies. Using the MEs, the uncertainty in an assigned value increases from 0.42 mmol/mol HbA(1c) (IFCC-RM) to 0.47 (NGSP), 0.49 (JDS/JSCC), and 0.51 (Mono-S)., Conclusions: We describe sound statistical methods for the investigation of relations between networks of reference laboratories. Application of these statistical methods to the relationship between the IFCC-RM and DCMs in the US, Japan, and Sweden shows that they are suitable for the purpose, and the results support the applicability of the ADA/EASD/IDF/IFCC Consensus Statement on HbA1c measurement.

Background: The IFCC Reference Measurement System for hemoglobin (Hb)A(1c) (IFCC-RM) has been developed within the framework of metrologic traceability and is embedded in a network of 14 reference laboratories. This paper describes the outcome of 12 intercomparison studies (periodic evaluations to control essential elements of the IFCC-RM)., Methods: Each study included: unknown samples (to test individual network laboratories); known samples (controls); recently manufactured calibrators (to check calculated assigned value); stored calibrators (to test stability) and a calibration-set (to calibrate the IFCC-RM). The unknown samples are measured by use of the IFCC-RM and the designated comparison methods [DCMs; the National Glycohemoglobin Standardization Program (NGSP) in the US, Japanese Diabetes Society/Japanese Society for Clinical Chemistry (JDS/JSCC) in Japan, and Mono-S in Sweden] are used to investigate the stability of the Master Equation (ME), the relationship between IFCC-RM and DCMs., Results: A total of 105 IFCC-RM data sets were evaluated: 95 were approved, 5 were not, and for 5 no data were submitted. Trend analysis of the MEs, expressed as change in percentage HbA(1c) per year, revealed 0.000% (NGSP, not significant), -0.030%, (JDS/JSCC; significant) and -0.016% (Mono-S; not significant). Evaluation of long-term performance revealed no systematic change over time; 2 laboratories showed significant bias, 1 poor reproducibility. The mean HbA(1c) determined by laboratories performing mass spectrometry (MS) was the same as the mean determined by laboratories using capillary electrophoresis (CE), but the reproducibility at laboratories using CE was better. One batch of new calibrators was not approved. All stored calibrators were stable., Conclusion: A sound reference system is in place to ensure continuity and stability of the analytical anchor for HbA(1c).

Background: Clinical trials require assays that provide consistent results during the course of a study. The hemoglobin A1c (HbA1c) assay, a measure of chronic glycemia, is critical to the study of diabetes control and complications., Methods: The Diabetes Control and Complications Trial (DCCT) and its follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC), required 20 years of consistent HbA1c results, measured by three different ion-exchange HPLC procedures. To maintain and document consistent HbA1c results measured in the DCCT and EDIC Central Biochemistry Laboratory, a backup laboratory used frozen hemolysates as long-term calibrators and a HPLC method with a single lot of Bio-Rex 70 resin., Results: Over 20 years, long-term quality-control values have remained constant. Four studies of nondiabetic ranges produced nearly identical values [mean (SD), 5.1 (0.5)%, 4.9 (0.3)%, 5.0 (0.4)%, and 5.0 (0.3)%]., Conclusion: The overall consistency of the HbA1c assays during the 20-year course of the DCCT and EDIC has been critical in establishing the benefits of intensive therapy and in understanding the relationship between long-term glycemia and the development and progression of the complications of diabetes.

Background: The national programs for the harmonization of hemoglobin (Hb)A(1c) measurements in the US [National Glycohemoglobin Standardization Program (NGSP)], Japan [Japanese Diabetes Society (JDS)/Japanese Society of Clinical Chemistry (JSCC)], and Sweden are based on different designated comparison methods (DCMs). The future basis for international standardization will be the reference system developed by the IFCC Working Group on HbA(1c) Standardization. The aim of the present study was to determine the relationships between the IFCC Reference Method (RM) and the DCMs., Methods: Four method-comparison studies were performed in 2001-2003. In each study five to eight pooled blood samples were measured by 11 reference laboratories of the IFCC Network of Reference Laboratories, 9 Secondary Reference Laboratories of the NGSP, 3 reference laboratories of the JDS/JSCC program, and a Swedish reference laboratory. Regression equations were determined for the relationship between the IFCC RM and each of the DCMs., Results: Significant differences were observed between the HbA(1c) results of the IFCC RM and those of the DCMs. Significant differences were also demonstrated between the three DCMs. However, in all cases the relationship of the DCMs with the RM were linear. There were no statistically significant differences between the regression equations calculated for each of the four studies; therefore, the results could be combined. The relationship is described by the following regression equations: NGSP-HbA(1c) = 0.915(IFCC-HbA(1c)) + 2.15% (r(2) = 0.998); JDS/JSCC-HbA(1c) = 0.927(IFCC-HbA(1c)) + 1.73% (r(2) = 0.997); Swedish-HbA(1c) = 0.989(IFCC-HbA(1c)) + 0.88% (r(2) = 0.996)., Conclusion: There is a firm and reproducible link between the IFCC RM and DCM HbA(1c) values.