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Impaired beta-cell function is a recognized cornerstone of diabetes pathophysiology. Estimates of insulin secretory capacity are useful to inform clinical practice, helping to classify types of diabetes, complication risk stratification and to guide treatment decisions. Because C-peptide secretion mirrors beta-cell function, it has emerged as a valuable clinical biomarker, mainly in autoimmune diabetes and especially in adult-onset diabetes. Nonetheless, the lack of robust evidence about the clinical utility of C-peptide measurement in type 2 diabetes, where insulin resistance is a major confounder, limits its use in such cases. Furthermore, problems remain in the standardization of the assay for C-peptide, raising concerns about comparability of measurements between different laboratories. To approach the heterogeneity and complexity of diabetes, reliable, simple and inexpensive clinical markers are required that can inform clinicians about probable pathophysiology and disease progression, and so enable personalization of management and therapy. This review summarizes the current evidence base about the potential value of C-peptide in the management of the two most prevalent forms of diabetes (type 2 diabetes and autoimmune diabetes) to address how its measurement may assist daily clinical practice and to highlight current limitations and areas of uncertainties to be covered by future research.

The standardization of C-peptide assays is highly desirable objective. Our groups have employed the use of a Certified Reference Material (CRM) to calibrate their respective measurement procedures and comparison studies have demonstrated good agreement between the two laboratories [Figure]. Although it was the original choice, The National Metrology Institute of Japan (NMIJ) CRM has not always been available. However, a new material from Cerilliant (C-161-0.1ML) proved equally well defined. Both materials include known amounts of pure C-peptide and small amounts of deamidated and pyroglutamated forms (Cerilliant Lot# FN0422195.6% modified; NMIJ CRM 6901-b, Lot# 058 1.9% modified) . The C-peptide CRMs from Cerilliant and from NMIJ behave identically when the mass concentration of the unmodified C-peptide is used to assign calibrator concentrations. To avoid potential bias, we conclude that the mass concentration of unmodified C-peptide (not the mass concentration of total C-peptide) in CRM should be used when making calibrators for mass spectrometry C-peptide assays to achieve comparable patient results. Variation in the relative amount of modified C-peptide is an obstacle to standardization, especially when comparing mass spectrometry-based assays with immunoassays, which use total C-peptide for calibration. Disclosure Z.Wu: Employee; Quest Diagnostics. K.Kabytaev: None. J.Mu: None. S.Connolly: None. M.J.Mcphaul: Employee; Quest Diagnostics. R.R.Little: None. Funding NIH/NIDDK (1UC4DK096587-01)

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

No point of care HbA1c (A1c) assays are CLIA waived for use in diagnosing diabetes. The accuracy of the Abbott Afinion HbA1c Dx (Afinion) was evaluated for this purpose. Operators with no laboratory training (N=21) tested fingerstick (FS) and venous (V) whole blood samples from subjects at 7 CLIA waived sites with 2 Afinion analyzer models (AS100 and Afinion 2). Operators self-trained on use of the Afinion using only materials that are provided when the test is purchased. A portion of each subject’s V sample was tested with a recognized comparative method (CM) at an NGSP Secondary Reference Laboratory (SRL). Consistent with FDA requirements for total error of A1c test systems, the percentage of Afinion results within an Allowable Total Error (ATE) zone of ±6% of the CM result was calculated, as well as the bias at 6.5% A1c. A total of 1,229 subjects with A1c values spanning the Afinion assay measuring range were enrolled. For the Afinion 2, 95.04% (95% lower confidence limit, LCL: 93.33%) of FS and 94.86% (95% LCL: 93.12%) of V results were within the ATE zone. For the AS100, 94.22% (95% LCL: 92.38%) and 93.36% (95% LCL: 91.41%) of Afinion results were within the ATE zone for FS and V samples, respectively. The bias at 6.5% A1c for the Afinion 2 was -0.13% (-0.008% A1c units) for FS and 0.01% (0.000% A1c units) for V samples. For the AS100, the bias was 0.62% (0.040% A1c units) and 1.13% (0.073% A1c units) for FS and V samples, respectively. No operator effects and no differences between the Afinion and CM results that could potentially impact clinical decision making were observed in this study. In subjects with unreported hemoglobin variants (detected by CM), 16/16 FS and 15/16 V Afinion results were within the ATE zone when compared to a second NGSP certified method at the same SRL. These data support the use of Afinion in CLIA waived settings to diagnose diabetes. Disclosure M. Clendenin: Employee; Self; Abbott. A. J. Nation: None. R. C. San george: Other Relationship; Self; Abbott. K. Kupfer: Employee; Self; Abbott. K. S. Fortner: Employee; Self; Abbott. R. R. Little: None. T. S. Bailey: Consultant; Self; Abbott Diabetes, LifeScan, Novo Nordisk, Sanofi, Research Support; Self; Abbott, Abbott Diabetes, Biolinq, Capillary Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Kowa Research Institute, Inc., Lexicon Pharmaceuticals, Inc., Livongo, Medtronic, Medtrum Technologies, Novo Nordisk, REMD Biotherapeutics, Sanofi, Sanvita, Viacyte, Inc., vTv Therapeutics, Zealand Pharma A/S, Speaker’s Bureau; Self; BD, Medtronic, Sanofi. K. N. Castorino: Consultant; Self; Dexcom, Inc., Research Support; Self; Abbott Diabetes, Abbott Laboratories, Dexcom, Inc., Drawbridge Health, Inc., Lilly Diabetes, Medtronic, Novo Nordisk Inc. D. S. Denham: None. E. Kerwin: Consultant; Self; Amphastar, AstraZeneca, Connect Biopharma, GlaxoSmithKline plc., Mylan N. V., Novartis Pharmaceuticals Corporation, Sunovion Pharmaceuticals Inc., Theravance Biopharma, Speaker’s Bureau; Self; Chiesi USA, Inc. M. Mickiewicz: None.

OBJECTIVE In chronic kidney disease, glycated albumin and fructosamine have been postulated to be better biomarkers of glycemic control than HbA1c. We evaluated the accuracy, variability, and covariate bias of three biomarkers (HbA1c, glycated albumin, and fructosamine) compared with continuous glucose monitoring (CGM)–derived measurement of glycemia across estimated glomerular filtration rate (eGFR) in type 2 diabetes. RESEARCH DESIGN AND METHODS A prospective cohort study was conducted of 104 participants with type 2 diabetes, 80 with eGFR RESULTS Within-person biomarker values were strongly correlated between the two CGM periods (r = 0.92–0.95), although no marker fully captured the within-person variability of mean CGM glucose. All markers were similarly correlated with mean CGM glucose (r = 0.71–77). Compared with mean CGM glucose, glycated albumin and fructosamine were significantly biased by age, BMI, serum iron concentration, transferrin saturation, and albuminuria; HbA1c was underestimated in those with albuminuria. CONCLUSIONS Glycated albumin and fructosamine were not less variable than HbA1c at a given mean CGM glucose level, with several additional sources of bias. These results support measuring HbA1c to monitor trends in glycemia among patients with eGFR

Background: Point-of-care (POC) hemoglobin A1c (HbA1c) testing has advantages over laboratory testing, but some questions have remained regarding the accuracy and precision of these methods. The accuracy and the precision of the POC Afinion™ HbA1c Dx test were investigated. Methods: Samples spanning the assay range were collected from prospectively enrolled subjects at three clinical sites. The accuracy of the POC test using fingerstick and venous whole blood samples was estimated via correlation and bias with respect to values obtained by an NGSP secondary reference laboratory (SRL). The precision of the POC test using fingerstick samples was estimated from duplicate results by calculating the coefficient of variation (CV) and standard deviation (SD), and separated into its components using analysis of variance (ANOVA). The precision of the POC test using venous blood was evaluated from samples run in four replicates on each of three test cartridge lots, twice per day for 10 consecutive days. The SD and CV by study site and overall were calculated. Results: Across the assay range, POC test results from fingerstick and venous whole blood samples were highly correlated with results from the NGSP SRL ( r = .99). The mean bias was −0.021% HbA1c (−0.346% relative) using fingerstick samples and −0.005% HbA1c (−0.093% relative) using venous samples. Imprecision ranged from 0.62% to 1.93% CV for fingerstick samples and 1.11% to 1.69% CV for venous samples. Conclusions: The results indicate that the POC test evaluated here is accurate and precise using both fingerstick and venous whole blood.

IA sensitively predict future T1D, but onset often occurs many years after seroconversion. Early diagnosis results in less DKA and milder initial disease, especially in young children. Using the international TEDDY cohort, we asked if quarterly HbA1c testing could predict T1D among pre-pubertal subjects with ≥1 persistent IA (GADA, IA2A, IAA). Mean(SD) age at seroconversion and T1D onset was 43(29) and 73(22) months respectively. Of 8,504 HLA high risk children, 456 had persistent confirmed IA, had undergone at least 3 quarterly HbA1c tests in the prior 12 months, and were not on diabetes drugs or diets. Of these, 104 progressed to T1D and 352 did not. Subjects were split into training (292 total, 62 progressors) and test (164 total, 40 progressors) datasets with similar characteristics. The optimal maximum HbA1c cutpoint within 1 year pre-onset to predict T1D, by ROC analysis, was similar in training and test datasets (p=0.66). For both, HbA1c ≥5.6% gave the best Youden index. Other factors significant for T1D risk in the training dataset included age at HbA1c test, month of HbA1c test, continent and IA2A titer, but not gender, family history, HLA type, seroconversion age, IAA titer nor T1D-related SNP genotypes. Adjusted for significant factors, the optimal HbA1c cutpoint of ≥5.6% for quarterly testing was 91% sensitive, 91% specific, 73% PPV and 98% NPV to predict T1D within 1 year in children with HLA and IA risk. The final predictive model fit both training and test data similarly (p=0.28). Median(SD) time from first HbA1c ≥5.6% to diagnosis was 8.6(4.5) months, enabling monitoring and education for earlier treatment. Quarterly HbA1c surveillance is cost-effective and clinically accessible. A hierarchical plan for pediatric T1D prediction is proposed comprising initial genetic screening, then IA surveillance of those at genetic risk, then HbA1c surveillance of those with IA, and finally close glycemic surveillance of those with HbA1c ≥5.6% to ascertain metabolic onset. Disclosure M. Killian: None. K. Vehik: None. R.R. Little: None. H. Elding Larsson: None. M.J. Haller: None. M. Rewers: None. J. She: None. J. Toppari: None. B. Akolkar: None. J. Krischer: None. W. Hagopian: None.

Background: Monitoring of HbA1c is the standard of care to assess diabetes control. In Trinidad & Tobago (T&T) there are no existing data on the quality of HbA1c measurement. Our study examined the precision and accuracy of HbA1c testing in T&T. Methods: Sets of 10 samples containing blinded duplicates were shipped to laboratories in T&T. This exercise was repeated 6 months later. Precision and accuracy were estimated for each laboratory/method. Results: T&T methods included immunoassay, capillary electrophoresis, and boronate affinity binding. Most, but not all, laboratories demonstrated acceptable precision and accuracy. Conclusions: Continuous oversight of HbA1c testing (eg, through proficiency testing) in T&T is recommended. These results highlight the lack of oversight of HbA1c testing in some developing countries.

Background Hemoglobin A1c (HbA1c) is used to monitor long-term glycemic control in individuals with diabetes, guide therapy, predict the risk of microvascular complications, and more recently to diagnose diabetes. An automated liquid-flow capillary electrophoresis method was recently developed to measure HbA1c using the Capillarys 2 Flex Piercing instrument. Methods Analytical evaluation was performed at 2 clinical centers. A clinical analysis was conducted in 109 African-born individuals, 24% of whom have variant hemoglobin (HbAS or HbAC). Abnormal glucose tolerance (which includes both diabetes and prediabetes) was defined as 2 h glucose of ≥ 140 mg/dl (7.8 mmol/l) during an oral glucose tolerance test. Results Interlaboratory CVs were ≤ 2.1%. The method showed satisfactory correlation with 2 other analyzers that measure HbA1c by high-performance liquid chromatography. Neither labile HbA1c, carbamylated hemoglobin, uremia, bilirubin nor common hemoglobin variants (HbC/HbS/HbE) interfered. Forty-five individuals (41%) had abnormal glucose tolerance. The sensitivity of HbA1c for diagnosing abnormal glucose tolerance was 38%, 36% and 42% for total, normal and variant hemoglobin groups, respectively. Conclusions The analytical performance of HbA1c on the Capillarys 2 is suitable for clinical application. Variant hemoglobin in Africans did not interfere with the detection of abnormal glucose tolerance by HbA1c measured on the Capillarys 2.

Glycated hemoglobin (GHb), reported as HbA1c, is used as marker of long-term glycemia for diabetic patients. HbA1c results from boronate affinity methods are generally considered to be unaffected by most hemoglobin variants; this assumes comparable glycation of variant and non-variant (HbAA) hemoglobins. In this report, glycation of HbA beta chain (βA) and HbS beta chain (βS) for the most common Hb variant trait (HbAS) are examined.We analyzed 41 blood samples from subjects with HbAS, both with and without diabetes. Using LC-MS, ratios of glycated HbS to glycated HbA were determined by comparison of areas under the curves from extracted ion chromatograms.Glycation of βS chains was significantly higher (p0.001) than βA chains; this difference was consistent across subjects. Total (α+β) glycated HbAS was theoretically estimated to be ~5% higher than glycated HbAA.This novel mass-spectrometric approach described allows for relative quantification of glycated forms of βS and βA. Although βS glycation was significantly higher than that of βA, the difference in total glycation of HbAS versus HbAA was smaller and unlikely to impact clinical interpretation of boronate affinity HbA1c results. These data support the continued use of boronate affinity to measure HbA1c in patients with HbAS.

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.

Glycated hemoglobin (GHB), reported as HbA 1c , has been used to monitor glycemic control in patients with diabetes for many years. The critical importance of the test was not fully realized until the Diabetes Control and Complications Trial (DCCT) 1 showed a strong relationship between HbA 1c and risk for diabetes complications. After the DCCT was completed, specific diabetes treatment goals were established 2 ; a general goal for most patients with diabetes was an HbA 1c of

Hemoglobin A1c (HbA1c) is used routinely to monitor long-term glycemic control in people with diabetes mellitus, as HbA1c is related directly to risks for diabetic complications. The accuracy of HbA1c methods can be affected adversely by the presence of hemoglobin (Hb) variants or elevated levels of fetal hemoglobin (HbF). The effect of each variant or elevated HbF must be examined with each specific method. The most common Hb variants worldwide are HbS, HbE, HbC, and HbD. All of these Hb variants have single amino acid substitutions in the Hb β chain. HbF is the major hemoglobin during intrauterine life; by the end of the first year, HbF falls to values close to adult levels of approximately 1%. However, elevated HbF levels can occur in certain pathologic conditions or with hereditary persistence of fetal hemoglobin. In a series of publications over the past several years, the effects of these four most common Hb variants and elevated HbF have been described. There are clinically significant interferences with some methods for each of these variants. A summary is given showing which methods are affected by the presence of the heterozygous variants S, E, C, and D and elevated HbF. Methods are divided by type (immunoassay, ion-exchange high-performance liquid chromatography, boronate affinity, other) with an indication of whether the result is artificially increased or decreased by the presence of a Hb variant. Laboratorians should be aware of the limitations of their method with respect to these interferences.

Background Hemoglobin C, D Punjab, E or S trait can interfere with hemoglobin A1c (HbA1c) results. We assessed whether they affect results obtained with 12 current assay methods. Methods Hemoglobin AA (HbAA), HbAC, HbAD Punjab, HbAE and HbAS samples were analyzed on one enzymatic, nine ion-exchange HPLC and two Capillary Electrophoresis methods. Trinity ultra2 boronate affinity HPLC was the comparative method. An overall test of coincidence of least-squared linear regression lines was performed to determine if HbA1c results were statistically significantly different from those of HbAA samples. Clinically significant interference was defined as > 7% difference from HbAA at 6 or 9% HbA1c compared to ultra2 using Deming regression. Results All methods showed statistically significant effects for one or more variants. Clinically significant effects were observed for the Tosoh G8 variant mode and GX (all variants), GX V1.22 (all but HbAE) and G11 variant mode (HbAC). All other methods (Abbott Architect c Enzymatic, Bio-Rad D-100, Variant II NU and Variant II Turbo 2.0, Menarini HA-8180T thalassemia mode and HA-8180V variant mode, Sebia Capillarys 2 and Capillarys 3) showed no clinically significant differences. Conclusions Several methods showed clinically significant interference with HbA1c results from one or more variants which could adversely affect patient care.

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.

Background Beta-thalassemia minor (BTM) is a common benign condition that can be present in patients with diabetes mellitus. There are conflicting reports about the effect of BTM on glycated hemoglobin (gHb) measurements. We evaluated 6 gHb methods using samples from non-diabetic subjects with BTM. Methods Samples submitted for hemoglobin phenotype analysis were evaluated. A total of 57 samples (30 controls and 27 with BTM) from non-diabetic subjects were selected. GHb analysis was performed by Tosoh A1c 2.2+, Primus CLC 330, Bayer DCA 2000, Beckman Coulter, Synchron CX7 and LX20, and Roche Tina-quant II assays. Results The A1c 2.2+, CLC 330, DCA 2000 and Tina-quant II assays showed no statistically significant difference between the control and BTM groups. In contrast, BTM results were significantly higher than controls on the Synchron CX7 analyzer and borderline significant on the Synchron LX20 (p=0.051). Further investigation demonstrated an increase in Synchron %HbA1c results with decreasing hemoglobin concentrations. Conclusions In this study using samples from subjects with normal or near-normal gHb, BTM does not affect gHb measurements per se. However, the Synchron methods yielded higher results for samples with lower hemoglobin concentrations, like those that can be seen in BTM. The Synchron method was improved at the end of 2003, which minimized this problem.

Monitoring of glycemic status, as performed by patients and health care providers, is considered a cornerstone of diabetes care. Results of monitoring are used to assess the efficacy of therapy and to make adjustments in diet, exercise, and medications in order to achieve the best possible blood glucose control. The purpose of this review is to summarize current knowledge about the tests used most widely in monitoring the glycemic status of people with diabetes. The review addresses both patient- and physician/laboratory-based testing, and it includes tests of urine glucose and ketones and tests of blood glucose and glycated proteins (hemoglobin and serum proteins). The major emphasis is on the advantages and limitations of each test for routine clinical practice. Use of these tests for diabetes screening and diagnosis will not be addressed in this review. Since this review was first published in 1995, there have been many advances in the field, most notably standardization of glycated hemoglobin testing and new approaches to self-monitoring of blood glucose (SMBG), including minimally invasive continuous glucose monitoring over hours to days at a time. These and other advances are presented in detail in a recent report that was prepared by the National Academy of Clinical Biochemistry (NACB) and published as an American Diabetes Association (ADA) position statement (1). This review will attempt to complement, rather than duplicate, the material in the NACB report. If there was an ideal method of monitoring glycemic status, it might be a small noninvasive device, perhaps similar to a wristwatch that people with diabetes could wear to continuously monitor their blood glucose level. The device would warn of impending hypoglycemia. It also would store blood glucose data and perform a variety of calculations such as hourly, daily, weekly, or monthly blood glucose averages. Unfortunately, such a monitoring device is …

Background: Previous studies have shown interference with HbA1c measurement from the 4 most common heterozygous Hb variants (HbAS, HbAE, HbAC, and HbAD) with some assay methods. Here we examine analytical interference from 49 different less common variants with 7 different HbA1c methods using various method principles. Methods: Hb variants were screened using the Bio-Rad Variant or Variant II beta thal short program, confirmed by alkaline and acid electrophoresis, and identified by sequence analysis. The Trinity ultra2 boronate affinity high-performance liquid chromatography (HPLC) method and Roche Tinaquant immunoassay were used as primary and secondary comparative methods, respectively, since these methods are least likely to show interference from Hb variants. Other methods included were the Tosoh G7 and G8, Bio-Rad D-10 and Variant II Turbo, Diazyme Enzymatic, and Sebia Capillarys 2 Flex Piercing. To eliminate any inherent calibration bias, results for each method were adjusted using regression verses the ultra2 with nonvariant samples. Each method’s calibration-adjusted results were compared and judged to be acceptable if within the 99% prediction interval of the regression line for nonvariant samples. Results: Almost all variant samples were recognized as such by the ion-exchange HPLC methods by the presence of abnormal peaks or results outside the reportable range. For most variants, interference was seen with 1 or more of the ion-exchange methods. Following manufacturer instructions for interpretation of chromatograms usually, but not always, prevented reporting of inaccurate results. Results: Laboratories must be cautious about reporting results when the presence of a variant is suspected.

OBJECTIVE— To define the relationship between HbA1c and plasma glucose (PG) levels in patients with type 1 diabetes using data from the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS— The DCCT was a multicenter, randomized clinical trial designed to compare intensive and conventional therapies and their relative effects on the development and progression of diabetic complications in patients with type 1 diabetes. Quarterly HbA1c and corresponding seven-point capillary blood glucose profiles (premeal, postmeal, and bedtime) obtained in the DCCT were analyzed to define the relationship between HbA1c and PG. Only data from complete profiles with corresponding HbA1c were used (n = 26,056). Of the 1,441 subjects who participated in the study, 2 were excluded due to missing data. Mean plasma glucose (MPG) was estimated by multiplying capillary blood glucose by 1.11. Linear regression analysis weighted by the number of observations per subject was used to correlate MPG and HbA1c. RESULTS— Linear regression analysis, using MPG and HbA1c summarized by patient (n = 1,439), produced a relationship of MPG (mmol/l) = (1.98 ○1 HbA1c) - 4.29 or MPG (mg/dl) = (35.6 ○1 HbA1c) - 77.3, r = 0.82). Among individual time points, afternoon and evening PG (postlunch, predinner, postdinner, and bedtime) showed higher correlations with HbA1c than the morning time points (prebreakfast, postbreakfast, and prelunch). CONCLUSIONS— We have defined the relationship between HbA1c and PG as assessed in the DCCT. Knowing this relationship can help patients with diabetes and their healthcare providers set day-to-day targets for PG to achieve specific HbA1c goals.

We read with concern the article by Lewis et al. (1) regarding HbA1c analysis in the Vitamin D and Type 2 Diabetes (D2d) Study. Although the article focused on reporting the presence of hemoglobin (Hb) variants after incidental detection of variants by HbA1c high-performance liquid chromatography (HPLC) methods, there was also clear mention of a lack of interference from HbS and HbC with the HbA1c assay used for the study—the Tosoh G8 HPLC. Unfortunately, although the authors claim that there is no interference of these common Hb variants with the Tosoh G8 method, there is clear evidence to the contrary. Our study (2) clearly showed a statistically and clinically significant bias in results from this …

OBJECTIVE: To evaluate the use of GHb as a screening test for undiagnosed diabetes (fasting plasma glucose > or =7.0 mmol/l) in a representative sample of the U.S. population. RESEARCH DESIGN AND METHODS: The Third National Health and Nutrition Examination Survey included national samples of non-Hispanic whites, non-Hispanic blacks, and Mexican Americans aged > or =20 years. Of these subjects, 7,832 participated in a morning examination session, of which 1,273 were excluded because of a previous diagnosis of diabetes, missing data, or fasting time of

Patients with diabetes mellitus routinely have glycohemoglobin (GHb) testing performed to monitor glycemic control and assess risk for developing complications of their disease (1). The accuracy of several GHb methods can be adversely affected by the presence of hemoglobin (Hb) C or S trait (2)(3)(4)(5)(6). It has been estimated that there are at least 200 000 Americans with diabetes mellitus who also have either Hb C or S trait (6). We have recently shown that the presence of Hb C or S trait does not affect the accuracy of GHb measurements made by the CLC 330 boronate affinity HPLC method (7). We therefore evaluated the effects of Hb C and S traits on 11 commercial GHb methods, using the CLC 330 assay as the comparison method. Whole blood samples from individuals homozygous for Hb A (n = 73) and heterozygous for Hb C or S (n = 46 and 76, respectively) were collected in EDTA-containing tubes. After routine clinical testing had been completed, Hb variants were identified by inspection of chromatograms obtained with a VARIANT analyzer (Bio-Rad Laboratories) and the Beta Thal Short program run according to the manufacturer’s instructions. Aliquots of these samples that had 4–14% Hb A1c were stored at 2–8 °C and analyzed within 10 days of collection except for aliquots for the HA8160 and HA8160 Beta Thal (BT) methods, which were shipped on dry ice and stored frozen until analysis. Not all samples were analyzed by each analytic method. This study was approved by the Institutional Review …

OBJECTIVE To determine whether the DCA 2000 analyzer provides valid and reliable HbA1c results when used under field conditions and operated by nonmedical personnel. This study was part of a community diabetes education program, the Native American Diabetes Project, in which HbA1c was measured as an indicator of average glycemic control. RESEARCH DESIGN AND METHODS Two study samples were taken, the first in the spring of 1994 and the second in the spring of 1995. Seven community members in 1994 and six new community members in 1995 were trained over 2 days, using standard protocol, to operate the DCA 2000 HbA1c analyzer and to collect two capillary blood samples from participants in the Native American Diabetes Project. Duplicate DCA 2000 HbA1c measurements performed by the community workers were compared with measurements from a high-performance liquid chromatography (HPLC) system. Validity and reliability measures were calculated. RESULTS Of the participants, 43 were studied in 1994 and 14 in 1995. Comparison of the mean DCA 2000 results with those of HPLC showed high validity, with the absolute relative difference between the mean DCA 2000 and the external reference of HPLC (│ mean DCA 2000-HPLC │ /HPLC) as 4.0 and 2.0% for 1994 and 1995, respectively. The Pearson correlation coefficients (r) between these two measures were 0.968 and 0.996 for 1994 and 1995, respectively. While the 1994 data appeared to have less validity for values > 10%, they included only one value with a 60-min warm-up of the DCA analyzer. The 1995 data, all collected after a 60-min warm-up, had good correlation throughout the range of values. The within-run reliability was excellent, with an intraclass correlation coefficient of reliability of 0.959 and 0.975 for paired samples, for 1994 and 1995 respectively. The mean coefficient of variation for these paired measures was 3.0% in 1994 and 2.8% in 1995. Both validity and reliability were improved by changing the warm-up period of the DCA 2000 analyzer from 5 to 60 min. All correlation coefficients were statistically significant (P < 0.0001). CONCLUSIONS The DCA 2000 gave valid and reliable HbA1c results when operated in a community setting by nonmedical personnel. Extending the warm-up period of the device to 60 min slightly improved the validity and reliability of the test.

The Afinion HbA1c (Axis-Shield) is a newer point-of-care device for measurement of hemoglobin A1c (A1C) using a boronate affinity method unlike the more commonly used DCA immunoassay method (Siemens Medical Solutions Diagnostics). The Afinion's accuracy and precision, when compared with high-performance liquid chromatography (HPLC) and DCA methods, have not been established in pediatric practice settings.Capillary blood was collected from 700 subjects with diabetes mellitus at seven Pediatric Diabetes Consortium sites. Each subject's A1C was measured locally using Afinion and DCA devices, and by a central laboratory (University of Minnesota) using a Tosoh HPLC method. In addition, repeated measurements on six whole blood samples provided by the National Glycohemoglobin Standardization Program (NGSP) were taken at three clinical centers using the Afinion and DCA methods and centrally using the Tosoh HPLC method to assess the precision of each device.The coefficient of variation for measurements of whole blood samples for precision analysis was 2% for Afinion, 3% for DCA, and 1% for HPLC. In the patient samples measured at the seven clinic sites, the Afinion generated higher A1C results than the HPLC (mean difference = +0.15; p0.001), while the DCA produced lower values (mean difference = -0.19; p0.001). The absolute differences with HPLC were similar for the Afinion and DCA (median 0.2%) with a slight advantage for the Afinion when compared with DCA (p0.001 by rank test). The DCA tended to read lower than HPLC, particularly at high A1C levels (p0.001), while the Afinion's accuracy did not vary by A1C.When compared to the central laboratory HPLC method, the differences between the results of the Afinion and DCA devices are clinically insignificant, and the Afinion and DCA have similar accuracy and precision when used in pediatric practice settings.

Glycated haemoglobin could offer several practical advantages over the OGTT for assessing glucose metabolism. Initial cross-sectional studies (1983-1985) on 381 subjects (mostly Pima Indians) described the relationship between HbA1c (a specific glycated Hb) and the OGTT. We performed follow-up OGTTs and HbA1c measurements on 257 of these same subjects 1.6-6.1 years later. Subjects were again grouped according to both the result of the OGTT (normal, IGT or diabetes, by WHO criteria) and HbA1c result (normal or elevated based on mean +/- 1.96 SD of normal). Of 66 subjects with IGT at baseline, 47 (71%) had normal HbA1c and 19 (29%) had elevated HbA1c. Twenty-six (39%) of these subjects had diabetes at follow-up. Of these subjects with IGT, a significantly greater percentage of subjects with elevated HbA1c at baseline (68%) showed worsening to diabetes than those with a normal HbA1c (28%); (chi-square = 7.8, df = 1, p0.01). Thus, in subjects with IGT, glycated Hb may be a useful predictor of progression to diabetes.

Many factors can affect interpretation of glycohemoglobin (GHB/HbA1c) measurements in patients with chronic renal failure (CRF). Several reports have suggested that erythrocyte survival is substantially lowered in most patients with CRF; this would be expected to lower GHB results (1)(2)(3)(4)(5)(6). Several reports have also suggested that GHB methods, especially those based on charge separation (e.g., ion-exchange HPLC), may have interference by carbamylated hemoglobin that would be expected to falsely increase GHB results (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Many of these reports evaluated older assay methods; newer ion-exchange methods may show improved separation of the HbA1c fraction from other hemoglobin adducts (15)(17). Because renal failure is common in patients with diabetes and GHB is widely used as an index of mean blood glucose in these patients, we examined GHB results in patients with CRF by several different GHB assay methods. We also investigated the impact of shortened erythrocyte lifespan by comparing the GHB results obtained for nondiabetic patients with and without CRF. Fifty-five patients with CRF (blood urea nitrogen >400 mg/L) were recruited for this study. Twenty-nine were not receiving dialysis and …

Glycohemoglobin (gHb) is a marker of long-term glycemic control that has been shown to correlate with complications of diabetes mellitus (1). The National Glycohemoglobin Standardization Program (NGSP) was established to standardize gHb results so that clinical laboratory results are comparable to those reported by the Diabetes Control and Complications Trial (2)(3). Previous studies have shown that some gHb methods yield inaccurate results with samples heterozygous for hemoglobin (Hb) C or Hb S (4)(5)(6). At least 10% of black Americans have either Hb C or S trait, and there were 19 million black Americans over age 19 in 1990 (7)(8)(9)(10). The prevalence of diabetes is estimated to be 5.1% of the adult population, with the rate for non-Hispanic blacks being 1.6-fold higher than that of non-Hispanic whites (11). It is therefore probable that at least 150 000 Americans with diabetes have Hb C or S trait. Here, we investigate the measurement of gHb in specimens containing Hb C or S trait using eight gHb methods currently in clinical use. Whole blood samples from individuals homozygous for Hb A (n = 43) and heterozygous for Hb C or S (n = 43 and 61, respectively) were collected in EDTA tubes. Hb variants were identified by their characteristic Variant A1c HPLC chromatograms (Bio-Rad Laboratories). Aliquots of these samples containing between 4% and 14% Hb A1c (NGSP Hb A1c evaluation range) were stored refrigerated (2–8 °C) and analyzed within 10 days of collection. This study was approved by the Institutional Review Board of the University of Utah. The CLC 330 gHb analyzer (Primus Corporation) was operated at the University of Missouri. This method was chosen as the comparison method for this study because results from boronate affinity chromatography should not …

Glycated albumin (GA) is a medium-term glycemic control marker of diabetes and may be more sensitive to changes in plasma glucose than hemoglobin A1c. We studied where and how many fructosyl groups bind to albumin, and which glycation sites are measured by the enzymatic method for GA. We also studied the basic performance of the enzymatic method for GA.Glycated albumin was measured using an enzymatic method (Lucica®GA-L, Asahi Kasei Pharma) on a biochemical autoanalyzer. Molecular weights of purified GA and nonglycated albumin were measured by a mass spectrometry system. Two hundred one healthy volunteers with normal results of oral glucose tolerance testing were recruited to determine the reference range in Americans.The present method measured only glycated amino acids from albumin in serum protein. We estimate that the number of glycated amino acids measured by this method was approximately two per molecule of albumin. The general performance (sensitivity, specificity, reproducibility, linearity, interference) of the method was good. The reference range of GA% in Americans with normal glucose tolerance was determined to be 11.9-15.8% (mean ± 2 standard deviations). Significant differences were not observed between the sexes; however, race differences were observed (higher levels in blacks relative to whites).The method was specific for measuring glycated amino acids in albumin and had good basic performance characteristics. The reference range in Americans was 11.9-15.8%. This method may be a useful indicator for diabetes control.

Background: In 1979, the authors began a prospective study of the natural history of retinopathy in youth-onset insulin-dependent diabetes mellitus (IDDM). Their major goal was to determine if there was an association between glycemic control and the development and progression of retinopathy. Methods: The study consisted of 420 individuals with IDDM (onset younger than 20 years of age) and no retinopathy at baseline. Study subjects were enrolled between 1979 and 1988. Stereo color fundus photographs were obtained annually. Two eye endpoints were recorded: duration when retinopathy was first detected, and when proliferative retinopathy was detected. Glycemic control was assessed by quarterly determinations of glycohemoglobin (GHb). Life-table analyses were performed relating duration of diabetes, sex, GHb, and age of diabetes onset to development of retinopathy. Results: Retinopathy did not develop before 2 years' duration or before puberty. The prevalence of retinopathy was 50% by 9 years' duration and 100% by 20 years' duration. Retinopathy developed in females approximately 2 years sooner than in males, but plotting duration as postpubertal years resulted in nearly identical rates. Retinopathy developed significantly earlier in subjects with prepubertal onset of diabetes than in subjects with postpubertal onset if duration was plotted as postpubertal years. When separated into three groups based on GHb levels ( 9%), retinopathy developed approximately 2 years later in subjects in the less than 7.5% GHb group than those in the higher GHb groups. Proliferative retinopathy developed in 11 subjects. Their mean GHb level was higher than the mean GHb for those without proliferative retinopathy (10.9 versus 8.6%; P Conclusion: Long-term glycemic control is significantly related to both development and progression of retinopathy. Prepubertal duration of diabetes is a significant risk factor for the development of retinopathy.

The prevalence of diabetes is increasing and currently affects more than 250 million people worldwide.1 Measurement of hemoglobin A1c (HbA1c) is fundamental to the management of patients with diabetes and has recently been recommended for diabetes and prediabetes diagnosis as well.2,3 There has therefore been much attention focused on performance criteria for this very important test. Results from several large-scale prospective trials, most notably the Diabetes Control and Complications Trial (DCCT)4 and the United Kingdom Prospective Diabetes Study5 (UKPDS) have shown that HbA1c levels are directly related to risks for diabetic complications and that a relatively small difference in HbA1c levels (

Diabetes mellitus is a major public health problem associated with serious long-term complications. Glycohemoglobin, a reliable index of the average blood glucose level during the previous 2 to 3 months, is now used routinely to monitor glycemic control in diabetic individuals. The assays most commonly used to measure glycohemoglobin levels include ion-exchange chromatography, electrophoresis, and affinity chromatography. Not all methods measure the same glycohemoglobin component, however; assay results depend on the component measured and the assay used. The need for standardization of glycohemoglobin values between laboratories has been recognized, but not yet implemented. Glycated serum protein and glycoalbumin measurements, which provide an index of glycemia over a 2- to 4-week period, have been investigated as alternatives for monitoring glycemic control. Methods to determine levels of these components in patients include nitroblue tetrazolium reduction and affinity chromatography. However, the value of these methods for monitoring glycemic control over a shorter period is still in question. Glycated protein measurements have been studied for their use in diabetes screening. Further studies are needed, however, to determine whether these measurements are sensitive enough to identify most individuals at risk for diabetic complications.

Description of recent developments in the standardization of HbA1c measurement and interpretation of HbA1c results.HbA1c is extensively used in the management of patients with diabetes. The two major schemes to standardize HbA1c produce values that differ substantially. A prospective, multinational study revealed a linear correlation between HbA1c and average blood glucose. Some, but not all, assay methods are able to accurately measure HbA1c in individuals with common hemoglobin variants.Progress in standardization of methods for HbA1c measurement has significantly reduced variation among different methods. The improved accuracy could allow HbA1c to be used for screening and diagnosis of diabetes. A consensus document recommends that HbA1c be reported in both NGSP (%) and IFCC (mmol/mol) units. HbA1c results can be translated into estimated average glucose (eAG), which could be reported in addition to HbA1c.

Background: Glycohemoglobin (GHB), reported as hemoglobin (Hb) A1c, is a marker of long-term glycemic control in patients with diabetes and is directly related to risk for diabetic complications. HbE and HbD are the second and fourth most common Hb variants worldwide. We investigated the accuracy of HbA1c measurement in the presence of HbE and/or HbD traits. Methods: We evaluated 23 HbA1c methods; 9 were immunoassay methods, 10 were ion-exchange HPLC methods, and 4 were capillary electrophoresis, affinity chromatography, or enzymatic methods. An overall test of coincidence of 2 least-squares linear regression lines was performed to determine whether the presence of HbE or HbD traits caused a statistically significant difference from HbAA results relative to the boronate affinity HPLC comparative method. Deming regression analysis was performed to determine whether the presence of these traits produced a clinically significant effect on HbA1c results with the use of ±10% relative bias at 6% and 9% HbA1c as evaluation limits. Results: Statistically significant differences were found in more than half of the methods tested. Only 22% and 13% showed clinically significant interference for HbE and HbD traits, respectively. Conclusions: Some current HbA1c methods show clinically significant interferences with samples containing HbE or HbD traits. To avoid reporting of inaccurate results, ion-exchange chromatograms must be carefully examined to identify possible interference from these Hb variants. For some methods, manufacturers’ instructions do not provide adequate information for making correct decisions about reporting results.

Glycated hemoglobin is widely used in the management of diabetes mellitus. At least 300,000 Americans with diabetes mellitus have the hemoglobin (Hb) C or S trait. The accuracy of HbA1c methods can be adversely affected by the presence of these traits. We evaluated the effects of HbC and HbS traits on the results of 14 commercial HbA1c methods that use boronate affinity, enzymatic, immunoassay, and ion exchange methods. Whole blood samples from people homozygous for HbA or heterozygous for HbC or HbS were analyzed for HbA1c. Results for each sample type were compared with those from the CLC 330 comparative method (Primus Diagnostics, Kansas City, MO). After correcting for calibration bias by comparing results from the homozygous HbA group, method bias attributable to the presence of HbC or HbS trait was evaluated with a clinically significant difference being more than 10% (ie, 0.6% at 6% HbA1c). One immunoassay method exhibited clinically significant differences owing to the presence of HbC and HbS traits.

Hemoglobin A 1c (HbA 1c ) is an important indicator of risk for complications in patients with diabetes mellitus. Elevated fetal hemoglobin (HbF) levels have been reported to interfere with results of some HbA 1c methods, but it has generally been assumed that HbA 1c results from boronate-affinity methods are not affected by elevated HbF levels. None of the previous studies used the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference method as the comparative HbA 1c method. We, therefore, measured HbA 1c in samples with normal and elevated HbF levels by several common assay methods and compared the results with those of the IFCC reference method. HbF levels of more than 20% artificially lowered HbA 1c results from the Primus CLC 330/385 (Primus Diagnostics, Kansas City, MO), Siemens DCA2000 (Siemens Healthcare Diagnostics, Tarrytown, NY), and Tosoh 2.2+ (Tosoh Bioscience, South San Francisco, CA), but not the Bio-Rad Variant II (Bio-Rad Laboratories, Hercules, CA) and Tosoh G7. Physicians and laboratory professionals need to be aware of potential interference from elevated HbF levels that could affect HbA 1c results, including those from boronate-affinity methods.

Background: C-peptide is a marker of insulin secretion in diabetic patients. We assessed within- and between-laboratory imprecision of C-peptide assays and determined whether serum calibrators with values assigned by mass spectrometry could be used to harmonize C-peptide results. Methods: We sent 40 different serum samples to 15 laboratories, which used 9 different routine C-peptide assay methods. We also sent matched plasma samples to another laboratory for C-peptide analysis with a reference mass spectrometry method. Each laboratory analyzed 8 of these samples in duplicate on each of 4 days to evaluate within- and between-day imprecision. The same 8 samples were also used to normalize the results for the remaining samples to the mass spectrometry reference method. Results: Within- and between-run CVs ranged from 10% and from 18%, respectively. Normalizing the results with serum samples significantly improved the comparability among laboratories and methods. After normalization, the differences among laboratories in mean response were no longer statistically significant (P = 0.24), with least-squares means of 0.93–1.02. Conclusions: C-peptide results generated by different methods and laboratories do not always agree, especially at higher C-peptide concentrations. Within-laboratory imprecision also varied, with some methods giving much more consistent results than others. These data show that calibrating C-peptide measurement to a reference method can increase comparability between laboratories.

A1C is formed when glucose reacts nonenzymatically with amino acids on hemoglobin. Its concentration represents an integrated measure of glucose concentration during hemoglobin's lifespan, which is about 2–3 months (1). Because A1C concentration predicts the risk for microvascular and macrovascular complications (2,3), it is used in the clinical setting to assess longer-term glycemic control among people with diabetes. Generally, A1C concentrations

OBJECTIVE—Insulin resistance and compensatory hyperinsulinemia have been proposed as increasing risk for a variety of abnormalities and clinical syndromes, including type 2 diabetes and cardiovascular disease. Our aim was to assess the trends in the mean concentrations of fasting serum insulin and the prevalence of hyperinsulinemia among nondiabetic adults during the periods of 1988–1994 and 1999–2002 in the U.S. RESEARCH DESIGN AND METHODS—We conducted analyses of data among men and nonpregnant women without diabetes aged ≥20 years from the Third National Health and Nutrition Examination Survey (NHANES III; 1988–1994; n = 7,926) and NHANES 1999–2002 (n = 2,993). Both surveys were designed to represent the noninstitutionalized civilian U.S. population. We calculated age-adjusted mean concentrations of fasting insulin and the prevalence of hyperinsulinemia defined using the 75th percentile of fasting insulin among nondiabetic individuals as the cutoff value. RESULTS—The geometric mean concentrations of fasting insulin increased by ∼5% from 1988–1994 to 1999–2002 among nondiabetic adults aged ≥20 years in the U.S. Mexican-American men, men and women aged 20–39 years, and non-Hispanic white women had a greater relative increase in the mean concentrations of fasting insulin than their counterparts. The prevalence of hyperinsulinemia increased by 35.1% overall (38.3% among men and 32.1% among women). CONCLUSIONS—In parallel with the obesity epidemic, concentrations of fasting insulin and prevalence of hyperinsulinemia have increased remarkably among nondiabetic U.S. adults.

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 Evaluation of glycated hemoglobin determination methods in patients with clinically silent hemoglobin variants. Methods HbA1c results were determined with various methods, including a new enzymatic assay, a boronate affinity HPLC, immunoassays and ion-exchange HPLC in patients with the clinically silent hemoglobin variants Hb Graz, Hb Sherwood Forest, Hb D and Hb O Padova. Results The effect of hemoglobin variants on glycated hemoglobin determination was method-dependent. The enzymatic and boronate affinity HPLC method did not interfere with any of the variants evaluated. In contrast, Hb Graz interfered with all immunoassay and ion-exchange HPLC methods evaluated. The Tosoh ion-exchange HPLC method HLC-723 did not detect the late migrating Hb O Padova in the chromatogram, but this hemoglobin variant still interfered causing artificially low HbA1c results. Conclusions Our study underscores the need for clinical laboratories and physicians to be aware of the limitations of their HbA1c assay methods as well as the importance of visual inspection of ion-exchange chromatograms to detect abnormalities caused by the hemoglobin variants. Samples with clinically silent Hb variants should be analyzed by a second method with a different assay principle, preferably a boronate affinity HPLC or an enzymatic assay. Copyright © 2004 John Wiley & Sons, Ltd.

OBJECTIVE To evaluate the prevalence and time trends for diagnosed and undiagnosed diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults by age, sex, and race or ethnic group, based on data from the Third National Health and Nutrition Examination Survey, 1988–1994 (NHANES 111) and prior Health and Nutrition Examination Surveys (HANESs). RESEARCH DESIGN AND METHODS NHANES III contained a probability sample of 18,825 U.S. adults ≥20 years of age who were interviewed to ascertain a medical history of diagnosed diabetes, a subsample of 6,587 adults for whom fasting plasma glucose values were obtained, and a subsample of 2,844 adults between 40 and 74 years of age who received an oral glucose tolerance test. The Second National Health and Nutrition Examination Survey, 1976–1980, and Hispanic HANES used similar procedures to ascertain diabetes. Prevalence was calculated using the 1997 American Diabetes Association fasting plasma glucose criteria and the 1980–1985 World Health Organization (WHO) oral glucose tolerance test criteria. RESULTS Prevalence of diagnosed diabetes in 1988–1994 was estimated to be 5.1% for U.S. adults ≥20 years of age (10.2 million people when extrapolated to the 1997 U.S. population). Using American Diabetes Association criteria, the prevalence of undiagnosed diabetes (fasting plasma glucose ≥126 mg/dl) was 2.7% (5.4 million), and the prevalence of impaired fasting glucose (110 to CONCLUSIONS The high rates of abnormal fasting and postchallenge glucose found in NHANES III, together with the increasing frequency of obesity and sedentary lifestyles in the population, make it likely that diabetes will continue to be a major health problem in the U.S

In this issue of Diabetes Care, Koskinen et al. report that fetal hemoglobin levels are increased in diabetic patients (this issue, L.K. Koskinen et al., p. 828–831). The study design was a cross-sectional one with glycohemoglobin and fetal hemoglobin determinations for 930 diabetic and 258 control subjects. The authors found thatalmost 7% of the diabetic subjects had fetal hemoglobin levels >1% compared with only∼2% of the control subjects. Furthermore, fetal hemoglobin levels were increased moreoften in those with IDDM than in those with NIDDM.

We appreciate the interest of M.B. Davidson (1) in our study on the use of GHb as a screening test for diabetes (2). We agree with the author's contention that “diagnosis of diabetes is untenable in a person with a normal HbAlc level,” because these individuals are …