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There is emerging evidence that background exposure to persistent organic pollutants (POPs) are important in the development of conditions predisposing to diabetes as well as of type 2 diabetes itself. We recently reported that low dose POPs predicted incident type 2 diabetes in a nested case-control study. The current study examined if low dose POPs predicted future adiposity, dyslipidemia, and insulin resistance among controls without diabetes in that study. The 90 controls were diabetes-free during 20 years follow-up. They were a stratified random sample, enriched with overweight and obese persons. POPs measured in 1987-88 (year 2) sera included 8 organochlorine (OC) pesticides, 22 polychlorinated biphenyls (PCBs), and 1 polybrominated biphenyl (PBB). Body mass index (BMI), triglycerides, HDL-cholesterol, LDL-cholesterol, and homeostasis model assessment value for insulin resistance (HOMA-IR) were study outcomes at 2005-06 (year 20). The evolution of study outcomes during 18 years by categories of serum concentrations of POPs at year 2 was evaluated by adjusting for the baseline values of outcomes plus potential confounders. Parallel to prediction of type 2 diabetes, many statistically significant associations of POPs with dysmetabolic conditions appeared at low dose, forming inverted U-shaped dose-response relations. Among OC pesticides, p,p'-DDE most consistently predicted higher BMI, triglycerides, and HOMA-IR and lower HDL-cholesterol at year 20 after adjusting for baseline values. Oxychlordane, trans-nonachlor, and hexachlorobenzene also significantly predicted higher triglycerides. Persistent PCBs with ≥7 chlorides predicted higher BMI, triglycerides, and HOMA-IR and lower HDL-cholesterol at year 20 with similar dose-response curves. Simultaneous exposure to various POPs in the general population may contribute to development of obesity, dyslipidemia, and insulin resistance, common precursors of type 2 diabetes and cardiovascular diseases. Although obesity is a primary cause of these metabolic abnormalities, POPs exposure may contribute to excess adiposity and other features of dysmetabolism.

This community-based study of nondiabetic adults compared the prognostic value of glycated hemoglobin and fasting glucose for identifying persons at risk for clinical outcomes such as diabetes. As compared with fasting glucose, glycated hemoglobin was similarly associated with the risk of diabetes and more strongly associated with the risks of cardiovascular disease and death from any cause, adding to data about the use of glycated hemoglobin as a diagnostic measure. As compared with fasting glucose, glycated hemoglobin was similarly associated with the risk of diabetes and more strongly associated with the risks of cardiovascular disease and death from any cause, adding to data about the use of glycated hemoglobin as a diagnostic measure. Fasting glucose is the standard measure used for the diagnosis of diabetes in the United States. 1 , 2 Historically, glycated hemoglobin has been recommended only for the determination of glucose control among persons who have already received the diagnosis of diabetes. New clinical practice recommendations from the American Diabetes Association advocate the use of glycated hemoglobin in the diagnosis of diabetes, largely on the basis of the established association between glycated hemoglobin and microvascular disease. 3 Compared with fasting glucose, glycated hemoglobin has several advantages as a diagnostic test: it has higher repeatability, 4 – 6 can be assessed in the nonfasting state, and . . .

Background: Low doses of some persistent organic pollutants (POPs) associate cross-sectionally with type 2 diabetes, whereas associations with high POP exposures are inconsistent. Objectives: We investigated whether several POPs prospectively predict type 2 diabetes within the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Methods: Participants in this nested case—control study were diabetes free in 1987-1988. By 2005-2006, the 90 controls remained free of diabetes, whereas the 90 cases developed diabetes. Using serum collected in 1987-1988, we measured 8 organochlorine pesticides, 22 polychlorinated biphenyl congeners (PCBs), and 1 polybrominated biphenyl (PBB). We compared POP concentrations from CARDIA and the National Health and Nutrition Examination Survey (NHANES) in 2003-2004. We computed odds ratios (ORs) for incident diabetes using logistic regression analysis. Results: Chlorinated POPs in CARDIA in 1987-1988 were much higher than corresponding NHANES 2003-2004 concentrations. POPs showed nonlinear associations with diabetes risk. The highest risk was observed in the second quartiles of trans-nonachlor, oxychlordane, mirex, highly chlorinated PCBs, and PBB153—a finding that suggests low-dose effects. We concentrated risk by summing these POPs and isolated very low concentrations of multiple POPs in the lowest sextile of the sum. The adjusted OR in the second sextile vs. the lowest sextile was 5.3 overall and 20.1 for body mass index ≥ 30 kg/m². Conclusions: Several POPs at low doses similar to current exposure levels may increase diabetes risk, possibly through endocrine disruption. Certain POPs may a play a role in the current epidemic of diabetes, which has been attributed to obesity.

We compared HbA1c values obtained from capillary blood collection kits versus venous whole blood collections in study participants with type 1 or type 2 diabetes. A total of 122 subjects, 64 with type 2 diabetes participating in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study and 58 with type 1 diabetes from the Epidemiology of Diabetes Interventions and Complications (EDIC) Study, participated in the validation study. Capillary tubes were filled by fingerstick by the participants on the same day as the collection of venous whole blood samples in EDTA-containing test tubes and were mailed to the central laboratory. HbA1c in all samples was measured with the same high-performance liquid chromatography. GRADE participants also completed a questionnaire on the ease of performing capillary collections. Participants from 22 clinical centers (GRADE n = 5, EDIC n = 17) were between 35 and 86 years of age, with 52% male and diverse race/ethnicities. Venous HbA1c results ranged between 5.4-11.9% (35.5-106.6 mmol/mol) with corresponding capillary results ranging between 4.2-11.9% (22.4-106.6 mmol/mol). The venous and capillary results were highly correlated (R2 = 0.993) and 96.7% differed by ≤0.2% (2.2 mmol/mol). Of participants surveyed, 69% indicated that the instructions and collection were easy to follow and 97% felt the collection method would be easy to do at home. The capillary blood HbA1c results compared well with the conventional venous whole blood results. The capillary kits can be employed in other studies to reduce interruption of critical data collection and potentially to augment clinical care when in-person visits are not possible.

OBJECTIVE: Although A1C is now recommended to diagnose diabetes, its test performance for diagnosis and prognosis is uncertain. Our objective was to assess the test performance of A1C against single and repeat glucose measurements for diagnosis of prevalent diabetes and for prediction of incident diabetes. RESEARCH DESIGN AND METHODS: We conducted population-based analyses of 12,485 participants in the Atherosclerosis Risk in Communities (ARIC) study and a subpopulation of 691 participants in the Third National Health and Nutrition Examination Survey (NHANES III) with repeat test results. RESULTS: Against a single fasting glucose ≥126 mg/dl, the sensitivity and specificity of A1C ≥6.5% for detection of prevalent diabetes were 47 and 98%, respectively (area under the curve 0.892). Against repeated fasting glucose (3 years apart) ≥126 mg/dl, sensitivity improved to 67% and specificity remained high (97%) (AUC 0.936). Similar results were obtained in NHANES III against repeated fasting glucose 2 weeks apart. The accuracy of A1C was consistent across age, BMI, and race groups. For individuals with fasting glucose ≥126 mg/dl and A1C ≥6.5% at baseline, the 10-year risk of diagnosed diabetes was 88% compared with 55% among those individuals with fasting glucose ≥126 mg/dl and A1C 5.7-<6.5%. CONCLUSIONS: A1C performs well as a diagnostic tool when diabetes definitions that most closely resemble those used in clinical practice are used as the \"gold standard.\" The high risk of diabetes among individuals with both elevated fasting glucose and A1C suggests a dual role for fasting glucose and A1C for prediction of diabetes.

β-Cell Function and the Development of Diabetes-Related Complications in the Diabetes Control and Complications Trial Michael W. Steffes , MD, PHD 1 , Shalamar Sibley , MD, MPH 2 , Melissa Jackson , MPH 3 and William Thomas , PHD 3 1 Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota 2 Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 3 Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, Minnesota Abstract In patients with type 1 diabetes, measurement of connecting peptide (C-peptide), cosecreted with insulin from the islets of Langerhans, permits estimation of remaining β-cell secretion of insulin. In this retrospective analysis to distinguish the incremental benefits of residual β-cell activity in type 1 diabetes, stimulated (90 min following ingestion of a mixed meal) C-peptide levels at entry in the Diabetes Control and Complications Trial (DCCT) were related to measures of diabetic retinopathy and nephropathy and to incidents of severe hypoglycemia. Based on the analytical sensitivity of the assay (0.03 nmol/l) and study entry criteria, the DCCT subjects were divided into four groups of stimulated C-peptide responses: ≤0.03, 0.04–0.20, 0.21–0.50 nmol/l at entry, and 0.21–0.50 nmol/l at entry and at least 1 year later (sustained C-peptide secretion). Uniformly in the intensive and partially in the conventional DCCT treatment groups, any C-peptide secretion, but especially at higher and sustained levels of stimulated C-peptide, was associated with reduced incidences of retinopathy (both a single three-step change and a repeated three-step change on the Early Treatment of Diabetic Retinopathy Study [ETDRS] scale at the next 6 month visit) and nephropathy (both albuminuria >40 mg/24 h once and repeated at the next annual visit). There were also differences in severe hypoglycemia across C-peptide levels in both treatment groups. In the intensively treated cohort there were essentially identical prevalences of severe hypoglycemia (∼65% of participants) in the first three groups; however, those subjects with mixed-meal stimulated C-peptide level >0.20 nmol/l for at least baseline and the first annual visit in the DCCT experienced a reduced prevalence of ∼30%. Therefore, even modest levels of β-cell activity at entry in the DCCT were associated with reduced incidences of retinopathy and nephropathy. Also, continuing C-peptide (insulin) secretion is important in avoiding hypoglycemia (the major complication of intensive diabetic therapy). AER, albumin excretion rate DCCT, Diabetes Control and Complications Trial ETDRS, Early Treatment of Diabetic Retinopathy Study HPLC, high-performance liquid chromatography Footnotes Address correspondence and reprint requests to Michael W. Steffes, Department of Laboratory Medicine and Pathology, Mayo Mail Code 609, 420 Delaware St. S.E., Minneapolis, MN 55455. E-mail: steff001{at}umn.edu . Received for publication 7 February 2002 and accepted in revised form 4 December 2002. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. DIABETES CARE

Chronic kidney disease is a worldwide public health problem with an increasing incidence and prevalence, poor outcomes, and high cost. Outcomes of chronic kidney disease include not only kidney failure but also complications of decreased kidney function and cardiovascular disease. Current evidence suggests that some of these adverse outcomes can be prevented or delayed by early detection and treatment. Unfortunately, chronic kidney disease is underdiagnosed and undertreated, in part as a result of lack of agreement on a definition and classification of its stages of progression. Recent clinical practice guidelines by the National Kidney Foundation 1) define chronic kidney disease and classify its stages, regardless of underlying cause, 2) evaluate laboratory measurements for the clinical assessment of kidney disease, 3) associate the level of kidney function with complications of chronic kidney disease, and 4) stratify the risk for loss of kidney function and development of cardiovascular disease. The guidelines were developed by using an approach based on the procedure outlined by the Agency for Healthcare Research and Quality. This paper presents the definition and five-stage classification system of chronic kidney disease and summarizes the major recommendations on early detection in adults. Recommendations include identifying persons at increased risk (those with diabetes, those with hypertension, those with a family history of chronic kidney disease, those older than 60 years of age, or those with U.S. racial or ethnic minority status), detecting kidney damage by measuring the albumin-creatinine ratio in untimed (\"spot\") urine specimens, and estimating the glomerular filtration rate from serum creatinine measurements by using prediction equations. Because of the high prevalence of early stages of chronic kidney disease in the general population (approximately 11% of adults), this information is particularly important for general internists and specialists.

Assays for serum total glycated proteins (fructosamine) and the more specific glycated albumin may be useful indicators of hyperglycemia in dialysis patients, either as substitutes or adjuncts to standard markers such as hemoglobin A1c, as they are not affected by erythrocyte turnover. However, their relationship with long-term outcomes in dialysis patients is not well described. We measured fructosamine and glycated albumin in baseline samples from 503 incident hemodialysis participants of a national prospective cohort study, with enrollment from 1995-1998 and median follow-up of 3.5 years. Outcomes were all-cause and cardiovascular disease (CVD) mortality and morbidity (first CVD event and first sepsis hospitalization) analyzed using Cox regression adjusted for demographic and clinical characteristics, and comorbidities. Mean age was 58 years, 64% were white, 54% were male, and 57% had diabetes. There were 354 deaths (159 from CVD), 302 CVD events, and 118 sepsis hospitalizations over follow-up. Both fructosamine and glycated albumin were associated with all-cause mortality; adjusted HR per doubling of the biomarker was 1.96 (95% CI 1.38-2.79) for fructosamine and 1.40 (1.09-1.80) for glycated albumin. Both markers were also associated with CVD mortality [fructosamine 2.13 (1.28-3.54); glycated albumin 1.55 (1.09-2.21)]. Higher values of both markers were associated with trends toward a higher risk of hospitalization with sepsis [fructosamine 1.75 (1.01-3.02); glycated albumin 1.39 (0.94-2.06)]. Serum fructosamine and glycated albumin are risk factors for mortality and morbidity in hemodialysis patients.

Fructosamine, glycated albumin, and 1,5-anhydroglucitol (1,5-AG) are of interest for monitoring short-term glycemic control in patients with diabetes; however, their associations with diabetes risk are uncharacterized. We used Cox proportional hazards models to examine the associations of fructosamine, glycated albumin, and 1,5-AG with incident diabetes in 1,299 participants, from the Atherosclerosis Risk in Communities (ARIC) Study (2005-2006), who had no history of diagnosed diabetes at baseline. Incident diabetes was self-reported during annual telephone calls. There were 119 new cases of diabetes during a median follow-up of 3.3 years. When compared with the lowest quartile, the fourth quartiles of fructosamine and glycated albumin were significantly associated with diabetes risk (hazard ratio [HR] 3.99 [95% CI 1.93-8.28] and 5.22 [2.49-10.94], respectively). The fourth quartile of 1,5-AG was associated with a significantly lower diabetes risk (0.27 [0.14-0.55]). Associations were attenuated but still significant after adjustment for hemoglobin A(1c) (A1C) or fasting glucose. Fructosamine, glycated albumin, and 1,5-AG were associated with the subsequent development of diabetes independently of baseline A1C and fasting glucose. Our results suggest these alternative biomarkers may be useful in identifying persons at risk for diabetes.

Background: Measurement of circulating insulin may improve the classification and management of diabetes mellitus and assist in treating people with insulin resistance. Methods: A work group convened by the American Diabetes Association evaluated results for a panel of 39 single donor sera measured by 10 commercial insulin methods from 9 manufacturers against an isotope dilution–liquid chromatography/tandem mass spectrometry (IDMS) measurement procedure calibrated using purified recombinant insulin. We used a candidate primary (pure substance) reference material, pooled serum, and single donor sera to evaluate approaches to achieve improved agreement of results between the routine and reference measurement procedures. Results: Four of 10 methods had ≥95% of individual serum results within 32% of the IDMS concentrations. However, the bias vs IDMS was more than 15.5% for 7 of 10 methods in 36%–100% of individual samples. A purified recombinant insulin preparation used as a common calibrator did not improve harmonization of results among routine methods but was not used as instructed by all participants. Calibration using serum pools achieved bias <15.5% for nearly all results in the concentration range covered by the pools (>60 pmol/L). Calibration using a panel of individual sera was the most effective to improve harmonization of results over the full measuring range. Conclusions: Agreement among methods can be improved by establishing traceability to the IDMS procedure using a panel of native sera. Pooled sera may be useful as trueness control materials. The usefulness of the pure insulin primary reference material [candidate reference material for insulin (cRMI)] requires clarification of protocols used by manufacturers.