Increases in Biomarkers of Hyperglycemia with Age in The

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e96 Diabetes Care Volume 40, August 2017

Increases in Biomarkers of Hyperglycemia Bethany Warren,1 Andreea M. Rawlings,1 With Age in the Atherosclerosis Risk in Alexandra K. Lee,1 Morgan Grams,1,2 Communities (ARIC) Study Josef Coresh,1 and Elizabeth Selvin1 Diabetes Care 2017;40:e96–e97 | https://doi.org/10.2337/dc17-0075

The American Diabetes Association’s Stan- glycated albumin, and some increase for the less consistent associations of age dards of Medical Care in Diabetesd2017 in fasting glucose, with modest impact of across the hyperglycemia biomarkers. Im- states that age should be “taken into con- adjustment for sex, race center (white, paired insulin secretion is common in sideration” when diagnosing diabetes Minneapolis, MN; black, Jackson, MS; white, older age. As HbA1c, fructosamine, and with HbA1c (1). Nonetheless, it is unclear Washington County, MD; black, Forsyth glycated albumin reflect postprandial how this recommendation might be im- County, NC; white, Forsyth County, NC; as glucose excursions in addition to fasting plemented. Population studies demon- defined by the ARIC study design), BMI, and concentrations, their stronger associa- 2 strate that HbA1c increases with age, BMI . At visit 5 among older adults tions with age as compared with fasting which some experts have suggested (21 years later), increases with age were glucose could reflectthatimpaired may be due to nonglycemic factors like less evident for fasting glucose and glucose tolerance is more common alterations in red cell turnover or hemo- HbA1c compared with fructosamine and than impaired fasting glucose in this globin glycation (2–4). However, prior glycated albumin. Associations of age population (5). studies lack concurrent comparisons with HbA1c, fructosamine, and glycated Similar to previous investigations, our across nonhemoglobin-related markers albumin at both visits persisted after fur- assessment is limited by its cross-sectional of hyperglycemia. We evaluated in- ther adjustment for fasting glucose. nature. Additionally, our analyses of older creases with age in fructosamine and gly- The magnitude of the association we adults could be subject to selection bias. cated albumindhemoglobin-independent observed between HbA1c and age, partic- Study strengths include the community- measures of hyperglycemiadin compar- ularly in middle age (0.11% [1.2 mmol/mol] based sample, broad age range, and mea- ison with HbA1c and fasting glucose in per 10 years of age), was similar to that in surements at different time points in the the community-based Atherosclerosis other studies (2–4). Prior investigations life span. Risk in Communities (ARIC) study. adjusted for glucose to account for glyce- In conclusion, we observed higher HbA1c We conducted serial cross-sectional anal- mia and attributed associations to non- at older ages but also saw comparable yses at visit 2 (1990–1992; n 5 11,632) and glycemic hemoglobin-related factors. associations for other (nonhemoglobin- visit 5 (2011–2013; n 5 3,876), excluding However, although HbA1c and fasting related) biomarkers of hyperglycemia. individuals with diagnosed diabetes. We glucose are highly related, they represent Our results provide some evidence that performed adjusted linear regression of different glycemic constructs. We ob- the age associations with HbA1c, fasting z scores of each biomarker (standardized served increases in HbA1c, fructosamine, glucose, fructosamine, and glycated albu-

OBSERVATIONS to visit 2) on age to allow head-to-head and glycated albumin independent of min may reflect increases in the preva- – comparisons of the associations. fasting glucose, suggesting that increases lence of hyperglycemia in aging. Age was significantly correlated with all may be primarily glycemic or that puta- biomarkers of hyperglycemia at visit tive nonglycemic factors may influence

e-LETTERS Ackowledgments. The authors thank the staff 2 (Fig. 1). In middle age (visit 2), we ob- nonhemoglobin biomarkers. and participants of the ARIC study for their served increases in HbA1c with age, com- The heterogeneity of dysglycemia across important contributions. Reagents for the gly- parable increases in fructosamine and the life span may offer some explanation cated albumin assays were donated by the

1Department of Epidemiology and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 2Johns Hopkins University School of Medicine, Baltimore, MD Corresponding author: Elizabeth Selvin, [email protected]. Received 12 January 2017 and accepted 22 April 2017. © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for proﬁt, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license. care.diabetesjournals.org Warren and Associates e97

Figure 1—Scatterplots with linear predictions, Pearson correlation coefﬁcients, and unadjusted b coefﬁcients (95% CIs) from linear regressions of z scores of markers of hyperglycemia (standardized to visit 2) on age (visit 2: 1990–1992 and visit 5: 2011–2013). HbA1c (A), fasting glucose (B), fructosamine (C), and glycated albumin (D). Black circles, visit 2 biomarker values; white line, visit 2 linear prediction; white circles, visit 5 biomarker values; black line, visit 5 linear prediction. *P , 0.05, **P , 0.001.

Asahi Kasai Pharma Corporation. Reagents for Duality of Interest. No potential conﬂicts of evidence from the Framingham Offspring Study thefructosamineassaysweredonatedbyRoche interest relevant to this article were reported. and the National Health andNutritionExamination Diagnostics. Author Contributions. B.W. and E.S. designed Survey 2001–2004. Diabetes Care 2008;31:1991– Funding. ARIC is carried out as a collaborative the study, researched the data, and wrote the 1996 study supported by National Heart, Lung, and manuscript. A.M.R., A.K.L., M.G., and J.C. all pro- 3. Dubowitz N, Xue W, Long Q, et al. Aging is Blood Institute contracts HHSN268201100005C, vided meaningful contributions to the revision of associated with increased HbA1c levels, indepen- HHSN268201100006C, HHSN268201100007C, the manuscript. E.S. is the guarantor of this work dently of glucose levels and insulin resistance, and HHSN268201100008C, HHSN268201100009C, and, as such, had full access to all the data in the also with decreased HbA1c diagnostic speciﬁcity. HHSN268201100010C, HHSN268201100011C, study and takes responsibility for the integrity of Diabet Med 2014;31:927–935 and HHSN268201100012C. B.W., A.M.R., and thedataandtheaccuracyofthedataanalysis. 4. Ravikumar P, Bhansali A, Walia R, A.K.L. were supported by National Institutes of Shanmugasundar G, Ravikiran M. Alterations in Health National Heart, Lung, and Blood Institute References HbA1c with advancing age in subjects with normal grant T32HL007024. This research was sup- 1. American Diabetes Association. Standards of glucose tolerance: Chandigarh Urban Diabetes ported by National Institutes of Health National Medical Care in Diabetesd2017. Diabetes Care Study (CUDS). Diabet Med 2011;28:590–594 Institute of Diabetes and Digestive and Kidney 2017;40(Suppl. 1):S1–S135 5. Kalyani RR, Egan JM. Diabetes and altered Diseases grant R01DK089174, and E.S. was also 2. Pani LN, Korenda L, Meigs JB, et al. Effect of glucose metabolism with aging. Endocrinol Metab supported by K24DK106414. aging on A1C levels in persons without diabetes: Clin North Am 2013;42:333–347