Page 1 of 4 Diabetic Medicine

Title: Fructosamine; is the current interest in alternative glycaemic markers justified?

Running ead: A role for fructosamine?

KE S ipman1 , M Jawad1 , KM Sullivan1 , C Ford 1 , R Gama1,2

1New Cross Hospital, Clinical C emistry, Wolver ampton WV10 0QP, UK. P one: 01902 695290 Fax: 01902 695618

2Researc Institute, Healt care Sciences, Wolver ampton University, Wolver ampton, UK.

Corresponding Aut or: Dr Kate S ipman, kate.s [email protected] Word count: 329 Funding sources: No sources of funding to declare. Conflicts of interest: T e aut ors of t is letter ave no conflicts of interest to disclose. Diabetic Medicine Page 2 of 4

Sir

Fructosamine; is the current interest in alternative glycaemic markers justified?

T e interest in alternative glycaemic markers, suc as fructosamine, as been rekindled due to increasing data on t eir ability to improve diagnosis [1] and predict onset and complications [2] of diabetes. Furt er clinical validation of t ese markers is called for [3]

owever t e limitations must also be elucidated so, rat er like HbA1c, t e non-glycaemic p ysiological, pat ological and analytical variables become well known.

Many of t e variables t at affect HbA1c appear to similarly affect fructosamine despite t e different p ysiological compartments. T e most commonly known non-glycaemic factor affecting fructosamine is albumin [3] alt oug data on t is is conflicting. We recently reported a multivariable univariate linear regression model of fructosamine (Table 3) [4] in w ic t e effect of et nicity (Sout Asian versus Caucasian), sex, age, presence of c ronic kidney disease (CKD), vitamin B12, ferritin, folate, aemoglobin, mean cell volume (MCV), fasting glucose, HbA1c, albumin and C reactive protein (CRP) were examined [4]. T e significant affect of albumin levels was confirmed as were t e effects of et nicity, age, presence of CKD (primarily CKD stage 3 versus CKD <3), vitamin B12, folate, albumin,

CRP, fasting glucose levels, HbA1c and aemoglobin. Ferritin, MCV and sex were t e only non-significant variables [4].

T e large number of significant variables ad not been anticipated, included due to t eir establis ed effect on HbA1c, confirming our current poor grasp of fructosamine metabolism.

Body mass index is also negatively associated wit fructosamine in t ose wit out diabetes [5] and falls during pregnancy [6] furt er complicating its interpretation. T yroid status may Page 3 of 4 Diabetic Medicine

affect fructosamine interpretation [3] owever not necessarily independently of deranged

glucose and protein metabolism [7].

We, t erefore, read wit interest t e new data but would urge caution on t e widespread

adoption of fructosamine until t e significance of non-glycaemic variables can be establis ed

in t e clinical field. In particular HbA1c remains t e biomarker of c oice for monitoring

glycaemic control in t ose wit CKD [8], w ereas fructosamine s ould be used wit caution

[4].

Yours sincerely

Kate E S ipman1 , Mo ammed Jawad1 , Katie M Sullivan1 , Clare Ford1 , Rousseau Gama1,2

1Clinical C emistry, New Cross Hospital, Wolver ampton, West Midlands and 2Researc Institute, Healt care Sciences, Wolver ampton University, Wolver ampton, West Midlands, UK.

REFERENCES

1. Malmström H, Walldius G, Grill V, Jungner I, Gudbjörnsdottir S, Hammar N. Fructosamine is a useful indicator of yperglycaemia and glucose control in clinical and epidemiological studies--cross-sectional and longitudinal experience from t e AMORIS co ort. PLoS One 2014 29;9(10):e111463.

2. Selvin E, Rawlings AM, Grams M, Klein R, S arrett AR, Steffes M, Cores J. Fructosamine and glycated albumin for risk stratification and prediction of incident diabetes and microvascular complications: a prospective co ort analysis of t e At erosclerosis Risk in Communities (ARIC) study. Lancet Diabetes Endocrinol 2014;2(4):279-88.

3. Parrinello CM, Selvin E. Beyond HbA1c and glucose: t e role of nontraditional glycemic markers in diabetes diagnosis, prognosis, and management. Curr Diab Rep 2014;14(11):548.

4. S ipman KE, Jawad M, Sullivan KM, Ford C, Gama R. Et nic/racial determinants of glycemic markers in a UK sample. Acta Diabetol 2015 [Epub a ead of print].

5. Poon AK, Jurasc ek SP, Ballantyne CM, Steffes MW, Selvin E. Comparative associations of diabetes risk factors wit five measures of yperglycemia. BMJ Open Diabetes Res Care 2014;2(1):e000002. Diabetic Medicine Page 4 of 4

6. Hartland AJ, Smit JM, Clark PM, Webber J, C owd ury T, Dunne F. Establis ing trimester- and et nic group-related reference ranges for fructosamine and HbA1c in non- diabetic pregnant women. Ann Clin Bioc em 1999;36:235-7.

7. Udupa SV, Manjrekar PA, Udupa VA, Vivian D. Altered fructosamine and lipid fractions in subclinical ypot yroidism. J Clin Diagn Res 2013;7(1):18-22.

8. S ipman KE, Jawad M, Sullivan KM, Ford C, Gama R. Effect of C ronic Kidney Disease on A1C in Individuals Being Screened for Diabetes. Prim Care Diab 2014;pii:S1751- 9918(14)00053-9.