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Glycated Albumin and GlycatedHemoglobin Are Influenced Differently byEndogenous Insulin Secretion in Patients

With Type 2 DiabetesMASAFUMIKOGA, MD, PHD1

JUNMURAI, MD1HIROSHISAITO, MD, PHD1

SOJIKASAYAMA, MD, PHD2

OBJECTIVE Glycated albumin (GA) relative to A1C is a useful marker of short-termglycemic control. We investigated whether endogenous insulin secretion in type 2 diabetes hasdifferent effects on GA and A1C levels.

RESEARCH DESIGN AND METHODS A1C, GA, and GA-to-A1C ratio were com-pared in 202 type 2 diabetic patients by type of treatment. Effect of-cell function determinedby homeostasis model assessment (HOMA-%) on GA-to-A1C ratio was examined. In addition,GA-to-A1C ratio was compared between type 2 diabetic patients and 16 patients with type 1

diabetes.

RESULTS In type 2 diabetic patients, GA-to-A1C ratio was significantly higher in thosetreated with insulin than in those treated with diet or oral hypoglycemic agents. HOMA-%showed a significant inverse correlation with GA-to-A1C ratio. This ratio was higher in type 1diabetic patients than in type 2 diabetic patients.

CONCLUSIONS In diabetic patients with decreased insulin secretion, serum GA levelsare higher relative to A1C.

Diabetes Care33:270272, 2010

A

1C is used clinically as a parameterof glycemic control state over the

previous 12 months (1). Measure-ment of A1C may be affected by condi-tions that shorten the l ife span oferythrocytes and variant hemoglobin,causing erroneous values for glycemiccontrol (2). As other markers of glycemiccontrol, serum glycated albumin (GA)and serum fructosamine are useful to re-flect shorter-term glycemic control (2weeks) (3). However, these glycated pro-teins do not accurately reflect glycemiccontrol in disorders of albumin metabo-lism.

Recently, GA-to-A1C ratio has beenreported to be significantly higher in pa-tients with type 1 diabetes than in thosewith type 2 diabetes, indicating that se-

rum GA is a more sensitive marker thanA1C for glucose excursions (4). The un-

derlying mechanism may involve markedfluctuation in plasma glucose levels asso-ciated with decreased insulin secretion intype 1 diabetic patients (4). The presentstudy investigated whether endogenousinsulin secretion has different effects onGA and A1C levels.

RESEARCH DESIGN AND

METHODS This study enrolled202 outpatients with type 2 diabetes (119male subjects and 83 female subjects) asdiagnosed based on American Diabetes

Association criteria (5). Exclusion criteriawere variation0.5% in A1C values dur-ing the previous 3 months, chronic liverdisease, renal disease, thyroiddisorder, ane-

mia, and corticosteroid treatment. Themean age was 64.2 10.7 years, BMI was24.2 3.7 kg/m2, and duration of diabe-tes was 13.1 9.7 years. Treatment in-volved diet alone in 41 patients, oralhypoglycemic agents (OHAs) in 112 pa-tients, and insulin in 49 patients. FastingC-peptide and fasting plasma glucosewere measured, and -cell function wasquantified using homeostasis model as-sessment (HOMA-%) (6). In addition,

GA-to-A1C ratio was compared betweenthe 202 type 2 diabetic patients and 16type 1 diabetic patients (8 male subjectsand 8 female subjects, aged 60.6 14.0years, BMI 22.7 2.8 kg/m2, and all re-ceiving insulin therapy).

Serum fasting C-peptide was deter-mined by chemiluminescent enzyme-immunoassay (Fujirebio, Tokyo, Japan).

A1C was measured with an ADAMS-A1C

HA-8160 a ut oma t ic A1C a na lyz e r(Arkray, Kyoto, Japan) based on high-performance liquid chromatography. Se-rum GA was determined by a Hitachi

7600 autoanalyzer (Hitachi InstrumentsService, Tokyo, Japan) based on an enzy-matic method using an albumin-specificproteinase, ketoamine oxidase, and an al-bumin assay reagent (Lucica GA-L; AsahiKasei Pharma, Tokyo, Japan).

RESULTS We compared A1C, GA,and GA-to-A1C ratio in 202 type 2 dia-betic patients with type of treatment. Both

A1C and GA were significantly higherin 49 patients treated with insulin and in112 patients treated with OHAs than in

41 patients treated with diet alone (datanot shown). By contrast, GA-to-A1C ratiodid not differ between patients treatedwith OHAs (2.86 0.34) and thosetreated with diet alone (2.79 0.28), andit was significantly higher in patientstreated with insulin (3.00 0.37) than inthose treated with OHAs (P 0.05) andthose treated with diet alone (P 0.01).In multivariate analysis performed withsex, age, BMI, and insulin therapy as ex-planatory variables for GA-to-A1C ratioin type 2 diabetic patients, BMI, age, andinsulin treatment were identified as inde-

From the 1Department of Internal Medicine, Kinki Central Hospital, Itami, Hyogo, Japan; and the 2Depart-ment of Medicine, Nissay Hospital, Osaka, Japan.

Corresponding author: Masafumi Koga, koga_m@kich.itami.hyogo.jp.Received 2 June 2009 and accepted 14 October 2009. Published ahead of print at http://care.

diabetesjournals.org on 21 October 2009. DOI: 10.2337/dc09-1002. 2010 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. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o n / P s y c h o s o c i a l R e s e a r c hB R I E F R E P O R T

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pendent explanatory variables (data notshown). GA-to-A1C ratio was signifi-cantly higher in 16 type 1 diabetic pa-tients (3.15 0.26) than in 202 type 2diabetic patients (2.87 0.36) (P 0.001) but showed no significant differ-ence compared with 49 type 2 diabeticpatients treated with insulin. By poweranalyses, each number of patients wasfound statistically adequate to make theconclusions when the analytical powerwas set at 80%.

HOMA-%was significantly lower in

type 2 diabetic patients treated with insu-lin than in those treated with diet aloneand those treated with OHAs (Fig. 1A). Asignificant inverse correlation was ob-served between GA-to-A1C ratio andHOMA-% (Fig. 1B). Stepwise multivar-iate analysis including HOMA-%, sex,age, and BMI to identify explanatory vari-ables for GA-to-A1C ratio showed thatBMI ( 0.203, F 9.6,P 0.015),age( 0.215, F 8.2, P 0.006), andHOMA-% ( 0.237, F 6.4,P 0.020) were found to be independent ex-

planatory variables.

CONCLUSIONS O u r fi n d i n g ssuggest that decreased endogenous insu-lin secretion is involved in elevated GA-to-A1C ratios. Yoshiuchi et al. (4)reported that in type 1 diabetic patients,glucose excursions or maximum glucoselevels based on diurnal plasma glucosevariations influence GA-to-A1C ratios. Inaddition, GA-to-A1C ratio in 158 subjectswith normal glucose tolerance was2.73 0.22 in our previous study (7),significantly lower than that in 202 type 2

diabetic patients in the present study. To-gether with these findings, it is suggestedthat decreased insulin secretion may in-crease the GA-to-A1C ratio by causingmarked glucose excursions.

The reasons why serum GA reflectspostprandial hyperglycemia better than

A1C are unknown. The shortened lifespan of erythrocytes in patients with dia-betes and poor glucose control (8), lag-ging GLUT1-mediated glucose uptake byerythrocytes resulting in a relatively lowerdegree of rise in A1C (9), different glyca-

tion rates between albumin and hemoglo-bin (10), and the direct effect of insulinand OHAs on serum albumin metabolism(11) may be involved.

In the present study, BMI was an in-dependent negative risk for GA-to-A1Cratio, as we previously reported (7,12),and was significantly lower in type 2 dia-betic patients treated with insulin andtype 1 diabetic patients than in type 2 di-abetic patients treated with OHA or dietalone. Thus, elevated GA-to-A1C ratio intype 2 diabetic patients treated with insu-

lin and type 1 diabetic patients may becaused by a lower BMI. However, adjust-ment of GA-to-A1C ratio by BMI gave thesame conclusions (data not shown).

In the Diabetes Control and Compli-cations Trial (DCCT), type 1 diabetic pa-tients treated with intensive insulintherapy had a markedly reduced preva-lence of diabetic retinopathy and macro-vascular complications compared withthose who had the same A1C levelstreated with conventional insulin therapy(13). The reason proposed was that inten-sive insulin therapy decreased glycemic

excursions thus emphasizing the need toreduce glucose fluctuations. If serum GAlevels had been measured in that study,the relationship between serum GA levelsand the diabetes complications in inten-sive versus conventional insulin therapywould have been an interesting observa-tion.

Postprandial hyperglycemia report-edly increases the prevalence of cardio-vascular diseases (14). If serum GA ishigher relative to A1C in the state of post-prandial hyperglycemia, serum GA mayoffer a better surrogate marker of cardio-vascular risk. Along this line, it has re-cently been reported that serum GA wassignificantly elevated in patients with cor-onary artery stenosis (15).

Acknowledgments No potential conflictsof interest relevant to this article were

reported.The authors thank Dr. Yasuhiro Tahara for

his help in the statistical analyses of the data.

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