Journal of Diabetes and Its Complications 28 (2014) 348–352

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Association of reduced levels of serum 1,5-Anhydro-d-glucitol with carotid atherosclerosis in patients with type 2 diabetes Takao Sato a,⁎, Tomoki Kameyama b, Hiroshi Inoue b a b

Itoigawa General Hospital, Niigata, Japan The Second Department of Internal Medicine, University of Toyama, Toyama, Japan

a r t i c l e

i n f o

Article history: Received 9 August 2013 Received in revised form 20 December 2013 Accepted 8 January 2014 Available online 15 January 2014 Keywords: Atherosclerosis Type 2 diabetes Maximum intima–media thickness Plaque score 1,5-anhydro-D-glucitol

a b s t r a c t Background: HbA1c level represents mean blood glycemic control. 1,5-Anhydro-D-glucitol (1,5-AG) level reflects glycemic fluctuations, a strong risk factor for the development of macroangiopathy. The present study investigated the relationship between serum 1,5-AG levels and macroangiopathy in patients with type 2 diabetes. Methods: A total of 115 consecutive patients with type 2 diabetes, aged 45–79 years, were included. HbA1c, 1,5-AG, and lipid profile were measured. Carotid maximum intima–media thickness (IMT) and plaque score (PS) were determined by carotid sonography. An 1,5-AG level b 14.2 μg/mL was used as a predictor of a postchallenge 2-h blood glucose level N 200 mg/dL. Patients were divided into four groups: A (n = 32), HbA1c≥6.5% and 1,5-AG b 14.2 μg/mL; B (n = 23), HbA1c ≥ 6.5% and 1,5-AG ≥ 14.2 μg/mL; C (n = 24), HbA1c b 6.5% and 1,5-AG b 14.2 μg/mL; and D (n = 36), HbA1c b 6.5% and 1,5-AG ≥ 14.2 μg/mL. Results: HbA1c level had significant positive correlation with IMT and PS. 1,5-AG level had a significant negative correlation with PS. PS was significantly higher in group C than in group D, but similar to that in group B. In multivariate analysis, HbA1c (β = 0.27, p = 0.03) and 1,5-AG (β = − 0.24, P = 0.04) were independent determinants of PS. Conclusions: 1,5-AG level might provide additional information to identify macroangiopathy of patients with type 2 diabetes, especially in those with excellent HbA1c levels. © 2014 Elsevier Inc. All rights reserved.

1. Introduction Death due to ischemic heart diseases and the risk of myocardial infarction are approximately 2 to 6 times greater and the risk of stroke is approximately 2 to 3 times greater in patients with type 2 diabetes mellitus (DM) than in the normal population (Haffner, Lehto, Rönnemaa, Pyörälä, & Laakso, 1998; Kannel & McGee, 1979; Stamler, Vaccaro, Neaton, & Wentworth, 1993). Microvascular complications may be ameliorated and/or inhibited by control of blood glucose levels through maintenance of glycated hemoglobin (HbA1c) below a critical level (Torimoto, Okada, Mori, & Tanaka, 2013). The Diabetes Control and Complications Trial and the UK Prospective Diabetes Study reported that lowering the HbA1c level could prevent development and progression of the chronic complications of DM (The Diabetes Control and Complications Trial Research Group, 1993; UK Prospective Diabetes Study (UKPDS) Group, 1998). That is,

There are neither conflicts of interest nor funding to declare related to this work. ⁎ Corresponding author at: The Second Department of Internal Medicine, Toyama University Hospital, 2630 Sugitani, Toyama 930-0194, Japan. Tel.: +81 76 434 7297; fax: +81 76 434-5026. E-mail address: [email protected] (T. Sato). 1056-8727/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jdiacomp.2014.01.004

thorough glucose control is necessary to prevent or delay the cardiovascular complications of DM. The HbA1c level is considered the gold standard of glycemic control and is widely used for education of patients with DM and monitoring of glycemic control in the clinical setting. However, in recently published randomized controlled trials, including ACCORD (Action to Control Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), and VADT (Veteran Affairs Diabetes Trial), intensive treatment for glycemic control, i.e., lowering of HbA1c to near-normal levels, did not reduce cardiovascular events compared to the standard glucose-lowering targets (Duckworth et al., 2009; The Action to Control Cardiovascular Risk in Diabetes Study Group, 2008; The ADVANCE Collaborative Group, 2008). The HbA1c level reflects mean blood glucose levels over the previous 2–3 months and does not accurately represent glucose fluctuation that may accompany postprandial hyperglycemia and/or hypoglycemic events (Dungan, 2008). 1,5-Anhydro-D-glucitol (1,5-AG) reflects daily glycemic excursions, especially in patients whose HbA1c levels are at or near the goal (Kishimoto et al., 1995), and it also reflects postprandial glucose levels in diabetic patients (Stettler et al., 2008). Recently, it has become clear that glucose fluctuation, especially postprandial

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hyperglycemia, may develop cardiovascular disease (Nakagami & DECODA Study Group, 2004). Therefore, the present study aimed to investigate the relationships between glycemic markers such as HbA1c and 1,5-AG and macroangiopathy in patients with type 2 diabetes. 2. Methods 2.1. Patient population A total of 115 consecutive patients with type 2 diabetes were recruited at the Itoigawa General Hospital, Japan. Based on a previous report (Esposito et al., 2008), the inclusion criteria were as follows: diagnosis of type 2 diabetes for at least 6 months, but less than 10 years; age 45–79 years; and treatment with diet or oral drugs. Comorbidities including hypertension (medication-dependent or documented history), hypercholesterolemia, and cigarette smoking were determined. Criteria for exclusion were: need for insulin use; concomitant chronic diseases including kidney, liver, and cardiovascular system; acute illness; or changes in diet, treatment, or lifestyle within 3 months before the initial assessment. The study protocol was approved by the institutional ethics committee of Itoigawa General Hospital, and written informed consent was obtained from all patients. 2.2. Laboratory assessment A blood sample was taken from the antecubital vein after a minimum of 12 h of fasting, and serum levels of creatinine, blood sugar, lipid profile [total cholesterol, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C)], HbA1c [National Glycohemoglobin Standardization Program (NGSP)], 1,5-AG, hemoglobin and hematocrit were measured.

Fig. 1. Measurement of maximum intima–media thickness (IMT) and plaque score (PS). See text for details. Bif, bifurcation; ECA, external carotid artery; CCA, common carotid artery; ICA, internal carotid artery.

2.4. Statistical analysis 2.3. Carotid ultrasonography assessment The severity of carotid artery atherosclerosis was determined using maximum intima–media thickness (max-IMT) and the plaque score (PS) on carotid ultrasonography as indices of macroangiopathy. High-resolution B mode, color Doppler, and pulse Doppler ultrasonography of both carotid arteries was performed with an ultrasound scanner (Aplio XV, Aplio XG, and Xario, Toshiba Inc., Tokyo, Japan) equipped with a 7.5-MHz linear array transducer by a single experienced sonographer. All images were stored electronically. The max-IMT value was measured as follows (Fig. 1a). The carotid artery was scanned in the longitudinal and transverse projections. The site of the most advanced atherosclerotic lesion showing the greatest distance between the lumen–intima interface and the media– adventitia interface was located in both the right and left carotid arteries. Plaque, designated as focal intima–media thickening ≥ 1.1 mm, was detected by ultrasonography as localized thickening rather than circumferential change of the vessel wall (Ikeda, Kogame, Iijima, Nakamura, & Sugi, 2012). The greatest thickness of the intima– media complex (including plaque) was used to represent the maxIMT value. The PS was calculated by adding the maximal thickness in millimeters of plaques in each segment of both carotid arteries (A + B + C) (Fig. 1b). Segment 1 (S1) was the region of the internal carotid artery (ICA) that was b 15 mm distal to its bifurcation from the common carotid artery (CCA). Segment 2 (S2) was the region of the ICA and the CCA that was b 15 mm proximal to the bifurcation. Segment 3 (S3) was the region of the CCA that was 15–30 mm proximal to the bifurcation. Segment 4 (S4) was the region of the CCA that was ≥30 mm proximal to the bifurcation and below the flow divider (Goto et al., 2011). The length of individual plaques was not considered in determining the PS.

All statistical analyses were performed using the Sigma-Plot software program (version 11, Systat Software, Inc., San Jose, CA, USA). Goto M et al. surveyed 77 Japanese men by performing 75 g OGTT, and suggested an 1,5-AG cutoff level of b 14.2 μg/mL as a predictor of a 2 h-blood glucose level ≥200 mg/dL with 0.78 area under the receiver operating characteristic curve (AUC), 78 % sensitivity, and 72 % specificity (Goto et al., 2011). Based on the levels of HbA1c (NGSP) and 1,5-AG, patients were divided into four groups: A (n = 32, HbA1c

Table 1 Patient characteristics of each group.

Number Age(years) Male BMI(kg/m2) Hypertension Smoking, ever Hemoglobin (g/dl) Hematocrit (%) HbA1c (%) 1.5-AG (μg/ml) Creatinine (mg/dl) LDL (mg/dl) TG (mg/dl) HDL (mg/dl)

Group A

Group B

Group C

Group D

P value

32 69 ± 8 24(75) 22.8 ± 1.9 16(50) 15(47) 12.3 ± 1.7

23 69 ± 6 15(65) 22.9 ± 2.1 10(43) 8(35) 13.1 ± 0.6

24 69 ± 8 16(66) 23.7 ± 3.3 12(50) 9(38) 13.3 ± 0.7

36 68 ± 9 20(56) 24.3 ± 5.0 15(42) 12(33) 13.7 ± 0.5

N.S. N.S. N.S. N.S. N.S. N.S.

37.2 ± 5.4 7.2 ± 0.7 7.6 ± 3.6 0.88 ± 0.14

39.2 ± 1.9 7.1 ± 0.5 17.6 ± 2.1 0.90 ± 0.15

39.3 ± 1.5 6.2 ± 0.2 9.1 ± 2.4 0.88 ± 0.21

40.1 ± 1.8 5.9 ± 0.3 21.1 ± 5.3 0.87 ± 0.24

N.S. b0.01 b0.01 N.S.

90 ± 26 111 ± 54 47 ± 16

100 ± 24 122 ± 30 49 ± 6

105 ± 22 142 ± 55 50 ± 12

94 ± 26 117 ± 51 53 ± 16

N.S. N.S. N.S.

Figures are number(%) or mean ± SD. 1.5-AG, 1,5-Anhydroglucitol; HOMA-IR, Homeostatic model assessment insulin resistance; HOMA-β, Homeostatic model assessment beta cell, BMI, body mass index; LDL, low density lipoprotein; TG, triglyceride; HDL, high density lipoprotein; N.S., not significant.

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T. Sato et al. / Journal of Diabetes and Its Complications 28 (2014) 348–352

Table 2 Medications of each subgroup.

Statins ARBs α-GIs DPP-4 Inhibitors Sulfonylurea Biguanide Pioglitazone

Group A

Group B

Group C

Group D

P value

13 (40) 17 (53) 12 (37) 18 (56) 12 (38) 5 (15) 15 (47)

10 12 6 13 4 2 8

11 (46) 15 (62) 5 (21) 13 (54) 3 (13) 0 (0) 9 (38)

20 (55) 25 (69) 7 (19) 18 (50) 1 (3) 1 (3) 14 (39)

N.S. N.S. N.S. N.S. b0.05 N.S. N.S.

(43) (52) (26) (57) (17) (9) (35)

Figures are number (%). ARBs, angiotensin receptor blockers; α-GIs, α-glucocydase inhibitors; DPP-4, dipeptidyl peptidase-4; N.S., significant.

≥6.5% and 1,5-AG b14.2 μg/mL); B (n = 23, HbA1c ≥6.5% and 1,5-AG ≥14.2 μg/mL); C (n = 24, HbA1c b6.5% and 1,5-AG b 14.2 μg/mL); and D (n = 36, HbA1c b 6.5% and 1,5-AG ≥14.2 μg/mL). The data are presented as means ± SD. Comparisons among the four groups were performed by the χ 2 or Fisher’s exact test for categorical data. Continuous variables, such as the PS and Max-IMT, were compared among the four groups using a Kruskal–Wallis one-way ANOVA on

ranks for nonparametric data, followed by multiple comparisons with Dunn’s method. Correlations of two variables were determined using Spearman’s correlation analysis. Multiple regression analysis (stepwise method) was performed to investigate independent determinants of PS using HbA1c, 1,5-AG and sulfonylurea prescription as explanatory variables. A P value of b0.05 was considered significant. 3. Results There were no significant differences in age, sex, body mass index, hypertension, lipid profile, renal function, hemoglobin and hematocrit among the four groups (Tables 1). However, there were significant differences in sulfonylurea prescription and, by definition, in HbA1c and 1,5-AG levels among the four groups (Tables 1 and 2). The HbA1c level had a significant positive correlation with max-IMT and the PS (R = 0.28, P = 0.01 and R = 0.33, P b 0.01, respectively) (Fig. 2a). The 1,5-AG level had a significant negative correlation with the PS (R = −0.32, P b 0.01), but not with max-IMT (Fig. 2b). The PS was significantly higher in group A than in group D (P b 0.001). In patients without elevated HbA1c, the PS was

a

b

Max-IMT (mm)

Max-IMT (mm) N.S.

R=0.28 P=0.01

HbA1c (%)

PS (mm)

1.5-AG (µg/mL)

PS (mm) R=-0.32 P < 0.01

R=0.33 P