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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-1566
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 3 837-842
Copyright © 2006 by The Endocrine Society

Effects of a Single Administration of Acarbose on Postprandial Glucose Excursion and Endothelial Dysfunction in Type 2 Diabetic Patients: A Randomized Crossover Study

Michio Shimabukuro, Namio Higa, Ichiro Chinen, Ken Yamakawa and Nobuyuki Takasu

Second Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan

Address all correspondence and requests for reprints to: Michio Shimabukuro, M.D., Second Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. E-mail: mshimabukuro-ur{at}umin.ac.jp or me447945{at}members.interq.or.jp.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Postprandial hyperglycemia has been reported to elicit endothelial dysfunction and provoke future cardiovascular complications. A reduction of postprandial blood glucose levels by the {alpha}-glucosidase inhibitor acarbose was associated with a risk reduction of cardiovascular complications, but effects of acarbose on endothelial function have never been elucidated.

Design: This study was aimed to assess the efficacy of acarbose on postprandial metabolic parameters and endothelial function in type 2 diabetic patients. Postprandial peakglucose (14.47 ± 1.27 vs. 8.50 ± 0.53 mmol/liter), plasma glucose excursion (PPGE), and change in the area under the curve ({Delta}AUC)glucose after a single loading of test meal (total 450 kcal; protein 15.3%; fat 33.3%; carbohydrate 51.4%) were significantly higher in diet-treated type 2 diabetic patients (n = 14) than age- and sex-matched controls (n = 12).

Results: The peak forearm blood flow response and total reactive hyperemic flow (flow debt repayment) during reactive hyperemia, indices of resistance artery endothelial function on strain-gauge plethysmography, were unchanged before and after meal loading in controls. But those of diabetics were significantly decreased 120 and 240 min after the test meal. A prior administration of acarbose decreased postprandial peakglucose, PPGE, and {Delta}AUCglucose. The peak forearm blood flow and flow debt repayment were inversely well correlated with peakglucose, PPGE, and {Delta}AUCglucose but not with {Delta}AUCinsulin or the other lipid parameters.

Conclusions: Even a single loading of test meal was shown to impair endothelial function in type 2 diabetic patients, and the postprandial endothelial dysfunction was improved by a prior use of acarbose. Acarbose might reduce macrovascular complication by avoiding endothelial injury in postprandial hyperglycemic status.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CARDIOVASCULAR COMPLICATIONS ARE related to prevailing hyperglycemia, particularly postprandial hyperglycemia. There is increasing epidemiological evidence for the association of postprandial glucose levels and macrovascular complications in nondiabetic (1) and diabetic individuals (2). A reduction of postprandial blood glucose levels by the {alpha}-glucosidase inhibitor acarbose, which delays glucose release from complex carbohydrates, was associated with a risk reduction of cardiovascular disease (3, 4). Metaanalysis of seven randomized, double-blind, placebo-controlled studies on the use of acarbose in diabetic patients indicated that acarbose treatment was associated with a 35% risk reduction of cardiovascular disease (4). The mechanism by which acarbose can lower the risk of cardiovascular events has been asked keenly but are currently unknown.

It is generally believed that vascular endothelium ultimately maintains vascular homoeostasis and endothelial dysfunction develops atherosclerosis and consecutive cardiovascular events (5, 6). Many studies (7, 8) have reported that endothelial function was impaired in type 2 diabetic patients. Although several perturbations such as hyperglycemia-induced oxidative stress, insulin resistance, and clustering of other risk factors (the metabolic syndrome) have been suggested as mechanisms of such endothelial dysfunction (9, 10), postprandial hyperglycemia would be one major cause (10). The profile of postprandial hyperglycemia is determined by many factors, including the timing, quantity, and composition of the meal and the resulting secretion of insulin, and may affect postprandial endothelial function. Postprandial insulin secretion, which is provoked further by mixed meals containing fatty acids and amino acids than glucose alone (10, 11), also may influence endothelial function. However, previous studies mostly have not taken into account direct effects of single loading of normal meal in daily life, which contains carbohydrate, lipid, and protein, on endothelial function.

This placebo-controlled, randomized, crossover study aimed to assess effects of single loading of standard meal with or without a prior use of acarbose on postprandial glucose and lipid profiles and endothelial function in type 2 diabetic patients.


   Subjects and Methods
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 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Diet-treated type 2 diabetic patients without a history of cardiovascular complication and age- and sex-matched healthy subjects with normal glucose tolerance were enrolled in this study. The study protocol was approved by the Ethical Committee of the University of the Ryukyus and carried out in accordance with the principles of the Declaration of Helsinki as revised in 2000, and all subjects gave informed consent. No subjects were taking any medications to influence endothelial function, and all abstained from alcohol, tobacco, and strenuous physical activity for 24 h and caffeine-containing drinks overnight.

Study protocol

The acute effects of a test meal (total 450 kcal; protein 15.3%; fat 33.3%; carbohydrate 51.4%, a recipe proposed by a working group of the Japan Diabetes Society) with a prior use of placebo or acarbose on forearm blood flow (FBF) was studied in a crossover design. Studies were done on two separate mornings at least 1 wk apart. After overnight fasting, either 100 mg acarbose (Bayer, Yakuhin, Tokyo, Japan) or placebo was ingested, followed by loading of test meal. The order to receive pills (placebo or acarbose) was randomized, and group (control or diabetic) and the kind of pills taken were blinded to the examiner. Blood samples were obtained at 0, 30, 60, 90, 120, and 240 min. FBF was measured using a mercury-filled SILASTIC (Dow Corning, Midland, MI) strain-gauge plethysmograph (EC-5R, D. E. Hokanson, Inc., Issaquah, WA) as described (12, 13). Calculations of blood flow debt incurred during arterial occlusion, reactive hyperemic flow, and blood flow debt repayments (FDRs) were made as described (14): blood flow debt (milliliters) = control flow rate (milliliters per second) x duration of occlusion (seconds); reactive hyperemic flow (milliliters) = [total flow during reactive hyperemia(milliliters)] – [control flow rate (milliliters per second) x duration of reactive hyperemia (seconds)]; blood FDR (percent) = (reactive hyperemic flow/blood flow debt) x 100. Before and after release of a 5-min upper arm cuff occlusion at 200 mm Hg (reactive hyperemia) and after a single sublingual administration of 0.3 mg nitroglycerin (NTG, Nihonkayaku Co., Tokyo, Japan), FBF was measured by repeated inflations of the upper arm at 40 mm Hg during a wrist cuff inflation at 200 mm Hg. In the preliminary study, we confirmed the reproducibility of reactive hyperemia and sublingual NTG-induced vasodilation on two separate occasions in healthy male subjects (12).

Biochemical measurements

Venous blood samples were obtained in tubes containing EDTA-sodium (1 mg/ml) and was immediately separated for plasma by centrifugation at 3000 rpm at 4 C for 10 min. Routine chemical methods were used to determine the plasma concentrations of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, free fatty acids, glucose, and insulin. Plasma endothelin-1 levels were measured with a commercial RIA kit (NEN Life Science Products, Boston, MA), and plasma nitrate plus nitrite (NOx) levels were determined as the metabolic end products, i.e. nitrite and nitrate, by enzymatic catalysis coupled with Griess reaction after deproteinization as reported (13).

Statistical analysis

Values are expressed as the mean ± SE. Two-tailed unpaired Student’s t test or one-way factorial ANOVA, followed by Bonferroni’s post hoc comparisons, was used to compare intergroup or intragroup means. Comparisons of time course curves during meal loading were analyzed by two-factor repeated-measures ANOVA, followed by Bonferroni’s post hoc intragroup comparisons. Relationships between variables were estimated with the simple regression analysis. P < 0.05 was considered statistically significant. Analyses were processed using StatView J-5.0 software package (SAS Institute Inc., Cary, NC) or InStat 3 for Macintosh (version 3.0b, GraphPad Software, Inc., San Diego, CA).


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The baseline characteristics of the 14 diabetic subjects and 12 healthy controls are shown in Table 1Go. The baseline metabolic parameters were shown as preprandial state in Table 2Go, and the mean value of glycosylated hemoglobin A1c in diabetic subjects was 8.0 ± 0.6%. All patients were well tolerated and no adverse events were observed during the study. Systemic hemodynamics and metabolic parameters at baseline were comparable between 2 study days of diabetic subjects.


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  		TABLE 1. General characteristics of studied patients

 

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  		TABLE 2. Plasma biochemical parameters at the pre- and postprandial state

 
The effects of test meal loading with placebo or acarbose 100 mg on plasma glucose, insulin, and lipid levels are shown in Fig. 1Go and Table 2Go. After the test meal with placebo, plasma glucose levels of controls were increased from baseline 4.87 ± 0.13 mmol/liter to a peak of 8.50 ± 0.53 mmol/liter at 60 min (peakglucose) and returned to baseline at 240 min (Fig. 1AGo), and those of diabetics were from baseline 9.48 ± 1.07 mmol/liter to a peak of 14.47 ± 1.27 mmol/liter at 60 min. Postprandial peakglucose, plasma glucose excursion (PPGE), and change in the area under the curve ({Delta}AUC)glucose were significantly higher in diabetics than controls. Plasma insulin levels of controls were rapidly increased and peaked at 30–60 min, but those of diabetics were increased slowly and peaked at 90 min (Fig. 1BGo). Plasma free fatty acid levels were rapidly decreased after the test meal in controls and diabetics (Fig. 1CGo). Triglyceride levels of controls were not changed after meal loading, but those of diabetics were gradually increased, reaching 2.30 ± 0.40 mmol/liter at 120 min and 2.43 ± 0.41 mmol/liter at 240 min (Fig. 1DGo). Total and HDL cholesterol levels were unchanged before and after test meal loading in controls and diabetics (Fig. 1Go, E and F).


Figure 1
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  		FIG. 1. Plasma glucose, insulin, free fatty acid (FFA), triglyceride, and total and HDL cholesterol levels after loading of test meal (total 450 kcal; protein 15.3%; fat 33.3%; carbohydrate 51.4%) in control subjects with a prior use of placebo ({triangleup}) or diabetic patients with a prior use of placebo ({circ}) or 100 mg acarbose (•). Data represent the mean ± SEM. The P values for curve difference by two-factor repeated-measures ANOVA, followed by Bonferroni’s post hoc intragroup comparisons, were shown. *, P < 0.01 vs. 0 min.

 
The peak FBF response and total reactive hyperemic flow (FDR), indices of resistance artery endothelial function, were unchanged before and after meal loading in controls. But those of diabetics were significantly decreased 120 and 240 min after the test meal. A prior administration of acarbose decreased peakglucose to 12.77 ± 1.25 mmol/liter, PPGE from 4.98 ± 0.40 to 3.34 ± 0.39 mmol/liter, and {Delta}AUCglucose from 536 ± 72 to 369 ± 62 min/mmol·liter. With acarbose, the postprandial decreases in peak FBF and FDR were abolished (Fig. 2Go). When plotted against plasma biochemical parameters, the peak FBF and FDR were inversely well correlated with peakglucose, PPGE, and {Delta}AUCglucose but not with {Delta}AUCinsulin (Fig. 3Go) or the other lipid parameters (data not shown). At baseline before meal loading, the maximal flow after NTG was comparable between diabetic and control subjects. The values did not change after meal loading and was not affected by acarbose pretreatment.


Figure 2
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  		FIG. 2. A, Baseline (open bars) and peak FBF (shaded bars) during reactive hyperemia before (0 min) and 120 and 240 min after loading of test meal (total 450 kcal; protein 15.3%; fat 33.3%; carbohydrate 51.4%) in control subjects with a prior use of placebo (left panel) or in diabetic patients with a prior use of placebo (middle panel) or 100 mg acarbose (right panel). B, Total reactive hyperemic flow (FDR) during reactive hyperemia. FDR (percent) = (reactive hyperemic flow/blood flow debt) x 100. Data represent the mean ± SEM. One-way factorial ANOVA, followed by Bonferroni’s post hoc comparisons, was used to compare intragroup means. *, P < 0.05; **, P < 0.01 vs. 0 min. T2DM, Type 2 diabetes mellitus.

 

Figure 3
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  		FIG. 3. Correlation between peak FBF and FDR and postprandial peakglucose, PPGE, {Delta}AUCglucose, and {Delta}AUCglucose in control subjects with a prior use of placebo ({triangleup}) or in diabetic patients with a prior use of placebo ({circ}) or 100 mg acarbose (•). Pearson’s correlation coefficients (r) and P values (p) were shown.

 
Plasma NOx values in controls were 51 ± 11 (baseline), 45 ± 10 (120 min), and 45 ± 10 (240 min) µmol/liter, and those in diabetic groups were 51 ± 11 (baseline), 45 ± 10 (120 min), and 45 ± 10 µmol/liter (240 min) (not significant). Acarbose pretreatment did not affect those values in diabetics (49 ± 10, 40 ± 7, and 36 ± 6 µmol/liter, respectively). Baseline plasma endothelin-1 values were not different between control and diabetic subjects (1.8 ± 0.1 vs. 2.0 ± 0.0 pg/ml) and those were not affected by test meal loading (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The major findings of this study are: first, endothelial function was impaired in type 2 diabetic patients by only a single loading of standard test meal; and second, such postprandial endothelial dysfunction was improved with a reduction of postprandial hyperglycemia by acarbose.

Postprandial endothelial function

It is generally believed that vascular endothelium ultimately maintains vascular homoeostasis and endothelial cell dysfunction develops atherosclerosis and consecutive cardiovascular events (5). In vivo assessment of endothelial cell function refers to a measure of endothelial cell response to stimulation such as vasoactive substances released by or those that interact with the vascular endothelium (6). Endothelium-dependent vasodilation in peripheral circulations can serve as a useful biomarker of atherosclerosis (6), and abnormality of endothelium-dependent vasodilation has been demonstrated in type 2 diabetic patients (7, 8).

In this study, the forearm endothelial function, assessed by a resistant vessel blood flow increase during reactive hyperemia, was impaired by only a single loading of test meal in diabetic patients but not in healthy controls. We (14) and others (15) previously demonstrated that the flow-mediated forearm blood increase was impaired by a single oral challenge of 75 g glucose in type 2 diabetic patients. Because not only postprandial hyperglycemia but also postprandial hyperlipidemia could cause endothelial dysfunction in diabetic patients (16), this study determined effects of postprandial glucose and lipid changes on endothelium-dependent vasodilatation using a standard test meal, which contains total energy of 450 kcal with 15.3% protein, 33.3% fat, and 51.4% carbohydrate. As shown in Fig. 1Go, plasma glucose levels reached to a peak at 60 min and returned to baseline at 240 min, whereas triglyceride levels remained high at 120 and 240 min. Decreases in the peak FBF and FDR at 240 min postprandial were inversely well correlated with peakglucose, PPGE, and {Delta}AUCglucose but not with glucose nor triglyceride level at 240 min. Given the facts, endothelial function was largely associated with intensity of the postprandial glucose peak but not with glucose and triglyceride levels of the time.

Effects of acarbose on postprandial endothelial function

With acarbose, the postprandial decreases in peak FBF and FDR were abolished (Fig. 2Go). When plotted against plasma biochemical parameters, the peak FBF and FDR were inversely well correlated with peakglucose, PPGE, and {Delta}AUCglucose but not with {Delta}AUCinsulin (Fig. 3Go) and the other lipid parameters (data not shown). As discussed earlier, postprandial endothelial function in diabetic subjects was mostly affected by intensity of the postprandial glucose peak. Because acarbose treatment decreased peakglucose, PPGE, and {Delta}AUCglucose but not the 240-min glucose level, it is possible that improvement of endothelial function by acarbose was achieved by decreasing the postprandial glucose peak. A potential mechanism by which postprandial hyperglycemia impairs endothelial function is generation of reactive oxygen species (ROS) (17). Yano et al. (18) reported that a short-time exposure (3 h) to 25 mmol/liter glucose increased intracellular ROS generation in cultured bovine aortic endothelial cells. Previously we reported that nateglinide, a phenylalanine-derived insulin secretagogue, could also improve postchallenge endothelial function in type 2 diabetic patients (14). Collectively, postprandial endothelial function could be improved by an intervention to reduce postprandial glucose peak at least in part.

Vallejo et al. (19) reported that acetylcholine-induced endothelium-dependent relaxations were impaired in aortic and mesenteric vessels isolated from streptozotocin-induced diabetic rats, and such endothelial dysfunction was improved either with suppression of blood glucose levels by acarbose or with ROS suppression by superoxide dismutase. Taken together, it was still possible that suppression of postchallenge hyperglycemia by acarbose decreased generation of ROS and the ROS-mediated impairment of endothelial function, although we could not detect changes of urinary 8-epi-prostaglandin-F2{alpha}, one reliable marker of whole-body oxygen stress, during the test meal loading (data not shown).

Previous studies showed that insulin can induce either vasodilation by increasing NOx levels or vasoconstriction by stimulating endothelin-1 levels (20), and the net balance between vasodilator and vasoconstrictor effects of insulin is altered in diabetic patients in favor of a relative vasoconstriction (21). In our study, there were no significant differences in plasma NOx and endothelin-1 levels before and after meal ingestion in control and diabetic subjects. Because plasma levels of endothelin-1 may not truly reflect the activity of endothelin-1 and endothelin receptor subtype A (ETA)-dependent mechanism could be involved in vascular derangements of diabetic condition, additional future studies need to be done.

Study limitations

First, we used a noninvasive FBF measurement during reactive hyperemia (RH) by strain-gauge plethysmography to assess endothelial function because the invasive measurements of FBF by intraarterial infusion of vasoactive agents (9, 10) is time consuming and cannot be used to assess a short-period change as in the postprandial state. It is known that vasodilation during reactive hyperemia is caused by multiple factors such as metabolic factors other than nitric oxide. Accordingly, we used peak FBF as a combination marker of shear stress and local metabolic factors at early phase of RH and FDR as a relatively hyperemia is caused by multiple factors such as metabolic factors other than nitric oxide-dependent marker at mid- to late phase of RH (12).

Second, there is no real-time tracking method to detect ROS in vivo, and that might be a reason we could not detect generation of ROS during meal loading.

In summary, only a single loading of test meal was shown to impair endothelial function in type 2 diabetic patients, and the postprandial endothelial dysfunction was improved by a prior use of acarbose. Acarbose might be a promising oral prandial therapy in treating endothelial function seen in patients with type 2 diabetes mellitus by decreasing the postprandial glucose excursion.


   Acknowledgments
 
We deeply appreciate members of the working group of the Japan Diabetes Society for a recipe of the test meal.


   Footnotes
 
First Published Online December 20, 2005

Abbreviations: {Delta}AUC, Change in the area under the curve; FBF, forearm blood flow; FDR, flow debt repayment; HDL, high-density lipoprotein; NOx, nitrate plus nitrite; NTG, nitroglycerin; peakglucose, peak plasma glucose level; PPGE, plasma glucose excursion; RH, reactive hyperemia; ROS, reactive oxygen species.

This work was supported by a grant from the Japanese Society for the Promotion of Science (14571103).

The authors have no conflict of interest.

Received July 14, 2005.

Accepted December 9, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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