Skip to content

Advertisement

Cardiovascular Diabetology

  • Original investigation
  • Open Access

Miglitol improves postprandial endothelial dysfunction in patients with acute coronary syndrome and new-onset postprandial hyperglycemia

  • Daisuke Kitano1,
  • Masaaki Chiku2,
  • Yuxin Li3,
  • Yasuo Okumura1,
  • Daisuke Fukamachi1,
  • Tadateru Takayama1,
  • Takafumi Hiro1, 3,
  • Satoshi Saito2, 3 and
  • Atsushi Hirayama1Email author
Cardiovascular Diabetology201312:92

https://doi.org/10.1186/1475-2840-12-92

©  Kitano et al.; licensee BioMed Central Ltd. 2013

Received: 5 February 2013

Accepted: 17 June 2013

Published: 19 June 2013

Abstract

Background

Hyperglycemia, a risk factor for development of cardiovascular disease, causes endothelial dysfunction. Alpha-glucosidase inhibitors (α-GIs) improve postprandial hyperglycemia (PPHG) and may have favorable effects on associated cardiovascular disease. Effects of α-GIs in patients with acute coronary syndrome (ACS) and PPHG remain unclear; thus, we assessed the effect of α-GI miglitol on endothelial function in such patients by digital reactive hyperemia peripheral arterial tonometry (RH-PAT).

Methods

Fifty-four patients with ACS who underwent primary percutaneous coronary intervention were enrolled in the study: 36 with new-onset PPHG and 18 with normal glucose tolerance. Eighteen PPHG patients were given 50 mg of miglitol with each meal for 1 week. Endothelial function was assessed on the basis of the RH-PAT index (RHI) before and after the 1-week miglitol treatment. The other 18 PPHG patients and the 18 NGT patients were not given any anti-diabetic agent for 1 week, and endothelial function was assessed.

Results

Postprandial RHI decreased significantly in patients with PPHG. Miglitol improved PPHG significantly; postprandial RHI also improved (p = 0.007). Significant inverse correlation was found between the postprandial change in RHI and postprandial fasting-to-60-minutes surge in glucose (r = -0.382, p = 0.009). Moreover, the improvement in endothelial function correlated with the reduced postprandial glucose surge achieved with miglitol (r = -0.462, p = 0.001).

Conclusions

Postprandial changes in glucose are related to endothelial dysfunction in ACS. Miglitol-based improvement in PPHG appears to improve endothelial function. The effect of miglitol on glucose-dependent endothelial function might improve outcomes of ACS.

Keywords

Postprandial hyperglycemiaEndothelial functionReactive hyperemia peripheral arterial tonometryAcute coronary syndromeAlpha-glucosidase inhibitorMiglitol

Introduction

Several studies have surprisingly shown that intensive glycemic control with insulin or sulfonylurea does not reduce the mortality associated with cardiovascular events in persons with diabetes [1–3]. Furthermore, cardiovascular morbidity and overall mortality are associated with postprandial hyperglycemia (PPHG) rather than the fasting blood glucose level [4–6], and chronic hyperglycemia induces endothelial dysfunction [7–9]. In animal studies, repetitive PPHG has been shown to produce endothelial dysfunction and increase cardiac ischemia and reperfusion injury [10–12]. In addition, vascular endothelial dysfunction contributes to cardiovascular events and can be useful for identifying patients at high risk for ischemic heart disease [13–15]. Thus, PPHG may cause endothelial dysfunction and subsequent atherosclerosis, increasing the risk of cardiovascular events. However, it remains unclear whether PPHG actually worsens endothelial function of patients with acute coronary syndrome (ACS).

Alpha-glucosidase inhibitors (α-GIs) competitively and reversibly inhibit intestinal membrane-bound α-glucosidase required for degradation of disaccharides and complex carbohydrates in the upper part of the small intestine [16–18]. The effect of α-GIs on the intestinal membrane manifests as a reduction in PPHG. Thus, treatment with α-GI acarbose might have a favorable effect on endothelial function in type 2 diabetes patients with ischemic heart disease [19–22]. Miglitol is an α-GI with unique pharmacokinetic properties. It is absorbed rapidly and almost completely from the small intestine after oral administration. In an animal study, miglitol was shown to reduce myocardial infarct size [23]. Moreover, vascular function of patients improved when miglitol was administrated repeatedly [24]. Thus, compared to other α-GIs, miglitol can be expected to suppress PPHG more strongly and thereby reduce the incidence of cardiovascular events. However, little is actually known regarding the specific effects of miglitol on postprandial glycemia and endothelial function in patients with ACS.

We investigated endothelial function in patients with and without PPHG who had undergone primary percutaneous coronary intervention (PCI) for ACS. We then assessed the effects of miglitol on postprandial glycemia and endothelial function in the ACS patients with PPHG.

Methods

Study participants

We recruited 54 ACS patients, aged 20 to 79 years, who underwent successful primary PCI at Nihon University Itabashi Hospital, Tokyo, Japan, between April 1, 2009 and March 31, 2011. The patients were not previously diagnosed with type 1 (insulin-dependent) or type 2 diabetes mellitus (DM), not previously treated with insulin or oral anti-diabetic agents, not on diet therapy, and without a hemoglobin A1c (HbA1c) level > 7.9% (NGSP units) or fasting blood glucose > 200 mg/dL. Patients with severe myocardial infarction, heart failure, severe hepatic disease, renal insufficiency (serum creatinine > 2 mg/dL or treatment by hemodialysis), or collagen disease patients were excluded. The 54 enrolled patients were diagnosed as having (n = 36) or not having (n = 18) PPHG, i.e., normal glucose tolerance (NGT), according the postprandial glucose level at 60 minutes after loading of a test meal. PPHG was defined as a postprandial glucose level ≥ 130 mg/dL at 60 minutes. The test meal was that recommended by the Japan Diabetes Society working group [25] and consisted of 56.5 g of carbohydrate, 16.0 g of protein, and 18.0 g of fat for a total 460 kcal of energy (Kewpie, Tokyo, Japan). The test meal was served with a 100-mL glass of water and ingested within 15 minutes. Yoshino et al. reported that the peak glucose level is reached 60 minutes after test meal loading, and that the glucose level at 60 minutes after test meal loading correlated with that at 120 minutes after glucose loading. A blood glucose value of 140 mg/dL at 120 minutes after glucose loading corresponds to 130 mg/dL at 60 minutes after test meal loading [25–27]. Thus, PPHG was defined as a postprandial glucose level ≥ 130 mg /dL at 60 minutes after test meal loading. For all patients enrolled, previously prescribed medications and daily diet were maintained throughout the study period. The study was approved by the Ethics Committee of Nihon University School of Medicine, and all participants provided written informed consent.

Study design

The study was a 1-week, randomized, single-blind controlled clinical trial. As shown in Figure 1, a baseline dietary tolerance test predicated on the test meal was performed 1 week after successful primary PCI to avoid any possible influence of ACS on dietary tolerance. All vasoactive medications were discontinued at least 12 hours prior to the test, and the test meal was given after a 12-hour overnight fast. We evaluated several biochemical markers associated with metabolism, inflammation, oxidative stress, and endothelial function in the fasting state and at 60 minutes and 120 minutes after test meal loading. The patients with PPHG were randomly divided into two groups; a PPHG-miglitol group (n = 18) that was given 50 mg of miglitol three times a day with each meal for 1 week and a PPHG-control group (n = 18) that was not given miglitol or any other anti-diabetic agent for 1 week. Upon completion of the 1-week miglitol intervention/non-intervention (control), the dietary tolerance test was repeated, and blood biochemical markers and endothelial function were re-assessed. The 18 remaining patients without PPHG (NGT group) also underwent a second dietary tolerance test at 1 week with re-assessment of blood biochemical markers and endothelial function.
Figure 1
Figure 1

Study flowchart. ACS acute coronary syndrome, PCI percutaneous coronary intervention, BGL blood glucose level, PPHG postprandial hyperglycemia, NGT normal glucose tolerance, DM: diabetes mellitus, RH-PAT reactive hyperemia peripheral arterial tonometry.

Laboratory tests

Standard blood samples were drawn in the fasting state to measure HbA1c, 1,5-anhydro-D-glucitol (1,5-AG), glycated albumin (GA), total cholesterol (T-CHOL), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), creatine phosphokinase (CPK), serum creatinine, estimated glomerular filtration rate (eGFR), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP). Insulin resistance was evaluated by means of homeostasis model assessment of insulin resistance (HOMA-IR).

Plasma glucose, serum insulin, triglyceride (TG), high sensitivity C-reactive protein (hs-CRP), and derivatives of reactive oxidative metabolites (d-ROMs) as an oxidative stress marker measured with a free radical analytical system (FRAS4; H-&-D srl, Parma, Italy) [28] were measured in the fasting state and at 60 minutes and 120 minutes after test meal loading.

We also assessed incretins glucagon-like petide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in the fasting state and at 60 minutes and 120 minutes after test meal loading. Blood samples were collected from 8 patients in the PPHG-miglitol group and 8 patients in the NGT group, and 10 μL of dipeptidyl peptidase-4 inhibitor per 1 mL blood was added immediately. The blood samples were centrifuged at 1,000 x g for 10 minutes under refrigeration. Total GLP-1 (9–36) was measured with an enzyme-linked immunosorbent assay (ELISA) kit (ALPCO Diagnostics Inc., Salem, NH, USA) and total GIP was measured with an ELISA kit (Millipore Corp., Billerica, MA, USA).

Assessment of endothelial function

Endothelial function was evaluated in the fasting state and at 60 minutes and 120 minutes after test meal loading by digital reactive hyperemia peripheral arterial tonometry (RH-PAT) (Endo-PAT 2000, Itamar Medical Ltd., Caesarea, Israel). RH-PAT was performed as previously described [29, 30]. Briefly, a blood pressure cuff was placed on the participant’s upper right arm; the left arm was used for control. A PAT probe was placed on the right and left forefingers. The RH-PAT protocol began with a 5-minute baseline measurement. The cuff on the test arm was then inflated to 60 mmHg above the baseline systolic pressure or to at least 200 mmHg for 5 minutes. The cuff was then deflated to induce RH. The RH-PAT data were digitally analyzed online (Endo-PAT 2000 software, ver. 3.0.4). The RH-PAT index (RHI), which reflects the extent of reactive hyperemia, was calculated as the ratio of the average amplitude of the PAT signal over 1 minute, starting 1.5 minutes after cuff deflation (occluded arm, A; control arm, C), divided by the average amplitude of the baseline PAT signal over a 2.5-minute period before cuff inflation (occluded arm, B; control arm, D). Thus, RHI = (A/B)/(C/D).

Statistical analysis

Continuous variables are presented as mean ± SEM; disorders, e.g., hypertension, are presented as the number and percentage of patients affected; and use of various medications is presented as the number and percentage of patients receiving them. Between-group differences in data were subjected to one-way analysis of variance (ANOVA). Between-group differences in the prevalence of risk factors and use of medications were analyzed by chi-square test. Two-way ANOVA with repeated measures followed by Tukey’s post hoc test was used to detect significant changes in measured variables. Correlation was determined by linear regression analysis. All statistical analyses were performed with JMP, ver. 9 (SAS Institute, Cary, NC, USA). p < 0.05 was considered statistically significant.

Results

Baseline patient characteristics and blood test results

Baseline characteristics and laboratory values of patients are shown per study group in Table 1. There was no statistical between-group difference in age; sex; body mass index (BMI); prevalence of hypertension, hyperlipidemia, or chronic kidney disease; or history of smoking. There was no significant difference in the use of most medications (calcium channel blockers, beta blockers, angiotensin II receptor blockers [ARBs]/angiotensin converting enzyme inhibitors [ACE-Is], or statins). Neither was there any between-group difference in the hemoglobin, serum creatinine, eGFR, T-CHOL, HDL-C, LDL-C, TG, CPK, or NT-proBNP level. Use of nitrates, including nicorandil, was more prevalent in the NGT group than in the PPHG groups. The baseline HbA1c, GA, and HOMA-IR levels were significantly higher and the 1,5-AG level was significantly lower in the patients with PPHG than in the NGT patients. As expected, fasting plasma glucose levels were significantly higher in the patients with PPHG than in the NGT patients (Additional file 1: Table S1). However, no differences in fasting serum insulin, TG, and oxidative stress marker d-ROMs were noted between groups. In addition, the fasting RHI did not differ between groups (Additional file 1: Table S1).
Table 1

Baseline characteristics of study patients per group

 

PPHG-miglitol

PPHG-control

NGT

 

n = 18

n = 18

n = 18

General characteristics

   

Age (years)

60.6 ± 2.1

65.1 ± 2.2

60.3 ± 2.1

Sex, male, n (%)

15 (83.3)

14 (77.8)

16 (88.9)

Body mass index (kg/m2)

25.1 ± 0.5

25.0 ± 0.7

25.3 ± 0.5

Hypertension, n (%)

15 (83.3)

16 (88.9)

16 (88.9)

Dyslipidemia, n (%)

15 (83.3)

14 (77.8)

14 (77.8)

Smoking, n (%)

12 (66.6)

11 (61.1)

10 (55.6)

Chronic kidney disease, n (%)

4 (22.2)

5 (27.8)

7 (38.9)

Laboratory values

   

Hemoglobin (mg/mL)

13.6 ± 0.3

13.2 ± 0.2

13.1 ± 0.3

Creatinine (mg/mL)

0.82 ± 0.04

0.85 ± 0.04

1.01 ± 0.06

eGFR (mL/min/1.73m2)

69.5 ± 3.5

70.7 ± 2.6

63.1 ± 3.5

Hemoglobin A1c (%)

6.4 ± 0.1*

6.5 ± 0.1†

5.6 ± 0.1

1,5-AG (μg/mL)

11.4 ± 1.1**

11.5 ± 1.0††

20.8 ± 1.8

Glycated albumin (%)

15.4 ± 0.4*

15.2 ± 0.5†

14.2 ± 0.3

HOMA-IR

2.69 ± 0.38*

2.22 ± 0.47†

1.69 ± 0.17

Total cholesterol (mg/dL)

196.0 ± 12.2

195.5 ± 8.2

202.1 ± 7.1

HDL cholesterol (mg/dL)

45.8 ± 2.1

47.0 ± 2.1

46.0 ± 2.5

LDL cholesterol (mg/dL)

126.6 ± 12.0

125.3 ± 7.6

136.3 ± 5.7

Creatine phospho-kinase (max) (IU/L)

2360.6 ± 465.2

2453.3 ± 487.6

3174.7 ± 626.2

NT-proBNP (pg/mL)

666.3 ± 280.5

664.9 ± 238.6

616.7 ± 279.9

Medications being used

   

Calcium channel blockers, n (%)

4 (22.2)

8 (44.4)

6 (33.3)

Beta blockers, n (%)

12 (66.7)

8 (44.4)

18 (44.4)

ACE-Is or ARBs, n (%)

13 (72.2)

12 (66.7)

12 (66.7)

Nitrates, n (%)

11 (61.1)**

12 (66.7)††

18 (100)

Statins, n (%)

15 (83.3)

14 (77.8)

14 (77.8)

Data are expressed as mean ± SEM or number and percentage of patients. *p < 0.05, PPHG-miglitol vs. NGT; **p < 0.01, PPHG-miglitol vs. NGT; †p < 0.05, PPHG-control vs. NGT; ††p < 0.01, PPHG-control vs. NGT.

PPHG-miglitol group: patients with postprandial hyperglycemia given miglitol for 1 week; PPHG-control group: patients with PPHG not given miglitol for 1 week; NGT group: patients with normal glucose tolerance; eGER: estimated glomerular filtration rate; 1,5-AG: 1,5-anhydro-D-glucitol; HOMA-IR: homeostasis model assessment of insulin resistance; HDL: high density lipoprotein; LDL: low density lipoprotein; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; ACE-I: angiotensin converting enzyme inhibitor; ARB: angiotensin II receptor blocker.

There were no differences in baseline patient characteristics or biochemical markers between the PPHG-miglitol group and the PPHG-control group.

Postprandial changes in blood glucose and insulin

Plasma glucose levels and serum insulin levels after overnight fasting and at 60 minutes and 120 minutes after the test meal are shown in Figure 2 and Additional file 2: Figure S1. With miglitol administration, postprandial plasma glucose levels were decreased significantly at 60 and 120 minutes after the test meal (from 175.2 ± 4.9 mg/dL to 132.2 ± 4.8 mg/dL at 60 minutes, p < 0.001; from 171.5 ± 6.6 mg/dL to 137.1 ± 6.1 mg/dL at 120 minutes, p < 0.001; Figure 2A), and postprandial serum insulin levels were also decreased significantly (from 47.1 ± 5.2 μU/mL to 27.0 ± 6.1 μU/mL at 60 minutes, p = 0.031; from 56.6 ± 5.8 μU/mL to 34.1 ± 5.5 μU/ml at 120 minutes, p = 0.015; Figure 2B). Plasma glucose levels and serum insulin levels improved significantly in the PPHG-miglitol group compared to those in the PPHG-control group. In the PPHG-control group and the NGT group, there were no significant time-specific changes in glucose or insulin levels between time point (Figure 2A and B, and Additional file 2: Figure S1A and B).
Figure 2
Figure 2

Changes in plasma glucose levels (A), serum insulin levels (B), triglyceride levels (C), and RHI (D) in the PPHG groups, before and after the 1-week intervention (miglitol)/non-intervention (control). Data are expressed as mean ± SEM. *p < 0.05, PPHG-miglitol before vs. PPHG-miglitol after; **p < 0.01, PPHG-miglitol before vs. PPHG-miglitol after; †p < 0.05, PPHG-miglitol after vs. PPHG-control after; ††p < 0.01, PPHG-miglitol after vs. PPHG-control after.RHI: RH-PAT index; PPHG: postprandial hyperglycemia; PPHG-miglitol before: patients with PPHG before miglitol administration; PPHG-miglitol after: patients with PPHG given 50 mg of miglitol every meal for 1 week; PPHG-control before: patients with PPHG before non-intervention; PPHG-control after; patients with PPHG after 1-week non-intervention.

Postprandial changes in lipids, oxidative stress and inflammatory markers

The postprandial TG levels increased gradually in both the PPHG-miglitol group and the PPHG-control group with no between-group-difference (Figure 2C). There was no statistical difference in the postprandial TG or d-ROMs levels either before or after 1-week therapy between the PPHG-miglitol group and PPHG-control group (Figure 2C and 3A). However, in the NGT group, there was a significant time-specific decrease in the fasting d-ROMs level (from 469.8 ± 14.6 U.CARR to 367.0 ± 24.5 U.CARR, p = 0.004; Additional file 1: Table S1). Furthermore, the fasting hs-CRP level in the PPHG-miglitol group decreased significantly (from 0.778 ± 0.105 mg/dL to 0.359 ± 0.094 mg/dL, p = 0.001), and it also decreased significantly compared to that in the PPHG-control group (p = 0.005) (Figure 3B).
Figure 3
Figure 3

Fasting d-ROMs levels (A), fasting hs-CRP levels (B), and postprandial percent changes in RHI (C) in the PPHG groups, before and after the 1-week intervention (miglitol)/non-intervention (control). Data are expressed as mean ± SEM. d-ROMs: derivatives of reactive oxidative metabolites; hs-CRP: high sensitivity C-reactive protein; RHI: RH-PAT index; PPHG: postprandial hyperglycemia; PPHG-miglitol before: patients with PPHG before miglitol administration; PPHG-miglitol after: patients with PPHG given 50 mg of miglitol every meal for 1 week; PPHG-control before: patients with PPHG before non-intervention; PPHG-control after; patients with PPHG after 1-week non-intervention; postprandial percent change in RHI: (120 minutes RHI – fasting RHI)/fasting RHI × 100; NS: not significant.

Postprandial changes in endothelial function

Baseline fasting RHI in the NGT group was 1.62 ± 0.07, and neither RHI at 60 minutes (1.61 ± 0.08) nor RHI at 120 minutes (1.55 ± 0.05) differed from the fasting value (p = 0.834 and p = 0.285, respectively) (Additional file 2: Figure S1D). Nor was there a significant change in postprandial endothelial function after the experimental week. In other words, postprandial endothelial function was not significantly impaired in this group.

RHI did change significantly, however, in patients with PPHG (Figure 2D). In the PPHG-miglitol group, postprandial RHI decreased significantly from a baseline value of 1.56 ± 0.06 to 1.43 ± 0.07 by 60 minutes, and to 1.37 ± 0.06 by 120 minutes (p = 0.040 and p = 0.002, respectively). In the PPHG-control group, RHI also decreased significantly from a baseline value of 1.49 ± 0.13 to 1.41 ± 0.10 by 60 minutes, and to 1.41 ± 0.09 by 120 minutes (p = 0.049 and p = 0.048, respectively). RHI values at 60 minutes and 120 minutes were decreased significantly in patients with PPHG in comparison to the values in the NGT patients, suggesting significantly impaired postprandial endothelial function in both PPHG groups.

After miglitol administration, the fasting RHI was decreased at 60 minutes (from 1.53 ± 0.07 upon fasting to 1.37 ± 0.19 at 60 minutes, p = 0.019) but was restored to above the fasting level by 120 minutes (from 1.37 ± 0.07 to 1.56 ± 0.09, p = 0.031), and it improved significantly compared to that in the PPHG-control group (p = 0.041). We also evaluated postprandial endothelial function as percent change in RHI: [(120 minutes RHI – fasting RHI)/fasting RHI × 100]. The percent postprandial change in RHI was significantly suppressed after miglitol administration in the PPHG-miglitol group compared to that in the same group before miglitol administration and that in the PPHG-control group at 1 week (p = 0.007, p = 0.031, respectively; Figure 3C).

Postprandial changes in incretins

We assessed incretins total GLP-1 and total GIP in the most recently enrolled patients in the PPHG-miglitol group (n = 8) and the NGT group (n = 8). After miglitol administration, total GLP-1 was significantly increased 60 minutes after the test meal (from 3.77 ± 0.43 pmol/L upon fasting to 4.58 ± 0.13 pmol/L at 60 minutes, p = 0.048; Additional file 3: Figure S2A). Moreover, the total GIP level was significantly decreased in patients in the PPHG-miglitol group 60 minutes after the test meal (from 514.7 ± 95.8 pg/mL upon fasting to 289.4 ± 58.6 pg/mL at 60 minutes, p = 0.006; Additional file 3: Figure S2B).

Major determinant of postprandial endothelial function

No significant relation was found between fasting RHI and any other variable (age, sex, BMI, or level of serum creatinine, eGFR, HbA1c, 1,5-AG, GA, HOMA-IR, T-CHOL, HDL-C, LDL-C, CPK, NT-proBNP and fasting plasma glucose, serum insulin, TG, hs-CRP, or d-ROMs).

To clarify the determinants of postprandial endothelial dysfunction, we assessed relations between the postprandial change in RHI and other variables (age, sex, BMI, or level of serum creatinine, eGFR, HbA1c, 1,5-AG, GA, HOMA-IR, T-CHOL, HDL-C, LDL-C, CPK, NT-proBNP and postprandial changes in plasma glucose, serum insulin, TG, hs-CRP, and d-ROMs). The postprandial decrease in RHI correlated with the fasting-to-60-minutes surge in plasma glucose (r = -0.382, p = 0.009; Figure 4A), but no correlations was observed between the change in RHI and any other variable. In addition, we investigated correlation between the improved postprandial change in RHI and changes in other postprandial variables. Significant correlation was found between the postprandial improvement in RHI and the reduction in fasting-to-60-minutes glucose surge by miglitol administration (r = -0.462, p = 0.001; Figure 4B).
Figure 4
Figure 4

Correlation between postprandial percent change in RHI and postprandial change in plasma glucose in the three groups before intervention (A), and in the PPHG-miglitol group before and after miglitol treatment (B). Linear regression analysis revealed a significant inverse correlation between postprandial change in RHI and postprandial change in the glucose level (A). In the PPHG-miglitol group, there was a significant correlation between improvement in endothelial function and the reduction in glucose surge (B).

Discussion

This is the first study to evaluate postprandial endothelial function on the basis of RHI in PPHG and NGT patients with early-phase ACS. It is also the first to investigate the effect of α-GI miglitol on RHI-determined postprandial endothelial function in ACS patients. Type 2 DM is a major risk factor for cardiovascular events [31–33]. However, several studies have shown that PPHG, more than impaired fasting glucose, is related to endothelial dysfunction and cardiovascular risk [4, 34–39]. Impaired glucose tolerance is also known to cause ACS [40, 41]. Vascular endothelial dysfunction may affect the initiation and progression of arteriosclerosis and cause coronary artery disease [42]. Postprandial hyperglycemic spikes have been suggested to induce endothelial dysfunction through an increase in hyperglycemia-induced oxidative stress. This may reduce production and bioavailability of nitric oxide (NO), since hyperglycemia-induced endothelial dysfunction is counterbalanced by arginine [43]. Previous studies have shown that oxygen-derived free radicals interfere with or destroy endothelium-dependent vasodilation by inactivating NO in normal vessels. In other words, a rapid glucose surge injures endothelial cells and suppresses NO production [44–47]. Results of the STOP-NIDDM trial, which showed that α-GIs reduce the incidence of cardiovascular events even in patients with impaired glucose tolerance, suggest the clinical importance of interfering with postprandial changes in glucose [19]. Thus, because repetitive PPHG is thought to cause cardiovascular events [46, 48], ameliorating PPHG may affect endothelial function and prevent cardiovascular events [22, 38, 46]. In the present study, we observed a significant inverse correlation between postprandial endothelial function and PPHG. Thus, it is reasonable to think that amelioration of PPHG would play an important role in endothelial function. There were no postprandial changes in oxidative stress marker d-ROMs and no relation between the RHI and d-ROMs. However, d-ROMs remained higher in both PPHG groups than in the NGT group under the experimental conditions, suggesting that with repetitive PPHG, there is more exposure to oxidative stress. Hyperinsulinemia and insulin resistance have also been shown to cause endothelial dysfunction and to be risk factors for atherosclerosis [46, 49–52]. However, the increased insulin after test meal loading may not have played an important role in the acute induction of endothelial dysfunction in our patients. We did not find a significant relation between the RHI and the serum insulin levels in our patients. Furthermore, our study did not show any relation between endothelial function and insulin resistance.

Evaluation of coronary endothelial function has made it possible to predict cardiovascular events. However, most of the evaluation methods used are invasive [53, 54]. PAT can be used to noninvasively evaluate the endothelial function of resistance arteries and changes in the flow response resulting from endothelial-derived vasoactive substances including NO [55, 56]. NO is an important factor contributing to augmentation of the PAT pulse amplitude after ischemia, and administration of endothelial NO inhibitor blunts the hyperemic response detected by PAT [56]. In addition, assessment by RH-PAT is independent of the examiner, and the probes are simply applied to the patient’s forefingers, one for control measurements. Moreover, the measured values are not affected by the autonomic nervous system. Previous studies have shown that measurement of endothelial dysfunction assessed by RH-PAT is related to cardiovascular risk [30] and that RH-PAT can be used to predict coronary endothelial dysfunction [15]. This makes it valuable for predicting coronary artery disease and cardiovascular events [15, 57, 58]. Because RH-PAT is a noninvasive, quantitative, and repeatable test, RH-PAT can serve as an important surrogate marker testing method for evaluating a patient’s vascular condition and the efficacy of treatment. The present study confirmed that RH-PAT measurements reflect coronary endothelial function after ACS. The fasting baseline RHI in our three patient groups was decreased significantly compared to the cutoff value (1.67), suggesting that endothelial function in patients with ACS is impaired. However, ACS did not influence postprandial endothelial function specifically, i.e., there were no time-specific changes under the experimental conditions. Moreover, we found a significant inverse correlation between postprandial endothelial function and PPHG, i.e., amelioration of postprandial glucose elevation suppressed postprandial endothelial dysfunction. Thus, measurement of endothelial function using RH-PAT may play an important role as surrogate marker.

Miglitol, in comparison to other α-GIs such as voglibose and acarbose, ameliorates the elevation in glucose shortly after test meal loading. This quick action may be associated with the unique pharmacokinetic properties of miglitol, i.e., rapid and almost complete absorption via the small intestine [17, 18, 59]. Therefore, miglitol may have a powerful inhibitory effect against α-glucosidase without additional adverse effects. It has been documented that α-GIs reduce cardiovascular events in patients with impaired glucose tolerance, suggesting the importance of interfering with postprandial glucose fluctuation [19]. Dramatic changes in endothelial function were observed with administration of miglitol. Not only was PPHG improved, but so was postprandial endothelial dysfunction. Our study showed that the glucose elevation between fasting and 60 minutes after test meal loading is significantly associated with postprandial endothelial function and that a reduction in the glucose surge indicates improved endothelial function. However, the effect of miglitol on endothelial function may not be totally dependent on the glucose level. In fact, although miglitol improved postprandial glucose levels measured at both 60 minutes and 120 minutes, endothelial function improved only between 60 minutes and 120 minutes. The below-baseline endothelial function at 60 minutes may be related to the glucose surge, but this decreased endothelial function was restored to the baseline fasting level by 120 minutes even though the blood glucose level remained high. Our data indicate that miglitol has a potent ameliorative effect on endothelial function in patients with ACS and PPHG, and the beneficial effects may not be totally dependent on postprandial glucose swings, but may rather be related to an additional pharmacologic mechanism of action. Incretins, especially GLP-1, secreted as a result of miglitol administration are thought to play an important role in endothelial function [60, 61]. Oral administration of miglitol has been shown to increase GLP-1 secretion [62–64], and GLP-1 upregulates NO production in endothelial cells [65], independently improving vascular function [66]. Results of the present study suggest that increasing GLP-1 and decreasing GIP might be important to postprandial endothelial function and to the time course of improvement. Moreover, the present study showed that miglitol decreases hs-CRP, suggesting miglitol suppresses inflammation and may act synergistically in preserving endothelial function.

There were some limitations to the study. First, the lack of significance in the levels of various markers could have resulted from the relatively small patient groups. The results should therefore be interpreted with caution. Second, this was a very short-term follow-up study; the long-term effects of miglitol on endothelial function and ACS outcomes remain unknown. Third, in this study, we excluded patients with type 1 DM and type 2 DM who were treated with insulin and oral anti-DM agents and patients with high HbA1c. We speculate that even if such patients were included, we might have seen postprandial endothelial dysfunction related to postprandial glucose elevation. Fourth, we excluded patients with heart failure resulting from severe myocardial infarction, because it has been reported that diabetes can lead to heart failure after myocardial infarction, and moreover, endothelial function may be impaired in patients with heart failure [67–70]. Fifth, incretins, especially active GLP-1, are unstable in vivo; they dissolve immediately. Thus, it is difficult to investigate the clinical effects of incretins. Furthermore, we assessed incretins in only a few subjects, (8 PPHG-miglitol patients and 8 NGT patients), so the results are inconclusive.

Conclusions

Noninvasive assessment of fingertip endothelial function may be clinically useful. In our patients with ACS, postprandial hyperglycemia rather than the fasting glucose level appeared to affect postprandial endothelial function. Miglitol is effective against postprandial hyperglycemia, hyperinsulinemia, inflammation, and endothelial dysfunction. Long-term follow-up studies are needed to confirm these findings.

Declarations

Acknowledgements

We express our appreciation to Professor Taro Matsumoto, Director of the Division of Cell Regeneration and Transplantation, Department of Functional Morphology, Nihon University School of Medicine, and his staff. We also thank all members of the Division of Cardiology, Nihon University School of Medicine.

Authors’ Affiliations

(1)
Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
(2)
Department of Cardiovascular Medicine, Keiai Hospital, Tokyo, Japan
(3)
Department of Advanced Cardiovascular Imaging, Nihon University School of Medicine, Tokyo, Japan

References

  1. Gerstein HC, Miller ME, Byington RP, Goff DC, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH, Probstfield JL, Simons-Morton DG, Friedewald WT, Action to Control Cardiovascular Risk in Diabetes Study Group: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008, 358: 2545-2559.View ArticlePubMedGoogle Scholar
  2. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F, ADVANCE Collaborative Group: Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008, 358: 2560-2572.View ArticlePubMedGoogle Scholar
  3. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD, VADT Investigators: Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009, 360: 129-139. 10.1056/NEJMoa0808431.View ArticlePubMedGoogle Scholar
  4. Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A: Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care. 1999, 22: 920-924. 10.2337/diacare.22.6.920.View ArticlePubMedGoogle Scholar
  5. DECODE Study Group: the European Diabetes Epidemiology Group: Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med. 2001, 161: 397-405. 10.1001/archinte.161.3.397.View ArticleGoogle Scholar
  6. Nakagami T, Qiao Q, Tuomilehto J, Balkau B, Tajima N, Hu G, Borch-Johnsen K: Screen-detected diabetes, hypertension and hypercholesterolemia as predictors of cardiovascular mortality in five populations of Asian origin: the DECODA study. Eur J Cardiovasc Prev Rehabil. 2006, 13: 555-561. 10.1097/01.hjr.0000183916.28354.69.View ArticlePubMedGoogle Scholar
  7. Lambert J, Aarsen M, Donker AJ, Stehouwer CD: Endothelium-dependent and -independent vasodilation of large arteries in normoalbuminuric insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol. 1996, 16: 705-711. 10.1161/01.ATV.16.5.705.View ArticlePubMedGoogle Scholar
  8. Thorne S, Mullen MJ, Clarkson P, Donald AE, Deanfield JE: Early endothelial dysfunction in adults at risk from atherosclerosis: different responses to L-arginine. J Am Coll Cardiol. 1998, 32: 110-116. 10.1016/S0735-1097(98)00211-3.View ArticlePubMedGoogle Scholar
  9. Evans M, Anderson RA, Graham J, Ellis GR, Morris K, Davies S, Jackson SK, Lewis MJ, Frenneaux MP, Rees A: Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus. Circulation. 2000, 101: 1773-1779. 10.1161/01.CIR.101.15.1773.View ArticlePubMedGoogle Scholar
  10. Frantz S, Calvillo L, Tillmanns J, Elbing I, Dienesch C, Bischoff H, Ertl G, Bauersachs J: Repetitive postprandial hyperglycemia increases cardiac ischemia/reperfusion injury: prevention by the alpha-glucosidase inhibitor acarbose. FASEB J. 2005, 19: 591-593.PubMedGoogle Scholar
  11. Azuma K, Kawamori R, Toyofuku Y, Kitahara Y, Sato F, Shimizu T, Miura K, Mine T, Tanaka Y, Mitsumata M, Watada H: Repetitive fluctuations in blood glucose enhance monocyte adhesion to the endothelium of rat thoracic aorta. Arterioscler Thromb Vasc Biol. 2006, 26: 2275-2280. 10.1161/01.ATV.0000239488.05069.03.View ArticlePubMedGoogle Scholar
  12. Mita T, Otsuka A, Azuma K, Uchida T, Ogihara T, Fujitani Y, Hirose T, Mitsumata M, Kawamori R, Watada H: Swings in blood glucose levels accelerate atherogenesis in apolipoprotein E-deficient mice. Biochem Biophys Res Commun. 2007, 358: 679-685. 10.1016/j.bbrc.2007.04.118.View ArticlePubMedGoogle Scholar
  13. Liao JK: Endothelium and acute coronary syndromes. Clin Chem. 1998, 44: 1799-1808.PubMedGoogle Scholar
  14. Glass CK, Witztum JL: Atherosclerosis. the road ahead. Cell. 2001, 104: 503-516. 10.1016/S0092-8674(01)00238-0.View ArticlePubMedGoogle Scholar
  15. Bonetti PO, Pumper GM, Higano ST, Holmes DR, Kuvin JT, Lerman A: Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol. 2004, 44: 2137-2141. 10.1016/j.jacc.2004.08.062.View ArticlePubMedGoogle Scholar
  16. Puls W, Keup U, Krause HP, Thomas G, Hoffmeister F: Glucosidase inhibition. A new approach to the treatment of diabetes, obesity, and hyperlipoproteinaemia. Naturwissenschaften. 1977, 64: 536-537. 10.1007/BF00483562.View ArticlePubMedGoogle Scholar
  17. Ahr HJ, Boberg M, Brendel E, Krause HP, Steinke W: Pharmacokinetics of miglitol. Absorption, distribution, metabolism, and excretion following administration to rats, dogs, and man. Arzneimittelforschung. 1997, 47: 734-745.PubMedGoogle Scholar
  18. Standl E, Schnell O: Alpha-glucosidase inhibitors 2012 - cardiovascular considerations and trial evaluation. Diab Vasc Dis Res. 2012, 9: 163-169. 10.1177/1479164112441524.View ArticlePubMedGoogle Scholar
  19. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M: Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003, 290: 486-494. 10.1001/jama.290.4.486.View ArticlePubMedGoogle Scholar
  20. Hanefeld M, Cagatay M, Petrowitsch T, Neuser D, Petzinna D, Rupp M: Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies. Eur Heart J. 2004, 25: 10-16. 10.1016/S0195-668X(03)00468-8.View ArticlePubMedGoogle Scholar
  21. Shimabukuro M, Higa N, Chinen I, Yamakawa K, Takasu N: Effects of a single administration of acarbose on postprandial glucose excursion and endothelial dysfunction in type 2 diabetic patients: a randomized crossover study. J Clin Endocrinol Metab. 2006, 91: 837-842.View ArticlePubMedGoogle Scholar
  22. Hirano M, Nakamura T, Obata JE, Fujioka D, Saito Y, Kawabata K, Watanabe K, Watanabe Y, Kugiyama K: Early improvement in carotid plaque echogenicity by acarbose in patients with acute coronary syndromes. Circ J. 2012, 76: 1452-1460. 10.1253/circj.CJ-11-1524.View ArticlePubMedGoogle Scholar
  23. Minatoguchi S, Arai M, Uno Y, Kariya T, Nishida Y, Hashimoto K, Kawasaki M, Takemura G, Fujiwara T, Fujiwara H: A novel anti-diabetic drug, miglitol, markedly reduces myocardial infarct size in rabbits. Br J Pharmacol. 1999, 128: 1667-1672. 10.1038/sj.bjp.0702970.PubMed CentralView ArticlePubMedGoogle Scholar
  24. Emoto T, Sawada T, Hashimoto M, Kageyama H, Terashita D, Mizoguchi T, Mizuguchi T, Motodi Y, Iwasaki M, Taira K, Okamoto H, Matsuo Y, Kim SK, Takarada A, Yokoyama M: Effect of 3-month repeated administration of miglitol on vascular endothelial function in patients with diabetes mellitus and coronary artery disease. Am J Cardiol. 2012, 109: 42-46. 10.1016/j.amjcard.2011.08.005.View ArticlePubMedGoogle Scholar
  25. Yoshino G, Tominaga M, Hirano M, Shiba T, Kashiwagi A, Tanaka A, Tada N, Onuma T, Egusa G, Kuwashima M, Sanke T, Oikawa S, Honda K, Tachikawa T: The test meal A: A pilot model for the international standard of test meal for an assessment of both postprandial hyperglycemia and hyperlipidemia. J Japan Diab Soc. 2006, 49: 361-371.Google Scholar
  26. Yoshino G: Test meal A for the simultaneous assessment of postprandial hyperglycemia and hyperlipidemia in diabetic subjects. Jpn J Nutr Diet. 2007, 65: 105-112. 10.5264/eiyogakuzashi.65.105.View ArticleGoogle Scholar
  27. Yoshino G: Clinical application of test meal A. Diabetes-Journal. 2008, 36: 70-78.Google Scholar
  28. Cesarone MR, Belcaro G, Carratelli M, Cornelli U, De Sanctis MT, Incandela L, Barsotti A, Terranova R, Nicolaides A: A simple test to monitor oxidative stress. Int Angiol. 1999, 18 (2): 127-130.PubMedGoogle Scholar
  29. Bonetti PO, Barsness GW, Keelan PC, Schnell TI, Pumper GM, Kuvin JT, Schnall RP, Holmes DR, Higano ST, Lerman A: Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease. J Am Coll Cardiol. 2003, 41: 1761-1768. 10.1016/S0735-1097(03)00329-2.View ArticlePubMedGoogle Scholar
  30. Hamburg NM, Keyes MJ, Larson MG, Vasan RS, Schnabel R, Pryde MM, Mitchell GF, Sheffy J, Vita JA, Benjamin EJ: Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation. 2008, 117: 2467-2474. 10.1161/CIRCULATIONAHA.107.748574.PubMed CentralView ArticlePubMedGoogle Scholar
  31. Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Stone NJ: Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004, 44: 720-732. 10.1016/j.jacc.2004.07.001.View ArticlePubMedGoogle Scholar
  32. Huxley R, Barzi F, Woodward M: Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ. 2006, 332: 73-78. 10.1136/bmj.38678.389583.7C.PubMed CentralView ArticlePubMedGoogle Scholar
  33. Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, Haase N, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O'Donnell CJ, Roger V, Rumsfeld J, Sorlie P, Steinberger J, Thom T, Wasserthiel-Smoller S, Hong Y, American Heart Association Statistics Committee and Stroke Statistics Subcommittee: Heart disease and stroke statistics--2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007, 115: e69-171. 10.1161/CIRCULATIONAHA.106.179918.View ArticlePubMedGoogle Scholar
  34. Rodriguez BL, Lau N, Burchfiel CM, Abbott RD, Sharp DS, Yano K, Curb JD: Glucose intolerance and 23-year risk of coronary heart disease and total mortality: the Honolulu Heart Program. Diabetes Care. 1999, 22: 1262-1265. 10.2337/diacare.22.8.1262.View ArticlePubMedGoogle Scholar
  35. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe. Lancet. 1999, 354: 617-621.Google Scholar
  36. Ceriello A: Postprandial hyperglycemia and diabetes complications: is it time to treat?. Diabetes. 2005, 54: 1-7. 10.2337/diabetes.54.1.1.View ArticlePubMedGoogle Scholar
  37. Suzuki K, Watanabe K, Futami-Suda S, Yano H, Motoyama M, Matsumura N, Igari Y, Suzuki T, Nakano H, Oba K: The effects of postprandial glucose and insulin levels on postprandial endothelial function in subjects with normal glucose tolerance. Cardiovasc Diabetol. 2012, 11: 98-10.1186/1475-2840-11-98.PubMed CentralView ArticlePubMedGoogle Scholar
  38. Kitasato L, Tojo T, Hatakeyama Y, Kameda R, Hashikata T, Yamaoka-Tojo M: Postprandial hyperglycemia and endothelial function in type 2 diabetes: focus on mitiglinide. Cardiovasc Diabetol. 2012, 11: 79-10.1186/1475-2840-11-79.PubMed CentralView ArticlePubMedGoogle Scholar
  39. Raz I, Wilson PW, Strojek K, Kowalska I, Bozikov V, Gitt AK, Jermendy G, Campaigne BN, Kerr L, Milicevic Z, Jacober SJ: Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D trial. Diabetes Care. 2009, 32: 381-386. 10.2337/dc08-1671.PubMed CentralView ArticlePubMedGoogle Scholar
  40. Tofler GH, Stone PH, Maclure M, Edelman E, Davis VG, Robertson T, Antman EM, Muller JE: Analysis of possible triggers of acute myocardial infarction (the MILIS study). Am J Cardiol. 1990, 66: 22-27. 10.1016/0002-9149(90)90729-K.View ArticlePubMedGoogle Scholar
  41. Norhammar A, Tenerz A, Nilsson G, Hamsten A, Efendic S, Ryden L, Malmberg K: Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet. 2002, 359: 2140-2144. 10.1016/S0140-6736(02)09089-X.View ArticlePubMedGoogle Scholar
  42. Vanhoutte PM: Endothelial dysfunction: the first step toward coronary arteriosclerosis. Circ J. 2009, 73: 595-601. 10.1253/circj.CJ-08-1169.View ArticlePubMedGoogle Scholar
  43. Inoue T, Matsuoka H, Higashi Y, Ueda S, Sata M, Shimada KE, Ishibashi Y, Node K: Flow-mediated vasodilation as a diagnostic modality for vascular failure. Hypertens Res. 2008, 31: 2105-2113. 10.1291/hypres.31.2105.View ArticlePubMedGoogle Scholar
  44. Gryglewski RJ, Palmer RM, Moncada S: Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature. 1986, 320: 454-456. 10.1038/320454a0.View ArticlePubMedGoogle Scholar
  45. Rubanyi GM, Vanhoutte PM: Oxygen-derived free radicals, endothelium, and responsiveness of vascular smooth muscle. Am J Physiol. 1986, 250: H815-821.PubMedGoogle Scholar
  46. Kawano H, Motoyama T, Hirashima O, Hirai N, Miyao Y, Sakamoto T, Kugiyama K, Ogawa H, Yasue H: Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery. J Am Coll Cardiol. 1999, 34: 146-154. 10.1016/S0735-1097(99)00168-0.View ArticlePubMedGoogle Scholar
  47. Marfella R, Verrazzo G, Acampora R, La Marca C, Giunta R, Lucarelli C, Paolisso G, Ceriello A, Giugliano D: Glutathione reverses systemic hemodynamic changes induced by acute hyperglycemia in healthy subjects. Am J Physiol. 1995, 268: E1167-1173.PubMedGoogle Scholar
  48. Watanabe M, Kokubo Y, Higashiyama A, Ono Y, Miyamoto Y, Okamura T: Serum 1,5-anhydro-D-glucitol levels predict first-ever cardiovascular disease: an 11-year population-based cohort study in Japan, the Suita study. Atherosclerosis. 2011, 216: 477-483. 10.1016/j.atherosclerosis.2011.02.033.View ArticlePubMedGoogle Scholar
  49. Despres JP, Lamarche B, Mauriege P, Cantin B, Dagenais GR, Moorjani S, Lupien PJ: Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med. 1996, 334: 952-957. 10.1056/NEJM199604113341504.View ArticlePubMedGoogle Scholar
  50. Stout RW: Hyperinsulinemia and atherosclerosis. Diabetes. 1996, 45 (Suppl 3): S45-46.View ArticlePubMedGoogle Scholar
  51. Arcaro G, Cretti A, Balzano S, Lechi A, Muggeo M, Bonora E, Bonadonna RC: Insulin causes endothelial dysfunction in humans: sites and mechanisms. Circulation. 2002, 105: 576-582. 10.1161/hc0502.103333.View ArticlePubMedGoogle Scholar
  52. Kato T, Inoue T, Node K: Postprandial endothelial dysfunction in subjects with new-onset type 2 diabetes: an acarbose and nateglinide comparative study. Cardiovasc Diabetol. 2010, 9: 12-10.1186/1475-2840-9-12.PubMed CentralView ArticlePubMedGoogle Scholar
  53. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR, Lerman A: Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000, 101: 948-954. 10.1161/01.CIR.101.9.948.View ArticlePubMedGoogle Scholar
  54. Lerman A, Zeiher AM: Endothelial function: cardiac events. Circulation. 2005, 111: 363-368. 10.1161/01.CIR.0000153339.27064.14.View ArticlePubMedGoogle Scholar
  55. Hamburg NM, Palmisano J, Larson MG, Sullivan LM, Lehman BT, Vasan RS, Levy D, Mitchell GF, Vita JA, Benjamin EJ: Relation of brachial and digital measures of vascular function in the community: the Framingham heart study. Hypertension. 2011, 57: 390-396. 10.1161/HYPERTENSIONAHA.110.160812.PubMed CentralView ArticlePubMedGoogle Scholar
  56. Nohria A, Gerhard-Herman M, Creager MA, Hurley S, Mitra D, Ganz P: Role of nitric oxide in the regulation of digital pulse volume amplitude in humans. J Appl Physiol. 2006, 101: 545-548. 10.1152/japplphysiol.01285.2005.View ArticlePubMedGoogle Scholar
  57. Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Lavi S, Nelson RE, Pumper GM, Lerman LO, Lerman A: Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J. 2010, 31: 1142-1148. 10.1093/eurheartj/ehq010.View ArticlePubMedGoogle Scholar
  58. Matsuzawa Y, Sugiyama S, Sugamura K, Nozaki T, Ohba K, Konishi M, Matsubara J, Sumida H, Kaikita K, Kojima S, Nagayoshi Y, Yamamuro M, Izumiya Y, Iwashita S, Matsui K, Jinnouchi H, Kimura K, Umemura S, Ogawa H: Digital assessment of endothelial function and ischemic heart disease in women. J Am Coll Cardiol. 2010, 55: 1688-1696. 10.1016/j.jacc.2009.10.073.View ArticlePubMedGoogle Scholar
  59. Scott LJ, Spencer CM: Miglitol: a review of its therapeutic potential in type 2 diabetes mellitus. Drugs. 2000, 59: 521-549. 10.2165/00003495-200059030-00012.View ArticlePubMedGoogle Scholar
  60. Hiki M, Shimada K, Kiyanagi T, Fukao K, Hirose K, Ohsaka H, Fukushima Y, Kume A, Matsumori R, Sumiyoshi K, Miyazaki T, Ohmura H, Kurata T, Miida T, Daida H: Single administration of alpha-glucosidase inhibitors on endothelial function and incretin secretion in diabetic patients with coronary artery disease - Juntendo University trial: effects of miglitol on endothelial vascular reactivity in type 2 diabetic patients with coronary heart disease (J-MACH). Circ J. 2010, 74: 1471-1478. 10.1253/circj.CJ-10-0013.View ArticlePubMedGoogle Scholar
  61. Kishimoto M, Noda M: A pilot study of the efficacy of miglitol and sitagliptin for type 2 diabetes with a continuous glucose monitoring system and incretin-related markers. Cardiovasc Diabetol. 2011, 10: 115-10.1186/1475-2840-10-115.PubMed CentralView ArticlePubMedGoogle Scholar
  62. Lee A, Patrick P, Wishart J, Horowitz M, Morley JE: The effects of miglitol on glucagon-like peptide-1 secretion and appetite sensations in obese type 2 diabetics. Diabetes Obes Metab. 2002, 4: 329-335. 10.1046/j.1463-1326.2002.00219.x.View ArticlePubMedGoogle Scholar
  63. Narita T, Katsuura Y, Sato T, Hosoba M, Fujita H, Morii T, Yamada Y: Miglitol induces prolonged and enhanced glucagon-like peptide-1 and reduced gastric inhibitory polypeptide responses after ingestion of a mixed meal in Japanese Type 2 diabetic patients. Diabet Med. 2009, 26: 187-188. 10.1111/j.1464-5491.2008.02651.x.View ArticlePubMedGoogle Scholar
  64. Iwasa M, Yamada Y, Kobayashi H, Yasuda S, Kawamura I, Sumi S, Shiraki T, Yamaki T, Ushikoshi H, Hattori A, Aoyama T, Nishigaki K, Takemura G, Fujiwara H, Minatoguchi S: Both stimulation of GLP-1 receptors and inhibition of glycogenolysis additively contribute to a protective effect of oral miglitol against ischaemia-reperfusion injury in rabbits. Br J Pharmacol. 2011, 164: 119-131. 10.1111/j.1476-5381.2011.01357.x.PubMed CentralView ArticlePubMedGoogle Scholar
  65. Hattori Y, Jojima T, Tomizawa A, Satoh H, Hattori S, Kasai K, Hayashi T: A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells. Diabetologia. 2010, 53: 2256-2263. 10.1007/s00125-010-1831-8.View ArticlePubMedGoogle Scholar
  66. Koska J, Schwartz EA, Mullin MP, Schwenke DC, Reaven PD: Improvement of postprandial endothelial function after a single dose of exenatide in individuals with impaired glucose tolerance and recent-onset type 2 diabetes. Diabetes Care. 2010, 33: 1028-1030. 10.2337/dc09-1961.PubMed CentralView ArticlePubMedGoogle Scholar
  67. von Bibra H, St John Sutton M: Impact of diabetes on postinfarction heart failure and left ventricular remodeling. Curr Heart Fail Rep. 2011, 8: 242-251. 10.1007/s11897-011-0070-8.PubMed CentralView ArticlePubMedGoogle Scholar
  68. Akiyama E, Sugiyama S, Matsuzawa Y, Konishi M, Suzuki H, Nozaki T, Ohba K, Matsubara J, Maeda H, Horibata Y, Sakamoto K, Sugamura K, Yamamuro M, Sumida H, Kaikita K, Iwashita S, Matsui K, Kimura K, Umemura S, Ogawa H: Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction. J Am Coll Cardiol. 2012, 60 (18): 1778-1786. 10.1016/j.jacc.2012.07.036.View ArticlePubMedGoogle Scholar
  69. AlZadjali MA, Godfrey V, Khan F, Choy A, Doney AS, Wong AK, Petrie JR, Struthers AD, Lang CC: Insulin resistance is highly prevalent and is associated with reduced exercise tolerance in nondiabetic patients with heart failure. J Am Coll Cardiol. 2009, 53: 747-753. 10.1016/j.jacc.2008.08.081.View ArticlePubMedGoogle Scholar
  70. Enomoto K, Yamabe H, Toyama K, Matsuzawa Y, Yamamuro M, Uemura T, Morihisa K, Iwashita S, Kaikita K, Sugiyama S, Ogawa H: Improvement effect on endothelial function in patients with congestive heart failure treated with cardiac resynchronization therapy. J Cardiol. 2011, 58 (1): 69-73. 10.1016/j.jjcc.2011.01.010.View ArticlePubMedGoogle Scholar

Copyright

© Kitano et al.; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement

Cardiovascular Diabetology

ISSN: 1475-2840