Relationship between Insulin Levels and Coronary Atherosclerosis in Newly Diagnosed Diabetes Mellitus and Impaired Glucose Tolerance

C l i n M e d International Library Citation: Nemoto N, Nakajima R, Ymazaki K, Utsunomiya M, Hori M, et al., (2015) Relationship between Insulin Levels and Coronary Atherosclerosis in Newly Diagnosed Diabetes Mellitus and Impaired Glucose Tolerance. Int J Clin Cardiol 1:020 Received: December 25, 2014: Accepted: February 03, 2015: Published: February 06, 2015 Copyright: © 2015 Nemoto N. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Nemoto et al. Int J Clin Cardiol 2015, 2:1 ISSN: 2378-2951


Introduction
Diabetes mellitus (DM) has been identified as a risk factor for cardiovascular disease.Mortality risk is 2-3 times greater in patients with DM than in those without [1,2].It is well known that Patients with proximal LAD (n=66) and left main (n=17) coronary disease with a %DS of >20% were excluded from IVUS analysis.
Patients aged >80 years (n=15), patients with cardiogenic shock, and cases of death (n=10) and hemodialysis (n=1) were also excluded from the study.The remaining 96 patients were divided on the basis of DM status (Figure 1).
Patients were considered to have DM if they met at least one of the following criteria: 1) history of DM treatment, such as diet therapy, medical therapy, or insulin use; 2) an HbA1c (National Glycohemoglobin Standardization Program; NSGP) level of ≥6.5%, and/or 3) a fasting plasma glucose (FPG) level of ≥126mg/dl.
Patients without DM underwent a 75-g oral glucose tolerance test (75-g OGTT) before discharge from the hospital and were divided into two groups according to the results.
Normal glucose tolerance (NGT) was defined as an FPG level of <100mg/dl and a 2h plasma glucose (2h-PG) level of <140 mg/dl.Abnormal glucose tolerance (AGT) was defined as the absence of DM and NGT.

OGTT and blood sampling
Immediately after admission, baseline venous blood samples were obtained to measure ratios (%) of HbA1c (Japan Diabetes Society), total cholesterol, low-density lipoprotein cholesterol, highdensity lipoprotein cholesterol, triglycerides, and creatinine before any medical agents or other interventions were administered.
A baseline 75g OGTT was performed 2-3 weeks after the coronary intervention to avoid the possible influence of acute coronary syndrome on glucose tolerance.Blood samples were collected after a 12h overnight fast.A total of 75g of glucose was orally administered over a period of 5 min, and plasma glucose and insulin levels were measured before administration and 30, 60, and 120 min after administration (Figure 2).

IVUS and percutaneous coronary intervention
All patients received aspirin (162-200mg) and intravenous heparin to achieve an activated clotting time of >250 s.Glycoprotein II b/III was not given to any patient.IVUS was performed with percutaneous coronary intervention and intracoronary administration of 125-250µg of nitroglycerin.Data were acquired with commercially available IVUS transducers (30MHz/3.2F,Ultracross or 40MHz/2.5F,Atlantis SR pro, Boston Scientific/SciMed, Natick, MA, USA).An imaging catheter was introduced into the mid-portion of the LAD and withdrawn to the left main by automatic pullback at a speed of 0.5mm/s.Ultrasound images were recorded on S-VHS tape for offline analysis.

Quantitative IVUS and QCA analysis
Quantitative analyses of gray-scale IVUS images were performed according to the criteria of the American College of Cardiology Clinical Expert Consensus Document on IVUS. 16Images of the site proximal to the LAD, 5 mm or more from a major branch such as the circumflex artery or major diagonal and diagnosed as normal on CAG, were evaluated for this study (Figure 3).The External Elastic Membrane (EEM) and lumen cross-sectional area (CSA) were measured.Plaque CSA was calculated as EEM minus lumen CSA, and plaque burden was calculated as plaque plus media CSA divided by EEM CSA.QCA, of the LAD proximal site assessed with IVUS, was performed with an automated edge detection system (CMS, Medis Medical Imaging Systems, Nuenen, The Netherlands) by experienced interventional cardiologists.

Statistical methods
Continuous variables are expressed as mean ± standard deviation (SD) and categorical variables as percentages.The chi-square test and  Fisher's exact test were used to compare frequency ratios between groups.Continuous variables were compared by analysis of variance (ANOVA).Differences between the mean 75g OGTT results were assessed by unpaired Student's t-tests.Linear regression was used to determine whether plasma insulin and glucose levels correlated with plaque CSA.To evaluate associations between plaque CSA and other variables, stepwise forward multivariate linear regression analyses were performed.Candidate variables included all those parameters significant in univariate correlations.The entry criterion in the multivariate analyses was set at a significance level of p<0.10.
A probability value of <0.05 was considered statistically significant.All analyses were performed with SAS software version 9.3 (SAS Institute, Cary, NC, USA).

Patient demographics
There were 35 patients with DM, 29 with AGT, and 32 with NGT (Table 1).The mean age was 65.8 ± 10.2, 62.4 ± 12.7, and 58.2 ± 13.0 years for patients with DM, AGT, and NGT, respectively; the DM patients were significantly older than the NGT patients (P<0.05).There were no significant differences among the three groups with regard to body mass index, family history, or history of hypertension, dyslipidemia, smoking, prior myocardial infarction, and prior percutaneous coronary intervention.
Biochemical data are detailed in Table 2 and 3.There were no significant differences among the three groups with regard to total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, and serum creatinine levels.FPG values were 168 ± 63 mg/dl in the DM group, 94 ± 10mg/dl in the AGT group, and 88 ± 7mg/dl in the NGT group, while HbA1c values were 8.0% ± 1.4%, 5.7% ± 0.3%, and 5.5% ± 0.3%, respectively; both values were significantly higher in the DM group than in the other two groups (P< 0.05).

Correlation of plaque CSA with insulin levels (fasting, 30 min, 60 min, 120 min, total), and glucose levels
The correlation of plaque CSA with insulin levels and glucose levels based on the 75g OGTT was evaluated.Insulin values at 120 min after the glucose challenge showed the strongest correlation with plaque CSA (R=0.505,P<0.01; Figure 5A).Total insulin values after the glucose challenge (Figure 5B), glucose values at 120 min after the challenge (Figure 5C), and total glucose values after the challenge (Figure 5D) correlated with plaque CSA.
Multivariable liner regression analysis found Insulin 120 min as the independent predictor of increasing Plaque CSA (Table 5).

Discussion
This study evaluated IVUS findings and revealed that the plaque 4B: Comparison of plaque CSA among the three groups.Plaque CSA was significantly greater in the DM and AGT groups than in the NGT group (P=0.0187,P=0.0010, respectively).There was no significant difference between the DM and IGT groups.
4C: Comparison of plaque burden among the three groups.Plaque burden was significantly greater in the DM and AGT groups than in the NGT group (P<0.0001,P=0.0015, respectively).There was no significant difference between the DM and AGT groups.CSA was significantly greater in patients with AGT than in those with NGT, that there was no significant difference in the plaque CSA between patients with AGT and those with DM, and that insulin levels at 120 min after the 75-g OGTT correlated with plaque CSA in patients with AGT and NGT.

Atherosclerosis at the time of IGT and newly diagnosed DM
The most common cause of cardiovascular events represented by acute coronary syndrome is thrombus formation due to rupture or erosion of coronary artery plaque [17,18].Existence of coronary plaque, regardless of the presence or absence of significant stenosis, is a risk factor for all-cause mortality and cardiovascular events [19,20].It has been reported that DM has a strong relationship with the amount of coronary plaque as evaluated by IVUS or coronary computed tomography angiography [21][22][23] and that atherosclerosis initiates before DM development [5].
It has also been reported that carotid artery intimal and medial thickness is strongly correlated with postprandial glucose and is increased in the pre-diabetes stage [24,25].These findings are consistent with the contention that atherosclerosis initiates before DM development, and they support the concept that atherosclerosis is not only a focal disease but also a systemic disease.Despite these findings, investigations of coronary artery plaque at various stages of IGT and the early phase of DM remain scarce.Therefore, we assessed coronary plaque in LAD proximal to the lesion, which appeared normal on CAG, using IVUS and revealed that the plaque CSA was significantly greater in the AGT group than in the NGT group and not significantly different in the DM group.These results strongly suggest that silent coronary atherosclerosis initiates and progresses during AGT.

Importance of coronary plaque during newly diagnosed DM and IGT
Many trials have demonstrated that the control of hypercholesterolemia [26][27][28] and hypertension [29,30] results in the prevention of cardiovascular events by control of cholesterol and blood pressure, regardless of the presence of DM.In contrast, intensive medical treatment targeted at HbA1c failed to demonstrate clinical benefits with regard to mortality [31][32][33][34].
However, it seems reasonable to expect that glucose control will contribute to the prevention of cardiovascular disease.In fact, metaanalysis of recent trials involving intensive DM control revealed that this strategy decreased the risk of myocardial infarction and cardiovascular death [35].
In addition, it was reported that diabetic intervention therapy at the stage of IGT and newly diagnosed DM is effective for the prevention of macrovascular disease [10][11][12]36].Furthermore, establishment of diabetic intervention therapy at the time of DM diagnosis is useful for the prevention of macrovascular disease, and these effects have been documented to last for >10 years [37].
Our study demonstrated that coronary plaque in patients with AGT is similar to that in patients with DM and that insulin levels at 120 min after the glucose challenge were significantly associated with the quantity of coronary plaque.These findings strongly suggest the clinical benefits of glucose control in the initial stages of AGT.Furthermore, it may be reasonable to consider that the treatment of hyperinsulinemia during IGT or early-phase DM is essential for the prevention of macrovascular disease.

Study Limitations
This study had some limitations.First, it was a retrospective, single-center study; therefore, selection bias cannot be entirely ruled out.Second, cases of in-hospital death, cardiogenic shock, hemodialysis, and left main and LAD proximal lesions were excluded.These are usually severe cases, and most had DM.The possibility that these exclusions may have affected the results cannot be denied.We used 2D gray scale IVUS in this study; however, gray-scale IVUS has significant limitations with regard to the quality assessment of plaque [38].
Currently, the quantity of coronary artery plaque can be measured using three-dimensional IVUS or coronary computed tomography angiography, while the quality of plaque can be evaluated using coronary computed tomography angiography, virtual histology-IVUS, and iMap-IVUS [39][40][41].
Future studies should assess both the quality and quantity of plaque using the available technology.

Conclusions
Coronary plaque in patients with AGT was identified to be similar to that in patients with DM, and it was correlated with insulin levels at 120 min after a 75g OGTT.These results suggest that the progression of atherosclerosis occurs in the AGT phase and that the prevention of atherosclerosis should be given more careful consideration at the time of AGT or newly diagnosed DM.

Figure 1 :
Figure 1: Enrollment criteria and study flow DM (diabetes mellitus) group: DM was considered present if at least one of the following criteria were present: 1) DM treatment, such as diet therapy, medical therapy, or insulin use; 2) an HbA1c (National Glycohemoglobin Standardization Program; NSGP) level of ≥6.5%; or 3) a Fasting Plasma Glucose (FPG) level of ≥126mg/dl.NGT (Normal Glucose Tolerance) group: NGT was considered present if the FPG level was <100mg/dl and the 2h plasma glucose (2h-PG) level was <140 mg/dl following the 75-g oral glucose tolerance test (OGTT).AGT (Abnormal Glucose Tolerance) group: Those without DM and NGT.

Figure 4 :
Figure 4: Intravascular ultrasound (IVUS) parameters 4A: Comparison of the lumen cross-sectional area (CSA) among the three groups.The lumen CSA was significantly smaller in the DM group than in the NGT group (P=0.0140).

Figure 5 :
Figure 5: Correlations of insulin and glucose levels with the plaque cross-sectional area (CSA) 5A: Insulin levels at 120 min are highly correlated with the plaque CSA 5B: Glucose levels at 120 min and plaque CSA also correlate, albeit less strongly than insulin levels at 120 min and plaque CSA.5C: Total immunoreactive insulin (ΣIRI) and plaque CSA show a significant but relatively weak correlation.5D: Total plasma glucose (ΣPG) and plaque CSA show a significant but relatively weak correlation.

Table 1 :
Baseline patient characteristics

Table 3 :
Results of the 75g OGTT

Table 5 :
Results of Multivariable linear regression analysis