Small Fibre Neuropathy Is Associated With Impaired Vascular Endothelial Function in Patients With Type 2 Diabetes.

Diabetic polyneuropathy (DPN) and endothelial dysfunction are prevalent complications of diabetes mellitus. Currently, there are two non-invasive markers for endothelial dysfunction: flow-mediated dilation and reactive hyperaemia peripheral arterial tonometry (RH-PAT). However, the relationship between diabetic small fibre neuropathy and macroangiopathy remains obscure thus far. Corneal confocal microscopy (CCM) has emerged as a new diagnostic modality to assess DPN, especially of small fibre. To clarify the relationship between diabetic small fibre neuropathy and vascular dysfunction, we aimed to determine the functions of peripheral nerves and blood vessels through clinical tests such as nerve conduction study, coefficient of variation in the R-R interval, CCM, and RH-PAT in 82 patients with type 2 diabetes. Forty healthy control subjects were also included to study corneal nerve parameters. Correlational and multiple linear regression analyses were performed to determine the associations between neuropathy indices and markers for vascular functions. The results revealed that patients with type 2 diabetes had significantly lower values for most variables of CCM than healthy control subjects. RH-PAT solely remained as an explanatory variable significant in multiple regression analysis for several CCM parameters and vice versa. Other vascular markers had no significant multiple regression with any CCM parameters. In conclusion, endothelial dysfunction as revealed by impaired RH-PAT was significantly associated with CCM parameters in patients with type 2 diabetes. This association may indicate that small fibre neuropathy results from impaired endothelial dysfunction in type 2 diabetes. CCM parameters may be considered surrogate markers of autonomic nerve damage, which is related to diabetic endothelial dysfunction. This study is the first to report the relationship between corneal nerve parameter as small fibre neuropathy in patients with type 2 diabetes and RH-PAT as a marker of endothelial dysfunction.

Cardio-Ankle Vascular Index and Indices of Diabetic Polyneuropathy in Patients with Type 2 Diabetes.

The cardio-ankle vascular index (CAVI) is used to test vascular function and is an arterial stiffness marker and potential predictor of cardiovascular events. This study aimed to analyze the relation between objective indices of diabetic polyneuropathy (DPN) and the CAVI. One hundred sixty-six patients with type 2 diabetes mellitus were included in this study. We used nerve conduction studies (NCSs) and the coefficient of variation of the R-R interval to evaluate DPN. We estimated arteriosclerosis by the CAVI. Simple and multiple linear regression analyses were performed between neuropathy indices and the CAVI. In univariate analysis, the CAVI showed significant associations with sural sensory nerve conduction velocity and median F-wave conduction velocity. Multiple linear regression analysis for the CAVI showed that sural nerve conduction velocity and median F-wave conduction velocity were significant explanatory variables second only to age. In multiple linear regression analysis for sural nerve conduction velocity among neuropathy indices, the CAVI remained the most significant explanatory variable. In multiple linear regression analysis for median nerve F-wave conduction velocity among neuropathy indices, the CAVI remained the second most significant explanatory variable following HbA1c. These results suggest a close relationship between macroangiopathy and DPN.

The Effect of Treatments for Rheumatoid Arthritis on Endothelial Dysfunction Evaluated by Flow-Mediated Vasodilation in Patients with Rheumatoid Arthritis.

Rheumatoid Arthritis (RA) is a chronic inflammatory disease with a potential cardiovascular (CV) risk. Flow-Mediated Vasodilation (FMD) is an ultrasonic method to evaluate endothelial function. RA is a contributor to endothelial dysfunction, a CV risk. Relevant insights on the improvement of the CV outcomes in RA patients may be obtained by a systematic review of trials that investigated the effects of RA treatment on FMD in RA patients. This review found that treatments with antirheumatic drugs and some non-antirheumatic drugs could improve the FMD in RA patients. Treatment with anti-tumour necrosis factor (TNF)-α drugs, including infliximab, etanercept and adalimumab, improved the FMD in RA patients. Treatment with non-anti-TNF-α drugs, including rituximab, anakinra and tocilizumab, also improved the FMD. One trial showed that conventional synthetic Disease-Modifying Antirheumatic Drugs (DMARDs) improved the FMD. Regarding non-antirheumatic drugs, treatment with ramipril, spironolactone and statins/ezetimibe improved the FMD in RA patients. Treatment of advanced glycation endproducts inhibitors improved the FMD in RA patients, while treatment of pioglitazone did not. Overall, treatments for RA improved endothelial dysfunction, as evaluated by FMD, in RA patients. This information may be useful in patient management, although further studies are necessary to establish strategies in relation to endothelial dysfunction among these patients.

Effect of non-antihypertensive drugs on endothelial function in hypertensive subjects evaluated by flow-mediated vasodilation.

Hypertension (HTN) is a major risk factor for atherosclerosis. Flow-mediated vasodilation (FMD) is an ultrasonic method used to evaluate endothelial function, which is associated with HTN and related complications. We summarized clinical trials focusing on the effects of non-antihypertensive drugs on endothelial function, as evaluated by FMD, in patients with HTN. Hypercholesterolemic patients with HTN who used the cholesterol- lowering drugs HMG-CoA reductase inhibitors (statins) had improved FMD with a reduction in cholesterol levels and no significant change in blood pressure (BP). Non-diabetic patients with HTN who used the insulinsensitizing drug pioglitazone had improved FMD with a reduction in insulin resistance. Obese patients with HTN who used the anti-obesity drug orlistat had improved FMD with a reduction in BP and weight, and the improvement in FMD was correlated with weight reduction. Patients with HTN who used the selective cyclocxygenase-2 inhibitor celecoxib had improved FMD with no significant change in BP. Hypercholesterolemic patients with HTN who used aspirin added to a statin had improved FMD with a reduction in BP. Patients with HTN who used the advanced glycation endproduct crosslink breaker alagebrium had improved FMD with no significant change in BP. Postmenopausal women with HTN who used estrogen-replacement therapy had improved FMD. The possibility of improvement in FMD levels has, therefore, been suggested with several non-antihypertensive drugs. In addition to the direct effects of antihypertensive drugs on endothelial function, use of these non-antihypertensive drugs may give important insights into HTN management.

[Ultrasonography in Large-Vessel Arteritis].

Vasculitides are a group of diseases in which inflammation occurs in various vascular walls of the whole body, and ischemic symptoms are caused by stenoses and occlusions of blood vessels. Various parts of blood vessels of the whole body are affected, and the clinical manifestations are diverse. In the Chapel Hill Consensus Conference (CHCC) 2012, vasculitides are classified into seven categories. Takayasu arteritis and giant cell arteritis are included in large-vessel vasculitis. Large-vessel arteritis is defined as vasculitis affecting the aorta and its major branches more often than other vasculitides, but any sized artery may be affected. Ultrasonography has been progressing rapidly, so we can easily depict vessels of the surface of the body, in 0.1-mm units, and indicate the blood flow noninvasively. Ultrasonography has been used for the diagnosis of and estimation of the treatment for large-vessel vasculitis, and its importance has been increasing.

Arterial wall elasticity measured using the phased tracking method and atherosclerotic risk factors in patients with type 2 diabetes.

AIM: The aim of this study was to investigate the relationship between atherosclerotic manifestations and brachial and radial arterial wall elasticity (AWE) measured using the phased tracking method in patients with type 2 diabetes mellitus (T2DM). METHODS: This study included T2DM patients (n= 220, mean age 59 years) without a history of stroke or coronary artery disease. The brachial AWE, radial AWE, carotid mean intima-media thickness (IMT), max-IMT and flow-mediated vasodilation (FMD) were measured. The patients were classified according to the number of atherosclerotic risk factors, including obesity, dyslipidemia and hypertension. Group 1 included T2DM patients only, group 2 included patients with two risk factors, group 3 included patients with three risk factors and group 4 included patients with four risk factors. The patients were also divided into two groups according to microangiopathic complications, including retinopathy and nephropathy. The between-group differences were analyzed. RESULTS: The brachial AWE (548, 697, 755 and 771 kPa for groups 1, 2, 3 and 4, respectively) and radial AWE (532, 637, 717 and 782 kPa for groups 1, 2, 3 and 4, respectively) significantly increased in association with an increasing number of risk factors. The brachial AWE and radial AWE were significantly higher in the patients with microangiopathic complications than in those without microangiopathic complications (brachial AWE 797 and 694 kPa and radial AWE 780 and 660 kPa, respectively). Receiver operating characteristic curve analyses revealed that, for brachial AWE and radial AWE, the area under the curve was equal to the max-IMT and higher than the mean-IMT and FMD. CONCLUSIONS: Upper limb AWE measurement can reflect the degree of atherosclerosis risk overload and may be useful for evaluating vascular complications in T2DM patients.

Ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein, decreases cholesteryl ester transfer protein in type 2 diabetes mellitus.

To address the effects of ezetimibe on high-density lipoprotein (HDL) metabolism, the HDL subclasses, cholesteryl ester transfer protein (CETP), and lecithin-cholesterol acyltransferase (LCAT) were measured in patients with type 2 diabetes mellitus (T2DM). Twenty-three hypercholesterolemic patients with T2DM were treated with 10 mg of ezetimibe daily for 12 weeks. Plasma total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol (C), HDL-C, HDL(2)-C, HDL(3)-C, CETP mass, and LCAT activity were measured. HDL-C and HDL(2)-C increased by 5% (p<0.05) and 12% (p<0.01), respectively, in response to ezetimibe. Of the 23 patients, 21 had decreased CETP mass, which led to an average reduction of 20% (p<0.0001). LCAT activity also decreased by 6% (p<0.01). A significant positive correlation was found in the changes from baseline between HDL(2)-C and CETP mass, whereas a significant inverse relationship was observed between HDL(3)-C and CETP mass. Furthermore, the change in HDL-C was positively correlated with the change in LCAT activity. In conclusion, ezetimibe may affect HDL metabolism and reverse cholesterol transport, especially CETP, in T2DM. These observations may provide some insights into how ezetimibe prevents atherosclerosis.

Current smoking status may be associated with overt albuminuria in female patients with type 1 diabetes mellitus: a cross-sectional study.

BACKGROUND: There are very few clinical reports that have compared the association between cigarette smoking and microangiopathy in Asian patients with type 1 diabetes mellitus (T1DM). The objective of this study was to assess the relationships between urinary protein concentrations and smoking and gender-based risk factors among patients with T1DM. METHODS: A cross-sectional study of 259 patients with T1DM (men/women = 90/169; mean age, 50.7 years) who visited our hospital for more than 1 year between October 2010 and April 2011 was conducted. Participants completed a questionnaire about their smoking habits. Patient characteristics included gender, age, body mass index, blood pressure, hemoglobin A1c, lipid parameters, and microangiopathy. Diabetic nephropathy (DN) was categorized as normoalbuminuria (NA), microalbuminuria (MA), or overt albuminuria (OA) on the basis of the following urinary albumin/creatinine ratio (ACR) levels: NA, ACR levels less than 30 mg/g creatinine (Cr); MA, ACR levels between 30 and 299 mg/g Cr; and OA, ACR levels over 300 mg/g Cr. RESULTS: The percentages of current nonsmokers and current smokers with T1DM were 73.0% (n = 189) and 27.0% (n = 70), respectively. In addition, the percentage of males was higher than that of females (52.2% versus 13.6%) in the current smoking population. The percentage of DN was 61.8% (n = 160) in patients with NA, 21.6% (n = 56) in patients with MA, and 16.6% (n = 43) in patients with OA. The percentage of males among OA patients was also higher than that of females (24.4% versus 12.4%). However, current smoking status was associated with OA in females with T1DM only [unadjusted odds ratio (OR), 4.13; 95% confidence interval (CI), 1.45-11.73, P < 0.01; multivariate-adjusted OR, 5.41; 95% CI, 1.69-17.30, P < 0.01]. CONCLUSIONS: Based on our results in this cross-sectional study of Asian patients with T1DM, smoking might be a risk factor for OA among female patients. Further research is needed of these gender-specific results.

Influence of atorvastatin on serum amyloid A-low density lipoprotein complex in hypercholesterolemic patients.

The complex of serum amyloid A(SAA) and low-density lipoprotein (LDL), SAA-LDL, is considered a new and unique marker of oxidatively-modified LDL particles, which is associated with atherosclerotic conditions. This study investigated the influence of atorvastatin treatment on circulating SAA-LDL levels among asymptomatic hypercholesterolemic patients. A total of 26 patients (mean age 63 years) received 10 mg/daily atorvastatin during a 12-week treatment period. The levels of LDL cholesterol and SAA-LDL, but not high-sensitivity C-reactive protein and SAA, were significantly reduced after the treatment. Stepwise adjusted regression analyses revealed that changes of SAA-LDL were significantly and positively correlated with those of SAA, while absolute changes were small, which warrants further investigation. The results suggest that atorvastatin may beneficially reduce SAA-LDL, and SAA-LDL may be a sensitive measure for monitoring the efficacy and antioxidant functions of atorvastatin.

The effect of antihypertensive drugs on endothelial function as assessed by flow-mediated vasodilation in hypertensive patients.

Endothelial dysfunction is found in hypertensive patients and may serve as a prognostic marker of future cardiovascular events. Endothelial function can be assessed noninvasively by flow-mediated vasodilation (FMD). The goal of this paper is to summarize comprehensively the clinical trials that investigated the effects of antihypertensive drugs on endothelial function assessed by FMD in hypertensive patients. A PubMed-based search found 38 clinical trial papers published from January 1999 to June 2011. Significant improvement of FMD after antihypertensive treatment was shown in 43 of 71 interventions (among 38 clinical trial papers). Angiotensin II receptor blockers and angiotensin converting enzyme inhibitors appeared to improve FMD more than other drug types. Antihypertensive treatment can improve endothelial dysfunction when assessed by FMD, although there are conflicting data that require further research.

The correlation of common carotid arterial diameter with atherosclerosis and diabetic retinopathy in patients with type 2 diabetes mellitus.

The clinical significance of the diameter of the common carotid artery (CCA) measured ultrasonographically in diabetic practice has not been sufficiently established. The objective of this study was to investigate the relationship of the ultrasonic CCA diameter with atherosclerotic measures and diabetic retinopathy as a microvascular complication in patients with type 2 diabetes mellitus (T2DM). This hospital-based cross-sectional study included 102 patients with T2DM (men: 65%, mean age: 57 years) who had no apparent carotid arterial stenosis and no history of cardiovascular or severe renal disease. The current smoking status, body mass index, blood pressure, hemoglobin A1c, serum low-density lipoprotein cholesterol, and ultrasonic measures of carotid arteries (CCA diameter, intima-media thickness (IMT), plaque score) were measured. The cardio-ankle vascular index (CAVI) and the presence of diabetic retinopathy were also assessed. The CCA diameter showed a significant positive correlation with the mean IMT or plaque score. The CAVI had a significant positive correlation with the mean IMT, plaque score, and CCA diameter, while diabetic retinopathy had a significant positive correlation with the CCA diameter, but not the mean IMT or plaque score. These results were unaltered after adjusting for multiple confounders. The CCA diameter may serve as a useful marker for atherosclerosis and diabetic retinopathy, and in particular, may be a marker associated with diabetic retinopathy more clearly than the carotid IMT and plaque score, in patients with T2DM.

The correlation between the cardio-ankle vascular index (CAVI) and serum amyloid A in asymptomatic Japanese subjects.

Chronic inflammation has received a great deal of attention due to the role it plays in cardiovascular disease (CVD). The cardio-ankle vascular index (CAVI) has recently been developed to evaluate arterial stiffness. This index is independent of blood pressure at the time that it is measured, making it a better measure for clinical studies on the prevention of CVD. Information on the association of serum amyloid A (SAA) with arterial stiffness in relatively healthy subjects is still scarce. The aim of the present study was to investigate the potential correlation between SAA and CAVI in asymptomatic Japanese subjects. In addition to SAA and CAVI, data on smoking status, body mass index, blood pressure, and serum/plasma biochemical indices such as glucose and total cholesterol were collected in 387 nonmedicated and CVD-free adult subjects during a health check examination (male/female 191/196, mean age 61.8 years). Among them, a randomly selected subgroup of 256 subjects (male/female 133/123, mean age 62.4 years) had a full dataset, including low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, and hemoglobin A1c. Among the whole population, CAVI levels were significantly higher in males than in females [mean 8.5 ± (SD 1.1) vs. 8.2 ± 1.1, p < 0.05], while SAA levels were slightly but nonsignificantly higher in females than in males [median 6.4 (interquartile range 4.0-9.3) µg/mL vs. 5.1 (3.5-8.4)]. In a multiple linear regression analysis, CAVI was weakly but significantly, independently, and positively correlated with SAA (ß-coefficient 0.200, p < 0.01). The results of the same analyses for the randomly selected subgroup were relatively similar to the findings for the whole population. SAA may be a positive inflammatory factor associated with arterial stiffness, and the clinical relevance and the biological mechanism for this relationship should be established in future studies.

Influence of ezetimibe monotherapy on ischemia-modified albumin levels in hypercholesterolemic patients.

Ischemia-modified albumin (IMA) is considered to be a novel biochemical marker for ischemic and atherosclerotic conditions. This study aimed to investigate the influence of ezetimibe monotherapy on circulating IMA levels in hypercholesterolemic patients. A total of 31 patients (mean age 65.7 years) received 10 mg of ezetimibe daily during a 12-week treatment period. The levels of low-density lipoprotein cholesterol and IMA were significantly reduced after ezetimibe treatment. The adjusted regression analyses revealed that the changes in the IMA levels were not significantly correlated with those of the other atherosclerotic risk markers, such as body mass index, blood pressure, glucose and lipid panels. The significant reduction of the IMA levels following ezetimibe treatment, which was independent of the reduction of low-density lipoprotein cholesterol levels, suggests that ezetimibe may improve the oxidative stress burden in hypercholesterolemic patients.

Urinary protein as a marker for systolic blood pressure reduction in patients with type 2 diabetes mellitus participating in an in-hospital diabetes education program.

Increased blood pressure (BP) and urinary protein (UP)/microalbuminuria are risk factors for cardiovascular disease in patients with diabetes. Although the management of BP in patients with diabetes should involve a multidisciplinary therapy, there are no reports in which modulators have been identified in an in-hospital diabetes education program. The aim of the present study was to investigate the change in BP levels in patients with type 2 diabetes mellitus (T2DM) during a short-term (2-week) in-hospital education program on lifestyle modifications. A total of 167 patients with T2DM (101 men, 66 women; mean age, 61.1 years; glycated hemoglobin, 9.2%) were divided into 2 groups on the basis of their urinary albumin levels: 1 group without UP (urinary albumin level < 30 mg/day) and 1 group with UP (urinary albumin level ≥ 30 mg/day). We defined efficacy in reducing BP as a 20-mm Hg reduction in systolic BP (SBP) and a 10-mm Hg reduction in diastolic BP, and compared the changes between the 2 groups. Although the group with UP had higher SBP levels than the group without UP at baseline, this difference disappeared at the end of the program. Adjusted multivariate logistic regression analysis showed that UP at baseline was associated with a reduction in SBP (odds ratio, 3.361; 95% confidence interval, 1.29-8.79; P = 0.013). The data suggest that UP may be a marker related to the management of SBP through lifestyle modifications in patients with T2DM.

[Common carotid arterial diameter and coronary artery disease].

The clinical significance of the diameter of common carotid artery (CCA) measured ultrasonographically has not been sufficiently established. The object of this cross-sectional study was to investigate the relationship of the ultrasonic CCA diameter with coronary artery disease (CAD). In the male patients (n=169, mean age: 61 years) who had no apparent carotid arterial stenosis and cerebrovascular disease, a history of CAD, current smoking, body mass index, blood pressure, hemoglobin A1c, serum low-density-lipoprotein cholesterol, estimated glomerular filtration rate and ultrasonic measures of CCA diameter were analyzed. A total of 25 patients had a history of CAD (15%). The CCA diameters of patients with CAD were significantly higher than those of patients without CAD (7.9 +/- 1.0 mm and 7.4 +/- 0.9 mm; p = 0.01). Receiver operating characteristic curve of boundary value of CCA diameter revealed an area under the curve to identify the patients with CAD (0.63, p = 0.04). When the cut off value was considered 8.5 mm, the odds ratio was 4.50 (95% confidence interval = 1.71-11.84, p < 0.01), and the ratio were not largely altered in multivariate logistic regression analyses. The CCA diameter may therefore serve as a useful predictive marker for CAD in men.

The relationship between urinary 8-hydroxydeoxyguanosine and metabolic risk factors in asymptomatic subjects.

OBJECTIVE: The aim of this study was to investigate the relationship between metabolic risk factors and oxidative stress using urinary 8-hydroxydeoxyguanosine (8-OHdG), a recently utilized biological marker, in asymptomatic subjects. METHODS: Ninety subjects (males/females = 30/60; mean age = 52 years), who were nonsmoking, nondiabetic and not on any medicine, were enrolled in the study. The body mass index, blood pressure, total cholesterol, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and glucose as well as urinary 8-OHdG and creatinine were measured. RESULTS: The median level of 8-OHdG was 9.3 ng/mg creatinine (interquartile range: 5.8-23.2). TG (Pearson's correlation: r = 0.262, p = 0.013) and HDL-C (r = -0.259, p = 0.014) showed a significant correlation with 8-OHdG. A multiple linear regression analysis adjusted for all the variables revealed that only TG had an independently significant and positive correlation with 8-OHdG (ß = 0.231, p = 0.046). CONCLUSION: The data in this population suggest that, among metabolic risk factors, hypertriglyceridemia may be weakly but significantly associated with hyperoxidative stress as assessed by 8-OHdG.

Degradation of ultrasound probes caused by disinfection with alcohol.

The aim of this study was to clarify the degree of degradation of ultrasonic probes that results from their disinfection with alcohol. No defect in the ultrasound beams was found in any of the probes, but a significant decrease of the brightness was found after a certain period of use of the linear-type probe. Disinfection with alcohol may degrade ultrasound probes despite its high degree of effectiveness in preventing iatrogenic bacterial transmission.

The relationship between serum C-reactive protein and daily physical activity in Japanese hypertensive patients.

Hypertension (HT) and C-reactive protein (CRP) are risk factors of cardiovascular diseases (CVD). The current study's purpose was to investigate the relationship between serum CRP levels and daily lifestyles, including physical activity, in Japanese HT patients. Lifestyle factors, blood pressure (BP), blood cholesterol, glucose, and CRP were measured in a total of 312 HT patients (153 men/159 women, mean age: 62.6 y). Women with physical activity of ≥ 1 time/week showed significantly lower CRP levels than those without it (p < 0.05). The data suggest that regular physical activity could reduce the CRP levels in HT patients, thereby maybe preventing CVD.

Relationship between reactive oxygen metabolites and carotid intima-media thickness in subjects with hypercholesterolemia.

OBJECTIVE: It was the aim of this study to investigate whether there is any relationship between oxidative stress, as assessed by the diacron reactive oxygen metabolite (d-ROM) test, and carotid atherosclerosis among hypercholesterolemic patients. SUBJECTS AND METHODS: A well-defined group of patients with type II hypercholesterolemia (n = 81, mean age 59 years) was studied to observe the correlation between the levels of serum d-ROMs and carotid artery intima-media thickness (IMT) using B-mode ultrasound, in relation to the traditional atherosclerotic risk factors (age, sex, smoking, body mass index, blood pressure, glucose and lipid panels). RESULTS: The mean level in low-density lipoprotein cholesterol (LDL-C) in this population was 4.45 mmol/l, d-ROMs were 323.2 Carr U, and IMT was 0.91 mm. A multiple regression analysis revealed a positive and significant correlation between IMT and d-ROMs (ß = 0.27, p < 0.05), along with age and LDL-C. CONCLUSION: These results indicate that the increased oxidative stress levels using the d-ROM test, independent of aging and increased LDL-C levels, may be associated with carotid atherosclerosis even in hypercholesterolemic patients.

The correlation between CVR-R and carotid atherosclerosis in type 2 diabetes mellitus patients with diabetic neuropathy.

We examined the relationship between the coefficient of variation in the R-R intervals (CVR-R) using electrocardiograms and the ultrasonic intima-media thickness (IMT) of the carotid artery, an atherosclerotic parameter, in type 2 diabetes mellitus (DM) patients with diabetic neuropathy (n=47, males/females: 29/18; mean age: 62 years). In this study, the CVR-R-related indexes, including CVR-R at rest (CVR-R(rest)), CVR-R with deep breaths (CVR-R(breath)) and their difference (CVR-R(breath) minus CVR-R(rest): CVR-R(dif)), were defined. Data such as body mass index, smoking habits, hemoglobin A1c, blood pressure, and serum low-density lipoprotein were collected. A significant inverse correlation was observed between max-IMT and CVR-R(dif) (beta=-0.34, p=0.042), but not CVR-R(rest) or CVR-R(breath), in multivariate analyses adjusted for all the data. Therefore, the CVR-R(dif) may serve as a clinical index for the diabetic autonomic neuropathy-atherosclerosis relation in type 2 DM patients.