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1.  Systemic arteriosclerosis and eating behavior in Japanese type 2 diabetic patients with visceral fat accumulation 
Visceral fat accumulation is a major etiological factor in the progression of type 2 diabetes mellitus and atherosclerosis. We described previously visceral fat accumulation and multiple cardiovascular risk factors in a considerable number of Japanese non-obese subjects (BMI <25 kg/m2). Here, we investigated differences in systemic arteriosclerosis, serum adiponectin concentration, and eating behavior in type 2 diabetic patients with and without visceral fat accumulation.
The study subjects were 75 Japanese type 2 diabetes mellitus (age: 64.8 ± 11.5 years, mean ± SD). Visceral fat accumulation represented an estimated visceral fat area of 100 cm2 using the bioelectrical impedance analysis method. Subjects were divided into two groups; with (n = 53) and without (n = 22) visceral fat accumulation. Systemic arteriosclerosis was scored for four arteries by ultrasonography. Eating behavior was assessed based on The Guideline for Obesity questionnaire issued by the Japan Society for the Study of Obesity.
The visceral fat accumulation (+) group showed significantly higher systemic vascular scores and significantly lower serum adiponectin levels than the visceral fat accumulation (−) group. With respect to the eating behavior questionnaire items, (+) patients showed higher values for the total score and many of the major sub-scores than (−) patients.
Type 2 diabetic patients with visceral fat accumulation showed 1) progression of systemic arteriosclerosis, 2) low serum adiponectin levels, and 3) differences in eating behavior, compared to those without visceral fat accumulation. Taken together, the findings highlight the importance of evaluating visceral fat area in type 2 diabetic patients. Furthermore, those with visceral fat accumulation might need to undergo more intensive screening for systemic arteriosclerosis and consider modifying their eating behaviors.
PMCID: PMC4301666  PMID: 25592402
Type 2 diabetes; Visceral fat accumulation; Adiponectin; Systemic arteriosclerosis; Vascular ultrasonography; Eating behavior
3.  Adipose Hypothermia in Obesity and Its Association with Period Homolog 1, Insulin Sensitivity, and Inflammation in Fat 
PLoS ONE  2014;9(11):e112813.
Visceral fat adiposity plays an important role in the development of metabolic syndrome. We reported previously the impact of human visceral fat adiposity on gene expression profile of peripheral blood cells. Genes related to circadian rhythm were highly associated with visceral fat area and period homolog 1 (PER1) showed the most significant negative correlation with visceral fat area. However, regulation of adipose Per1 remains poorly understood. The present study was designed to understand the regulation of Per1 in adipose tissues. Adipose Per1 mRNA levels of ob/ob mice were markedly low at 25 and 35 weeks of age. The levels of other core clock genes of white adipose tissues were also low in ob/ob mice at 25 and 35 weeks of age. Per1 mRNA was mainly expressed in the mature adipocyte fraction (MAF) and it was significantly low in MAF of ob/ob mice. To examine the possible mechanisms, 3T3-L1 adipocytes were treated with H2O2, tumor necrosis factor-α (TNF-α), S100A8, and lipopolysaccharide (LPS). However, no significant changes in Per1 mRNA level were observed by these agents. Exposure of cultured 3T3-L1 adipocytes to low temperature (33°C) decreased Per1 and catalase, and increased monocyte chemoattractant protein-1 (Mcp-1) mRNA levels. Hypothermia also worsened insulin-mediated Akt phosphorylation in 3T3-L1 adipocytes. Finally, telemetric analysis showed low temperature of adipose tissues in ob/ob mice. In obesity, adipose hypothermia seems to accelerate adipocyte dysfunction.
PMCID: PMC4232416  PMID: 25397888
4.  Protocol for a large-scale prospective observational study with alogliptin in patients with type 2 diabetes: J-BRAND Registry 
BMJ Open  2014;4(9):e004760.
Dipeptidyl peptidase-4 (DPP-4) inhibitors including alogliptin are categorised as a newer class of oral hypoglycaemic, antidiabetic drugs to suppress the degradation of incretin hormones ((glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)) by DPP-4. We have scheduled a large-scale, multicentre, prospective, observational study (Japan-Based clinical ReseArch Network for Diabetes Registry: J-BRAND Registry) to construct an extensive database over a long-term clinical course in patients with type 2 diabetes receiving oral hypoglycaemic agents (OHAs) and to evaluate the safety and efficacy of alogliptin in Japanese population.
Methods and analysis
20 000 patients with type 2 diabetes will be registered into two groups of 10 000 each: group A patients will be treated with alogliptin, while group B patients will be treated with non-DPP-4 inhibitor OHA(s). Approximately 300 institutions nationwide will enrol and assign eligible patients equally to either group. Each patient's data will be collected every 6 months for a 3-year period, during which time treatment with OHA(s) may be changed or discontinued, as per package insert for each OHA. Primary end points are safety variables to be compared between the two groups and their subgroups, with respect to hypoglycaemia, pancreatitis, skin disorders, infections and cancer. Secondary end points are efficacy variables including from-baseline changes of A1c, fasting glucose, fasting insulin and urinary albumin, which will be compared between groups/subgroups. New onset and progression of microangiopathy will also be evaluated against OHA(s). Overall, the J-BRAND Registry will evaluate the safety and efficacy of antidiabetic OHA(s) including alogliptin, based on a large-scale database.
Ethics and dissemination
This study will be conducted with the highest respect for individual participants according to this protocol, the Declaration of Helsinki, the Ethical Guidelines for Clinical Research (Japan Ministry of Health, Labour and Welfare, 2008) and relevant laws/regulations. The present study will construct a valuable database of patients with type 2 diabetes treated with OHA(s) including alogliptin.
Trial registration number
PMCID: PMC4166248  PMID: 25227623
type 2 diabetes; DPP-4 inhibitor; alogliptin; observational study
5.  Long-term impact of liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, on body weight and glycemic control in Japanese type 2 diabetes: an observational study 
Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been shown to possess pleiotropic effects including body weight reduction. However, long-term effect of liraglutide on body weight and glycemic control has not been elucidated in Japanese type 2 diabetes (T2D) subjects. Present study investigates whether liraglutide treatment maintains the body weight-decreasing and glucose-lowering effects for 2 years in Japanese T2D subjects.
The enrolled subjects were 86 T2D patients [age; 59.8 ± 12.8 years, duration of diabetes; 15.8 ± 9.5 years, glycated hemoglobin (HbA1c); 8.5 ± 1.5%, body mass index (BMI); 27.3 ± 5.4 kg/m2 (15.8 - 46.5 kg/m2), mean ± SD]. Among 86 subjects, liraglutide was introduced in 25 inpatients and 61 outpatients, and 46 subjects were followed for 2 years. Clinical parameters were measured at baseline and 3, 6, 9, 12, and 24 months after liraglutide introduction. The increase in liraglutide dosage and the additional usage of glucose-lowering agents depended on each attending physician.
At 1 year after liraglutide introduction, 69 patients (80.2%) decreased body weight and 58 patients (67.4%) improved glycemic control. Body mass index (BMI) was changed 27.3 ± 5.4 kg/m2 to 25.9 ± 4.8 kg/m2 and percent reduction of body weight was significant and maintained over 4% at 2 years after liraglutide introduction. HbA1c was significantly decreased from 8.5 ± 1.5% to 7.7 ± 1.2% for 2 years. Liraglutide treatment tended to ameliorate lipid profile and hepatic enzymes. Stepwise regression analysis demonstrated that baseline BMI and previous insulin dose were positively associated with body weight reduction and baseline HbA1c was positively associated with reduction of HbA1c at 2 years after liraglutide introduction.
Long-term liraglutide treatment effectively maintained the reduction of body weight and the fair glycemic control, and also improved lipid profile and liver enzymes in Japanese T2D subjects.
PMCID: PMC4167135  PMID: 25237400
Liraglutide; Glucagon-like peptide-1; Obesity; Diabetes; Metabolic syndrome; Eating behavior
6.  Clinical utility of brachial-ankle pulse wave velocity in the prediction of cardiovascular events in diabetic patients 
Cardiovascular Diabetology  2014;13(1):128.
Brachial-ankle pulse wave velocity (baPWV) is a method to estimate arterial stiffness, which reflects the stiffness of both the aorta and peripheral artery; it would be applicable to general practice, since its measurementis automated. The aim of this study was to evaluate whether baPWV can be predictors of future cardiovascular events (CVE) in diabetic patients.
We prospectively evaluated the association between baPWV or carotid intima-media thickness (carotid IMT) at baseline and new onset of CVE in 1040 type 2 diabetic patients without CVE. The predictability of baPWV and/or carotid IMT for identifying patients at high risk for CVE was evaluated by time-dependent receiver-operating-characteristic (ROC) curve analysis.
During a median follow-up of 7.5 years, 113 had new CVD events. The cumulative incidence rates of CVE were significantly higher in patients with high baPWV values (≥1550 cm/s) as compared to those with low baPWV values (<1550 cm/s) (p < 0.001, log-rank test). Similarly, the cumulative incidence rate of CVE was significantly higher in patients with higher maximum carotid IMT (maxIMT) values (≥1.0 mm) as compared to those with lower maxIMT values (<1.0 mm) (p < 0.001, log-rank test). Subjects with both “high PWV” and “high IMT” had a significantly higher risk of developing CVE as compared to those with either “high PWV” or “high IMT,” as well as those with neither. A multivariate Cox proportional hazards regression model revealed that both baPWV (HR = 1.30, [95%CI: 1.07-1.57]; p = 0.009) and maxIMT (HR = 1.20, [95%CI: 1.01-1.41]; p = 0.033) were independent predictors for CVE, even after adjustment for the conventional risk factors. Time-dependent ROC curve analyses revealed that the addition of maxIMT to the Framingham risk score resulted in significant increase in AUC (from 0.60 [95%CI: 0.54-0.67] to 0.63 [95%CI: 0.60-0.82]; p = 0.01). Notably, the addition of baPWV to the Framingham risk score and maxIMT resulted in further and significant (p = 0.02) increase in AUC (0.72 [95%CI: 0.67-0.78]).
Evaluation of baPWV, in addition to carotid IMT and conventional risk factors, improved the ability to identify the diabetic individuals with high risk for CVE.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-014-0128-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4172854  PMID: 25186287
Brachial-ankle pulse wave velocity (baPWV); Carotid intima-media thickness (carotid IMT); Cardiovascular risk; Diabetes mellitus
7.  Short‐ and long‐term effect of sitagliptin after near normalization of glycemic control with insulin in poorly controlled Japanese type 2 diabetic patients 
The aim of the present study was to examine the short‐ and long‐term effect of sitagliptin on glucose tolerance after near normalization of glycemic control with insulin in poorly controlled type 2 diabetic patients.
Materials and Methods
We consecutively enrolled a total of 30 type 2 diabetic patients whose glycated hemoglobin levels (National Glycohemoglobin Standardization Program) were ≥7.4%, stopped all oral antidiabetic drugs and started insulin therapy. When fasting plasma glucose levels became <140 mg/dL, we carried out the first oral glucose tolerance test (OGTT). After 1‐week sitagliptin treatment (50 mg/day), the second OGTT was carried out. Furthermore, we evaluated the long‐term efficacy of sitagliptin on glucose tolerance after near normalization of glycemic control with insulin.
After 1‐week sitagliptin treatment, the area under the curve of insulin was markedly increased, and the area under the curve of glucagon and glucose was markedly decreased. Duration of diabetes and insulin secretory capacity were correlated with the effect of sitagliptin. Furthermore, interestingly, near normalization of glycemic control with insulin therapy for 1–2 weeks brought out the long‐term effectiveness of sitagliptin on glucose tolerance for 24 weeks, which was not observed with other antidiabetic drugs.
These findings suggest that near normalization of glycemic control with insulin improves the clinical response to sitagliptin in poorly controlled type 2 diabetic patients.
PMCID: PMC4188113  PMID: 25411623
Dipeptidyl peptidase‐4 inhibitor; Insulin therapy; Sitagliptin
8.  Clinical significance of visceral adiposity assessed by computed tomography: A Japanese perspective 
World Journal of Radiology  2014;6(7):409-416.
Abdominal obesity, rather than total amount of fat, is linked to obesity-related disorders. Visceral adiposity is an important component of obesity-related disorders in Japanese individuals with a mild degree of adiposity compared with Western subjects. In 1983, our group reported techniques for body fat analysis using computed tomography (CT) and established the concept of visceral fat obesity in which intra-abdominal fat accumulation is an important factor in the development of obesity-related complications, such as diabetes, lipid disorders, hypertension and atherosclerosis. Our group also established ideal imaging conditions for determining abdominal fat area at the umbilical level CT scan. Visceral fat area (VFA) measured in a single slice at L4 level correlated significantly with the total abdominal visceral fat volume measured on multislice CT scan. In a large-scale study of a Japanese population, the mean number of obesity-related cardiovascular risk factors (hypertension, low high-density lipoprotein cholesterolemia and/or hypertriglyceridemia, and hyperglycemia) was greater than 1.0 at 100 cm2 of VFA, irrespective of gender, age and body mass index. Our group also demonstrated that reduction of visceral fat accumulation subsequent to voluntary lifestyle modification, “Hokenshido”, correlated with a decrease in the number of obesity-related cardiovascular risk factors. It is important to select the most appropriate subjects from the general population (e.g., non-obese subjects with a cluster of risk factors for the metabolic syndrome) that are most suitable for body weight reduction, with the goal of preventing atherosclerotic cardiovascular diseases.
PMCID: PMC4109092  PMID: 25071881
Visceral fat; Metabolic syndrome; Computed tomography; Atherosclerotic cardiovascular diseases
9.  Increased serum C1q-binding adiponectin complex to total-adiponectin ratio in men with multi-vessel coronary disease 
Adiponectin plays a role as a positive contributor to the stabilization of atherosclerotic plaques. Circulating total adiponectin (Total-APN) levels associates with the number of coronary vessels in men with coronary artery disease (CAD). We recently reported that adiponectin binds to C1q in human blood, and serum C1q-binding adiponectin (C1q-APN) /Total-APN levels are associated with CAD in type 2 diabetic subjects. The present study investigated the relationship between circulating C1q-APN levels and the number of angiographic coronary artery vessel in male subjects.
The study subjects were 53 male Japanese patients who underwent diagnostic coronary angiography. Blood total adiponectin (Total-APN), high-molecular weight adiponectin (HMW-APN), C1q-APN and C1q were measured by enzyme-linked immunosorbent assays.
Serum C1q-APN/Total-APN ratio significantly increased in subjects with single and multi-vessel coronary diseases (p = 0.029 for trend, the Kruskal-Wallis test). However, serum Total-APN, HMW-APN, C1q-APN and C1q levels did not correlate with number of diseased coronary vessels.
Serum C1q-APN/Total-APN ratio progressively increases in men with single and multi-vessel coronary disease.
Trial registration
PMCID: PMC4038830  PMID: 24883115
Adiponectin; C1q; C1q-binding adiponectin; Coronary artery disease; Angiographic coronary vessel
10.  A pilot three-month sitagliptin treatment increases serum adiponectin level in Japanese patients with type 2 diabetes mellitus- a randomized controlled trial START-J study 
The dipeptidyl-peptidase-IV (DPP-4) inhibitors, including sitagliptin, are used for the treatment of type 2 diabetes mellitus (T2DM). Adiponectin, an adipocyte-derived circulating protein, has anti-atherosclerotic and anti-diabetic properties and is effectively elevated in bloodstream by thiazolidinediones, an insulin sensitizer. However, the effect of sitagliptin treatment on serum adiponectin level in T2DM has not fully elucidated in Japanese T2DM patients. The aim of the present study was to examine the effect of sitagliptin treatment on serum adiponectin levels in T2DM subjects.
Twenty-six consecutive Japanese T2DM outpatients were recruited between April 2011 and March 2013, and randomized into the control (conventional treatment, n = 10) group and sitagliptin treatment group (n = 16). Serum adiponectin was measured by enzyme-linked immunosorbent assay.
Indices of glycemic control, such as hemoglobin A1c, glycated albumin, and 1.5-anhydro-D-glucitol, were significantly improved after the three-month treatment in both the control and sitagliptin groups. Serum adiponectin level was significantly increased in sitagliptin group from 6.7 ± 0.8 to 7.4 ± 1.0 μg/mL without change of body mass index (p = 0.034), while serum adiponectin level was not altered in the control group (p = 0.601).
In Japanese T2DM patients, serum adiponectin level was elevated by three-month treatment with sitagliptin without change of body weight.
Trial registration
PMCID: PMC4049487  PMID: 24884787
Sitagliptin; Adiponectin; DPP4 inhibitor; Inctrein; Diabetes; Oxidative stress
11.  Ultrastructural Localization of Adiponectin protein in Vasculature of Normal and Atherosclerotic mice 
Scientific Reports  2014;4:4895.
Adiponectin, adipose-specific secretory protein, abundantly circulates in bloodstream and its concentration is around 1000-fold higher than that of other cytokines and hormones. Hypoadiponectinemia is a risk factor for atherosclerosis. There is little or no information on ultrastructural localization of adiponectin in the vasculature. Herein we investigated the localization of vascular adiponectin in the aorta using the immunoelectron microscopic technique. In wild-type (WT) mice, adiponectin was mainly detected on the luminal surface membrane of endothelial cells (ECs) and also found intracellularly in the endocytic vesicles of ECs. In the atherosclerotic lesions of apolipoprotein E-knockout (ApoE-KO) mice, adiponectin was detected in ECs, on the cell surface membrane of synthetic smooth muscle cells, and on the surface of monocytes adherent to ECs. Changes in adiponectin localization within the wall of the aorta may provide novel insight into the pathogenesis of atherosclerosis.
PMCID: PMC4013939  PMID: 24809933
12.  Usefulness of the insulin tolerance test in patients with type 2 diabetes receiving insulin therapy 
To establish the validity of the plasma glucose disappearance rate (KITT), derived from an insulin‐tolerance test (ITT), for evaluating the insulin sensitivity of patients with type 2 diabetes after insulin therapy.
Materials and Methods
In the first arm of the study, 19 patients with poorly controlled diabetes were treated with insulin and underwent an ITT and a euglycemic clamp test (clamp‐IR). The relationship between the insulin resistance index, as assessed by both the clamp‐IR and KITT tests, was examined. In the second arm of the study, the relationships between KITT values and various clinical parameters were investigated in 135 patients with poorly controlled diabetes, after achieving glycemic control with insulin.
In study 1, a close correlation between KITT and the average glucose infusion rate during the last 30 min of the standard clamp‐IR test (M‐value) was noted (P < 0.001). In study 2, body mass index (P = 0.0011), waist circumference (P = 0.0004), visceral fat area (P = 0.0011) and the log‐transformed homeostasis model assessment of insulin resistance value (P = 0.0003) were negatively correlated with the log‐transformed KITT. High‐density lipoprotein cholesterol (P = 0.0183), low‐density lipoprotein cholesterol (P = 0.0121) and adiponectin (P = 0.0384) levels were positively correlated with the log‐transformed KITT.
The ITT is a valid and useful test for evaluating the insulin sensitivity of patients with diabetes, even after treatment with insulin.
PMCID: PMC4020335  PMID: 24843779
Insulin resistance; Insulin therapy; Insulin tolerance test
13.  The Utility of Carotid Ultrasonography in Identifying Severe Coronary Artery Disease in Asymptomatic Type 2 Diabetic Patients Without History of Coronary Artery Disease 
Diabetes Care  2013;36(5):1327-1334.
Although many studies have shown that carotid intima-media thickness (IMT) is associated with coronary artery disease (CAD), it remains inconclusive whether assessment of carotid IMT is useful as a screening test for asymptomatic but severe CAD in diabetic patients.
A total of 333 asymptomatic type 2 diabetic patients without history of CAD underwent exercise electrocardiogram or myocardial perfusion scintigraphy for detection of silent myocardial ischemia, and those whose test results were positive were subjected to coronary computed tomography angiography or coronary angiography. The ability of carotid IMT to identify severe CAD corresponding to treatment with revascularization was examined by receiver-operating characteristic (ROC) curve analyses.
Among the 333 subjects, 17 were treated with revascularization. A multiple logistic regression analysis showed that maximum IMT was an independent predictor of severe CAD even after adjustment for conventional risk factors. ROC curve analyses revealed that the addition of maximum IMT to conventional risk factors significantly improved the prediction ability for severe CAD (from area under the curve, 0.67 to 0.79; P = 0.039). The greatest sensitivity and specificity were obtained when the cut-off value of maximum IMT was set at 2.45 mm (pretest probability, 5%; posttest probability, 11%; sensitivity, 71%). When we applied age-specific cut-off values, the sensitivity of screening further increased in both the nonelderly (pretest probability, 6%; posttest probability, 10%; sensitivity, 100%) and the elderly subjects (pretest probability, 5%; posttest probability, 15%; sensitivity, 100%).
Our study suggests that carotid maximum IMT is useful for screening asymptomatic type 2 diabetic patients with severe CAD equivalent to revascularization.
PMCID: PMC3631883  PMID: 23404302
14.  Tracing the movement of adiponectin in a parabiosis model of wild-type and adiponectin-knockout mice 
FEBS Open Bio  2014;4:276-282.
•We generated a hetero parabiosis model of wild type and adiponectin knockout (KO) mice.•Adiponectin protein was detected in adipose tissues of the KO parabiotic partner.•High adiponectin levels were found in stromal vascular fraction of the obese KO partner.•Obese parabiotic mice exhibited marked hypoadiponectinemia.
Adiponectin is exclusively synthesized by adipocytes and exhibits anti-diabetic, anti-atherosclerotic and anti-inflammatory properties. Hypoadiponectinemia is associated in obese individuals with insulin resistance and atherosclerosis. However, the mechanisms responsible for hypoadiponectinemia remain unclear. Here, we investigated adiponectin movement using hetero parabiosis model of wild type (WT) and adiponectin-deficient (KO) mice. WT mice were parabiosed with WT mice (WT–WT) or KO mice (WT–KO) and adiponectin levels were measured serially up to 63 days after surgery. In the WT–KO parabiosis model, circulating adiponectin levels of the WT partners decreased rapidly, on the other hand, those of KO partners increased, and then these reached comparable levels each other at day 7. Circulating adiponectin levels decreased further to the detection limit of assay, and remained low up to day 63. However, adiponectin protein was detected in the adipose tissues of not only the WT partner but also WT–KO mice. In the diet-induced obesity model, high adiponectin protein levels were detected in adipose stromal vascular fraction of diet-induced obese KO partner, without changes in its binding proteins. The use of parabiosis experiments shed light on movement of native adiponectin among different tissues such as the state of hypoadiponectinemia in obesity.
PMCID: PMC4048846  PMID: 24918039
APN, adiponectin; KO, adiponectin deficient mice; HF/HS, high fat/high sucrose diet; KO (WT–KO), KO partner of WT–KO; MAF, mature adipocyte fraction; NC, normal chow diet; SVF, stromal vascular fraction; WATmes, mesenteric white adipose tissue; WATsub, subcutaneous white adipose tissue; WT (WT–KO), WT partner of WT–KO; WT (WT–WT), WT partner of WT–WT; WT, wild type mice; WT–KO, parabiosis between WT and KO; WT–WT, parabiosis between WT and WT; Adiponectin; Adipose tissue; Obesity; Parabiosis
15.  Rationale, design, and baseline characteristics of a clinical trial for prevention of atherosclerosis in patients with insulin-treated type 2 diabetes mellitus using DPP-4 inhibitor: the Sitagliptin Preventive study of Intima-media thickness Evaluation (SPIKE) 
Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is currently used to achieve glycemic targets in patients with type 2 diabetes mellitus (T2DM). The addition of DPP-4 inhibitors to ongoing insulin therapy is expected to reduce insulin dosage, leading to a reduction in the frequency of hypoglycaemia and/or weight gain. Recent studies have demonstrated potential anti-atherosclerotic effects for DPP-4 inhibitors. The aim of the present ongoing study is to assess the effects of sitagliptin on the progression of atherosclerosis in patients with insulin-treated T2DM using carotid intima-media thickness (IMT), an established marker of cardiovascular disease.
Methods and Design
The Sitagliptin Preventive study of Intima media thickness Evaluation (SPIKE) is a prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study. Between February 2012 and September 2012, 282 participants who failed to achieve glycemic control despite insulin therapy were recruited at 12 clinics and randomly allocated to the sitagliptin group (n = 142) or the control group (n = 140). Primary outcomes are changes in maximum and mean IMT of the common carotid artery after 24-month treatment period measured by carotid arterial echography. Secondary outcomes include changes in glycemic control, parameters related to beta-cell function and diabetic nephropathy, occurrence of cardiovascular events and adverse events such as hypoglycaemia, and biochemical markers of vascular function.
The present study is designed to assess the effects of sitagliptin on the progression of carotid IMT. Results will be available in the near future, and the findings are expected to provide new strategy to prevent atherosclerosis in patients with insulin-treated T2DM.
Clinical Trial Registration
PMCID: PMC3973974  PMID: 24607023
Sitagliptin; DPP-4; Diabetes; Atherosclerosis; Intima-media thickness (IMT)
16.  Carotid ultrasonography: A potent tool for better clinical practice in diagnosis of atherosclerosis in diabetic patients 
Cardiovascular disease (CVD) remains the main cause of death in diabetic patients, and once it has developed, diabetic patients have a worse outcome as compared with non‐diabetic patients. One reason for this is the difficulty of early diagnosis of atherosclerotic change in these patients. Although cardiovascular risk assessment based on conventional risk factors is recommended for predicting cardiovascular risk, validation studies showed only moderate performance. In contrast, it is unrealistic to screen for subclinical or silent atherosclerosis by sophisticated modalities, such as myocardial perfusion scintigraphy, coronary computed tomography angiography or conventional angiography in all diabetic patients, as these tests are limited by the potential of significant adverse effects, technical difficulty, availability and high cost. Therefore, a non‐invasive and inexpensive tool for risk prediction of subclinical atherosclerosis is required for identifying individuals at high risk of CVD. Recently, a number of studies have shown close associations between carotid atherosclerosis and cerebrovascular or coronary artery disease. Carotid ultrasonography has allowed clinicians to visualize the characteristics of the carotid wall and lumen surfaces to quantify the severity of atherosclerosis. Carotid intima‐media thickness (IMT) is an especially useful marker of the progression of atherosclerosis throughout the body, and is an excellent predictor of cardiovascular events. As a simple and non‐invasive procedure, measurement of carotid IMT is one of the most appropriate screening methods to specify high‐risk individuals in subjects with and without diabetes. Therefore, it is expected that carotid ultrasonography will become a potent tool for better clinical practice of atherosclerosis in diabetic patients.
PMCID: PMC4025224  PMID: 24843729
Cardiovascular diseases; Carotid ultrasound; Diabetes mellitus
17.  Assessment of vibratory sensation with a tuning fork at different sites in Japanese patients with diabetes mellitus 
The current study compared the vibratory sensations at different sites, using a retrospective database of 547 Japanese diabetic patients. The vibratory sensation was assessed with a 128‐Hz tuning fork at the medial malleolus, the great toe and the fifth toe. The vibratory sensations at different sites were significantly associated with one another (all P < 0.01). The vibratory sensation at one site corresponding to 10 s at another site was calculated to be 9–11 s. Although the vibratory sensations at the three sites had different associations with the pressure sensation and the ankle reflex, they showed similar C‐statistics for the impaired pressure sensation and the disappeared ankle reflex. In conclusion, the vibratory sensations at different sites were strongly associated with one another. They would be clinically acceptable alternatives to one another in the assessment of diabetic peripheral neuropathy.
PMCID: PMC4025230  PMID: 24843743
Diabetic peripheral neuropathy; Medial malleolus; Vibratory sensation
18.  Possible Involvement of Opa-Interacting Protein 5 in Adipose Proliferation and Obesity 
PLoS ONE  2014;9(2):e87661.
Obesity is an epidemic matter increasing risk for cardiovascular diseases and metabolic disorders such as type 2 diabetes. We recently examined the association between visceral fat adiposity and gene expression profile of peripheral blood cells in human subjects. In a series of studies, Opa (Neisseria gonorrhoeae opacity-associated)-interacting protein 5 (OIP5) was nominated as a molecule of unknown function in adipocytes and thus the present study was performed to investigate the role of OIP5 in obesity. Adenovirus overexpressing Oip5 (Ad-Oip5) was generated and infected to 3T3-L1 cells stably expressing Coxsackie-Adenovirus Receptor (CAR-3T3-L1) and to mouse subcutaneous fat. For a knockdown experiment, siRNA against Oip5 (Oip5-siRNA) was introduced into 3T3-L1 cells. Proliferation of adipose cells was measured by BrdU uptake, EdU-staining, and cell count. Significant increase of Oip5 mRNA level was observed in obese white adipose tissues and such increase was detected in both mature adipocytes fraction and stromal vascular cell fraction. Ad-Oip5-infected CAR-3T3-L1 preadipocytes and adipocytes proliferated rapidly, while a significant reduction of proliferation was observed in Oip5-siRNA-introduced 3T3-L1 preadipocytes. Fat weight and number of adipocytes were significantly increased in Ad-Oip5-administered fat tissues. Oip5 promotes proliferation of pre- and mature-adipocytes and contributes adipose hyperplasia. Increase of Oip5 may associate with development of obesity.
PMCID: PMC3916335  PMID: 24516558
19.  High serum C1q-binding adiponectin levels in male patients with acute coronary syndrome 
The complement system is part of the immune system in acute coronary syndrome (ACS). Adiponectin has anti-atherogenic and anti-inflammatory properties. Adiponectin and C1q form a protein complex in blood, and serum C1q binding adiponectin (C1q-APN) can be measured. We investigated the comparative evaluation of serum C1q-APN levels in males with ACS, stable angina pectoris (SAP) versus controls.
The study subjects were 138 Japanese patients who underwent diagnostic coronary angiography. Blood total adiponectin (Total-APN), C1q-APN and C1q were measured by enzyme-linked immunosorbent assays. Patients were divided into three groups according to the clinical condition: ACS (n = 78), SAP (n = 41) or normal coronary (NC, n = 19) groups.
Serum C1q levels were significantly higher in the ACS group (54.9±1.2 μg/mL) than in the NC group (48.0±2.5 μg/mL). Although serum Total-APN levels were significantly lower in the SAP and ACS groups, compared with the NC group (7.0±0.5, 7.2±0.3, 10.6±2.0 μg/mL, respectively), serum C1q-APN levels were significantly higher in the ACS group than in the NC and SAP groups (112.1±4.1, 66.3±4.4, 65.7±2.9 units/mL, respectively).
Patients with ACS had higher serum C1q-APN levels.
Trial Registration
PMCID: PMC3893390  PMID: 24400991
Adiponectin; C1q; C1q-binding adiponectin; Acute coronary syndrome
21.  Ultrasonic Tissue Characterization of Carotid Plaque Improves the Prediction of Cardiovascular Events in Diabetic Patients 
Diabetes Care  2012;35(12):2640-2646.
The aim of this study is to evaluate whether noninvasive ultrasonic tissue characterization of carotid plaque using integrated backscatter (IBS) analysis can be a predictor of future cardiovascular events (CVE) in asymptomatic type 2 diabetic patients.
We prospectively evaluated the association between Calibrated-IBS value, an ultrasonic marker for tissue characteristics of carotid plaque, and CVE in 85 asymptomatic type 2 diabetic patients with carotid plaque.
The median follow-up period was 7.9 years, and there were 20 new CVE. The risk of CVE was significantly higher in the subjects with low Calibrated-IBS values (<−17.1 dB; n = 42) as compared with those with high values (≥−17.1 dB; n = 43) (P = 0.004, log-rank test). Cox proportional hazards regression analysis revealed that both Calibrated-IBS value (hazard ratio [HR] 0.802 [95% CI 0.710–0.906]; P < 0.0001) and plaque thickness (1.938 [1.170–3.213]; P = 0.010) were independently associated with CVE, even after adjustment for the 10-year risk for a general cardiovascular disease estimated by Framingham risk scoring (FRS). Time-dependent receiver operating characteristic curve analysis for CVE at 10 years after the baseline examinations revealed that area under the curve for Calibrated-IBS was 0.76 (0.60–0.90) and substantially higher than those for plaque thickness (0.60 [0.45–0.79]) and FRS (0.60 [0.40–0.78]). These analyses also revealed that the addition of both plaque thickness and Calibrated-IBS value to conventional risk factors significantly improved the event prediction.
Calibrated-IBS value could improve the risk prediction of CVE in asymptomatic type 2 diabetic patients with carotid plaque.
PMCID: PMC3507570  PMID: 23043165
23.  Painful Diabetic Neuropathy in Japanese Diabetic Patients Is Common but Underrecognized 
Pain Research and Treatment  2013;2013:318352.
Although chronic pain due to diabetic neuropathy, defined as painful diabetic neuropathy (PDN), is a debilitating and distressing complication of diabetes, epidemiological data on PDN has been scarce, especially in Asia. We evaluated the prevalence of Japanese PDN and its impact on their quality of life (QOL) and metnal state. In addition, we examined to which extent physicians are aware of patients' PDN. A total of 298 patients with diabetes were found to be eligible for the study. We revealed that substantial percentage (22.1%) of Japanese diabetic patients had PDN and that PDN had negative effect on patients' QOL and mental state. However, physicians were aware of PDN in only 36.4% of patients with the condition. To the best of our knowledge, this is the first report showing the extent of physicians' awareness of patients' PDN. In conclusion, physicians treating diabetes need to be more aware of patients' PDN in everyday clinical practice to prevent the progression of PDN and improve the patients' QOL and mental state.
PMCID: PMC3860156  PMID: 24377045
24.  Association of Diabetes and Hemodialysis With Ankle Pressure and Ankle-Brachial Index in Japanese Patients With Critical Limb Ischemia 
Diabetes Care  2012;35(10):2000-2004.
To investigate whether diabetes and regular hemodialysis are associated with false elevation of ankle systolic blood pressure and ankle-brachial systolic pressure index (ABI) because of their arterial calcification in patients with critical limb ischemia (CLI).
We recruited 269 Japanese patients who underwent endovascular therapy for CLI. Ankle systolic blood pressure and ABI were assessed before endovascular therapy. Arterial stenosis and calcification were evaluated angiographically. We investigated the associations among clinical comorbidities, arterial calcification, and measurements of ankle systolic blood pressure and ABI.
Ankle systolic blood pressure was 85 ± 56 mmHg, and ABI was 0.59 ± 0.37. Arterial calcification was observed in 69% of the patients. The prevalence of diabetes and regular hemodialysis was 71 and 47%. Diabetes and regular hemodialysis were both significantly associated with the presence of arterial calcification; their adjusted odds ratios were 2.33 (P = 0.01) and 7.40 (P < 0.01), respectively. However, there was no significant difference in ankle systolic blood pressure or ABI level between those with and without these comorbidities. Furthermore, the presence of arterial calcification was not associated with ankle systolic blood pressure or ABI level, whereas arterial stenoses of all segments in the lower body had independent associations with reduced ankle systolic blood pressure and ABI level.
Diabetes and regular hemodialysis were significantly associated with arterial calcification, but not with elevated measurements of ankle systolic blood pressure or ABI, in CLI patients.
PMCID: PMC3447830  PMID: 22723344
25.  A Novel Role for Adipose Ephrin-B1 in Inflammatory Response 
PLoS ONE  2013;8(10):e76199.
Ephrin-B1 (EfnB1) was selected among genes of unknown function in adipocytes or adipose tissue and subjected to thorough analysis to understand its role in the development of obesity.
Methods and Results
EfnB1 mRNA and protein levels were significantly decreased in adipose tissues of obese mice and such reduction was mainly observed in mature adipocytes. Exposure of 3T3-L1 adipocytes to tumor necrosis factor-α (TNF-α) and their culture with RAW264.7 cells reduced EFNB1 levels. Knockdown of adipose EFNB1 increased monocyte chemoattractant protein-1 (Mcp-1) mRNA level and augmented the TNF-α-mediated THP-1 monocyte adhesion to adipocytes. Adenovirus-mediated adipose EFNB1-overexpression significantly reduced the increase in Mcp-1 mRNA level induced by coculture of 3T3-L1 adipocytes with RAW264.7 cells. Monocyte adherent assay showed that adipose EfnB1-overexpression significantly decreased the increase of monocyte adhesion by coculture with RAW264.7 cells. TNF-α-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) was reduced by EFNB1-overexpression.
EFNB1 contributes to the suppression of adipose inflammatory response. In obesity, reduction of adipose EFNB1 may accelerate the vicious cycle involved in adipose tissue inflammation.
PMCID: PMC3787942  PMID: 24098442

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