Fumie Sakamoto

Circulating soluble RAGE as a predictive biomarker of cardiovascular event risk in patients with type 2 diabetes.

It is still controversial whether circulating soluble form of receptor for AGE (sRAGE) is associated with atherosclerosis in diabetic patients. In this study, we enrolled 276 Japanese type 2 diabetic subjects without history of cardiovascular disease (CVD), assessed their baseline clinical and biochemical data including serum sRAGE levels, and prospectively evaluated the association between these parameters and CVD events. The median follow-up period was 5.6 years and there were 25 new CVD events. The tertile analysis showed that the risk for CVD events was higher as serum sRAGE levels were increased (p for trend = 0.046). A multivariate Cox proportional hazards regression analysis revealed that serum sRAGE levels were independently associated with CVD (HR per 1SD = 1.59, 95% CI 1.04-2.45, p = 0.034), even after adjusting for conventional coronary risk factors. In summary, elevated sRAGE levels were associated with the increased risk of CVD in Japanese type 2 diabetic subjects.

Serum vitamin D levels are decreased and associated with thyroid volume in female patients with newly onset Graves' disease.

It has been shown that vitamin D deficiency is associated with autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), multiple sclerosis (MS) and type 1 diabetes (T1DM), and that vitamin D supplementation prevents the onset and/or development of these autoimmune diseases [1]. Furthermore, it was reported more recently that patients with Hashimoto’s thyroiditis, an autoimmune thyroid disease had lower vitamin D levels [2]. However, there are few studies examining vitamin D status in patients with newly onset Graves’ disease. In the present study, we evaluated the vitamin D status in female patients with newly onset GD and the association of serum vitamin D levels with the clinical factors related to GD.

Serum vitamin D levels are decreased in patients without remission of Graves’ disease

Graves’ disease (GD) is an autoimmune thyroid disease in which thyrotropin receptor autoantibodies (TRAb) cause hyperthyroidism. Although medical treatment with antithyroid drugs (ATD) is the first choice treatment for GD in Japan and Europe, a remission rate of GD with ATD is not satisfactory, and many patients need long-term treatment with ATD or further treatments such as radioactive iodine therapy or thyroidectomy [1]. Therefore, it is very important to identify the factors relating to the remission of GD. It has been recently shown that vitamin D deficiency is associated with the onset and/or development of several autoimmune diseases, including multiple sclerosis (MS), inflammatory bowel disease (IBD), and type 1 diabetes (T1DM) [2]. Furthermore, it has been reported more recently that patients with autoimmune thyroid diseases including GD have lower vitamin D status [3, 4]. However, there is no study comparing vitamin D status between the patients with and without remission of GD. In the present study, we examined vitamin D status in female patients with and without remission of GD and discussed the role of vitamin D in the pathogenesis and/or prognosis of GD.

Basal Insulin Requirement Is ∼30% of the Total Daily Insulin Dose in Type 1 Diabetic Patients Who Use the Insulin Pump

OBJECTIVE To investigate the basal insulin requirement in total daily insulin dose in Japanese type 1 diabetic patients who use the insulin pump. RESEARCH DESIGN AND METHODS The basal insulin requirement in 35 type 1 diabetic patients without detectable C-peptide using the insulin pump (Paradigm 712) was investigated during 2–3 weeks of hospitalization. The patients were served diabetic diets of 25–30 kcal/kg ideal body weight. Each meal omission was done to confirm stable blood glucose levels within 30 mg/dL variance until the next meal. Target blood glucose level was set at 100 mg/dL before each meal and 150 mg/dL at 2 h after each meal. RESULTS Total daily insulin dose was 31.6 ± 8.5 units, and total basal insulin requirement was 8.7 ± 2.9 units, which was 27.7 ± 6.9% of the total daily dose. CONCLUSIONS Basal insulin requirement is ∼30% of the total daily dose in Japanese type 1 diabetic patients who use the insulin pump.

Usefulness of lipoprotein ratios in assessing carotid atherosclerosis in Japanese type 2 diabetic patients

OBJECTIVE It is indicated that total/HDL cholesterol and LDL/HDL cholesterol ratios have more predictive power for cardiovascular disease compared to classic lipid parameters. However, there have been few reports about the usefulness of these indices for the assessment of early stage atherosclerosis in Japanese type 2 diabetic subjects. METHODS We examined the relation between various lipid parameters and carotid atherosclerosis in 934 type 2 diabetic subjects without apparent atherosclerotic diseases (males, 71.7%; age, 59.6 ± 10.5 years (mean ± SD)). Serum concentrations of total cholesterol (TC), HDL cholesterol (HDL-C), and triglyceride were measured. LDL cholesterol (LDL-C) level was calculated using the Friedewald formula. The presence of carotid plaque and intima-media thickness (IMT) were evaluated by ultrasonography. RESULTS A stepwise multivariate regression analysis demonstrated that HDL-C (β = -0.110, p<0.001), TC/HDL-C (β = 0.132, p < 0.001) and LDL-C/HDL-C ratios (β = 0.132, p < 0.001) were independent determinants of IMT even after adjustment of other conventional risk factors. However, there was no significant correlation between IMT and TC, triglyceride, LDL-C, and non-HDL-C levels. TC/HDL-C and LDL-C/HDL-C ratios and non-HDL-C levels were significantly higher, but HDL-C levels were significantly lower in patients with carotid plaque than those without it (p < 0.05). There was no significant difference between the groups regarding TC, LDL-C, and triglyceride levels. Furthermore, TC/HDL-C (OR; 1.34, p < 0.001) and LDL-C/HDL-C (OR; 1.54, p < 0.001) ratios showed a positive and linear relationship with the prevalence of carotid plaque, whether covariates were adjusted or not. CONCLUSIONS TC/HDL-C and LDL-C/HDL-C ratios are useful as a tool to assess the risk of early stage atherosclerosis in Japanese type 2 diabetic patients.

Subclinical hypothyroidism is independently associated with albuminuria in people with type 2 diabetes.

We examined a possible association between subclinical hypothyroidism and albuminuria in 159 people with type 2 diabetes. Patients with subclinical hypothyroidism had significantly higher levels of urinary albumin-to-creatinine ratio (UACR) than those with euthyroidism. Multivariate logistic regression analyses demonstrated that serum TSH level was an independent risk factor of albuminuria.

Vitamin D deficiency is significantly associated with retinopathy in young Japanese type 1 diabetic patients.

The aim of this study was to examine the possible association of vitamin D deficiency with diabetic retinopathy in 75 young Japanese type 1 diabetic patients. A multivariate regression analysis, duration of diabetes and vitamin D deficiency were independent determinants of diabetic retinopathy.

Different Impacts of Cardiovascular Risk Factors on Arterial Stiffness versus Arterial Wall Thickness in Japanese Patients with Type 2 Diabetes Mellitus

AIM We statistically investigated whether the impact of cardiovascular risk factors on arterial stiffness would be different from that on arterial wall thickness. METHODS We analyzed 1648 Japanese type 2 diabetic patients. Arterial stiffness was evaluated by pulse wave verbosity (PWV) and wall thickness was assessed with carotid intima-media thickness (IMT) by ultrasonography. We developed a common regression model to PWV and IMT by extending the linear mixed model and statistically detected the difference in the impact of cardiovascular risk factors between the two indices. RESULTS There was a significant correlation between PWV and IMT (r=0.365, p ＜ 0.001). Sex, diabetic duration, hemoglobin A1c levels, and the presence of retinopathy and cardiovascular disease were comparable independent risk factors for elevated PWV and IMT. On the other hand, the impact of age, systolic blood pressure, and low- and high-density lipoprotein cholesterol levels were significantly different between the two measurements (all p ＜ 0.05). Cholesterol levels were significantly associated with IMT but not with PWV. Age and systolic blood pressure had a significant impact on both measurements, but the impact on PWV was significantly greater than that on IMT. Indeed, patients with low IMT but with advanced age and high systolic pressure had high PWV, whereas patients with low PWV but with impaired cholesterol levels had high IMT. CONCLUSION The extended linear mixed model statistically confirmed that the impact of cardiovascular risk factors on elevated PWV and IMT were not identical in Japanese patients with type 2 diabetes mellitus.

Shared and additional risk factors for decrease of toe-brachial index compared to ankle-brachial index in Japanese patients with diabetes mellitus.

OBJECTIVE Some diabetic patients have a low toe-brachial index (TBI) despite their normal ankle-brachial index (ABI). We statistically investigated whether the impact of risk factors on TBI would be different compared to ABI. RESEARCH DESIGN AND METHODS We used a database of 1738 limbs of consecutive 869 Japanese diabetic patients whose ABI and TBI were simultaneously evaluated. We developed a common regression model to ABI and TBI by extending the linear mixed model, and statistically detected the difference in the impact of risk factors between the two indices. RESULTS Sex, smoking, proteinuria, hypertension, and history of stroke and coronary artery disease were common independent risk factors for the decrease of ABI and TBI; their impacts on ABI and TBI were not significantly different. On the other hand, the impact of age, diabetic duration, and body mass index was significantly different between the two indices (all p < 0.05). Age and body mass index were significantly associated with TBI but not with ABI. Diabetic duration had a significant impact both on TBI and ABI, but the impact on TBI was significantly greater than that on ABI (β = -0.144 vs. -0.087; p < 0.05). In the population with normal ABI, patients with these risk factors had a higher prevalence of decreased TBI. CONCLUSIONS The risk factors for the decrease of ABI and TBI were not identical in Japanese diabetic patients. Age, diabetic duration and body mass index were associated with reduced TBI in patients with normal ABI.

Significant elevation of serum dipeptidyl peptidase-4 activity in young-adult type 1 diabetes.

AIMS Currently, inhibition of dipeptidyl peptidase-4 (DPP-4) is widely used in the treatment of type 2 diabetes. Application of this strategy is awaited as a new therapeutic approach for type 1 diabetes, but the scientific basis is still lacking. This report describes the evaluation of serum DPP-4 activity in type 1 diabetes compared with control subjects, and assessment of relationships between DPP-4 activity and diabetic complication markers and metabolic variables in type 1 diabetes. METHODS We examined serum DPP-4 activity in Japanese young-adult type 1 diabetes (n=76, females 69.7%, age 30.9 ± 6.2 years, duration of diabetes 16.5 ± 11.1 years; mean ± SD) and healthy controls (n=22). Association of the enzymatic activity with diabetic micro- and macro- vascular complication markers and clinical parameters was also assessed. RESULTS Subjects with type 1 diabetes displayed significantly higher serum DPP-4 activity than healthy controls (relative value, control: 1.00 ± 0.28, T1D, 1.29 ± 0.38; p=0.0011) independent of other clinical parameters. In type 1 diabetes, DPP-4 activity was positively correlated with duration of diabetes (r=0.248, p=0.031), while not correlated with HbA1c level. In univariate correlation analysis of diabetic complication markers and other metabolic parameters, coefficient of variation of R-R intervals (CVR-R) and gamma (γ)-glutamyltransferase (GGT) levels were correlated with DPP-4 activity. GGT was extracted as an independent variable of DPP-4 activity in multivariate analysis (β=0.213, p=0.035). CONCLUSIONS Serum DPP-4 activity is significantly elevated in Japanese type 1 diabetes, suggesting pathophysiological significance of the enzyme in type 1 diabetes.