Tetsuhiro Kitamura

Peroxisome Proliferator-Activated Receptor α Agonists Increase Nitric Oxide Synthase Expression in Vascular Endothelial Cells

Objective—There has been accumulating evidence demonstrating that activators for peroxisome proliferator-activated receptor &agr; (PPAR&agr;) have antiinflammatory, antiatherogenic, and vasodilatory effects. We hypothesized that PPAR&agr; activators can modulate endothelial nitric oxide synthase (eNOS) expression and its activity in cultured vascular endothelial cells. Methods and Results—Bovine aortic endothelial cells were treated with the PPAR&agr; activator fenofibrate. The amount of eNOS activity and the expression of eNOS protein and its mRNA were determined. Our data show that treatment with fenofibrate for 48 hours resulted in an increase in eNOS activity. Fenofibrate failed to increase eNOS activity within 1 hour. Fenofibrate also increased eNOS protein as well as its mRNA levels. RU486, which has been shown to antagonize PPAR&agr; action, inhibited the fenofibrate-induced upregulation of eNOS protein expression. WY14643 and bezafibrate also increased eNOS protein levels, whereas rosiglitazone did not. Transient transfection experiments using human eNOS promoter construct showed that fenofibrate failed to enhance eNOS promoter activity. Actinomycin D studies demonstrated that the half-life of eNOS mRNA increased with fenofibrate treatment. Conclusions—PPAR&agr; activators upregulate eNOS expression, mainly through mechanisms of stabilizing eNOS mRNA. This is a new observation to explain one of the mechanisms of PPAR&agr;-mediated cardiovascular protection.

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.

Liraglutide is effective in type 2 diabetic patients with sustained endogenous insulin‐secreting capacity

Aims/Introduction:  Recently, glucagon‐like peptide‐1 (GLP‐1) receptor agonists of liraglutide have become available in Japan. It has not yet been clarified what clinical parameters could discriminate liraglutide‐effective patients from liraglutide‐ineffective patients.

Risk factors for asymptomatic atherosclerosis in Japanese type 2 diabetic patients without diabetic microvascular complications.

Atherosclerotic vascular diseases are frequently associated with diabetes mellitus. There has been increasing evidence showing that the atherosclerotic diseases in diabetic patients are distinct from diabetic microvascular complications as to their pathophysiology and epidemiology. However, we have no information on the prevalence of asymptomatic atherosclerosis in diabetic patients before the onset of microvascular diseases. In the present investigation, we aimed to evaluate risk factors for the atherosclerosis in type 2 diabetic patients without the microvascular diseases. For this purpose, we evaluated atherosclerotic change of carotid arteries in 125 Japanese type 2 diabetic patients who had neither atherosclerotic vascular diseases nor diabetic microvascular complications. When atherosclerotic change was defined as the mean intima-media thickness (IMT) of >/= 1.1 mm and/or the presence of plaque lesion, 50% of patients had atherosclerosis of the carotid arteries. Risk factors for the carotid atherosclerosis were age, low-density lipoprotein (LDL)-cholesterol, hypertension, and diabetes treatment. Age and LDL-cholesterol were associated with mean IMT. Age, diabetes treatment, LDL-cholesterol, and hypertension were positively associated with plaque lesion, while high-density lipoprotein (HDL)-cholesterol was negatively associated with it. Fasting plasma glucose, glycosylated hemoglobin (HbA(1c)), and known diabetes duration remained unassociated with any parameters of asymptomatic atherosclerosis of the carotid arteries. These results indicate that glycemic control is unrelated with asymptomatic atherosclerosis in type 2 diabetic patients without diabetic microvascular complications. Conventional risk factors and diabetes treatment are independently associated with atherosclerosis of the carotid arteries in these patients.

Glycated albumin is set lower in relation to plasma glucose levels in patients with Cushing's syndrome

BACKGROUND Glycated albumin (GA) is an indicator of glycemic control, which has some specific characters in comparison with HbA1c. Since glucocorticoids (GC) promote protein catabolism including serum albumin, GC excess state would influence GA levels. We therefore investigated GA levels in patients with Cushings syndrome. METHODS We studied 16 patients with Cushings syndrome (8 patients had diabetes mellitus and the remaining 8 patients were non-diabetic). Thirty-two patients with type 2 diabetes mellitus and 32 non-diabetic subjects matched for age, sex and BMI were used as controls. RESULTS In the patients with Cushings syndrome, GA was significantly correlated with HbA1c, but the regression line shifted downwards as compared with the controls. The GA/HbA1c ratio in the patients with Cushings syndrome was also significantly lower than the controls. HbA1c in the non-diabetic patients with Cushings syndrome was not different from the non-diabetic controls, whereas GA was significantly lower. In 7 patients with Cushings syndrome who performed self-monitoring of blood glucose, the measured HbA1c was matched with HbA1c estimated from mean blood glucose, whereas the measured GA was significantly lower than the estimated GA. CONCLUSIONS We clarified that GA is set lower in relation to plasma glucose levels in patients with Cushings syndrome.

Systemic arteriosclerosis and eating behavior in Japanese type 2 diabetic patients with visceral fat accumulation.

BackgroundVisceral 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.MethodsThe 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.ResultsThe 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.ConclusionsType 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.

Dipeptidyl peptidase-4 inhibitors are effective in Japanese type 2 diabetic patients with sustained endogenous insulin-secreting capacity, a higher body mass index and insulin resistance

Recently, dipeptidyl peptidase‐4 (DPP‐4) inhibitors have become available in Japan. It has not yet been clarified what clinical parameters could discriminate DPP‐4 inhibitor‐effective patients from DPP‐4 inhibitor‐ineffective patients.

Biological Characteristics of Growth Hormone-Producing Pituitary Adenomas Are Different According to Responsiveness to Thyrotropin-Releasing Hormone

OBJECTIVE The paradoxical response of GH to TRH in patients with acromegaly has been previously reported. However, few reports have focused on tumor characteristics reflected by this response. This study aimed to clarify the relationship between TRH-induced GH responsiveness and other tumor characteristics. METHODS Patients with acromegaly who underwent initial surgery between 2000 and 2012 were divided into TRH-responder and nonresponder groups. Clinical features were compared between the two groups with respect to tumor size, Knosp grade, endocrinological profiles, and histopathological findings revealed by cytokeratin staining. Tumor size was quantitatively evaluated with volumetry. Cytokeratin staining patterns were categorized into three groups: sparsely granulated type, densely granulated type, and intermediate type. RESULTS Sixty-two patients were included in the study. TRH responders (n = 45) showed significantly smaller tumor size than nonresponders (n = 17) (2.78 ± 4.71 vs. 7.56 ± 9.00 ml, P < 0.005). In addition, TRH responders showed significantly higher preoperative basal GH per volume ratio than nonresponders (10.1 ± 8.4 vs. 7.72 ± 11.85 ng/ml(2), P < 0.05). Logarithmic regression modeling showed significant correlation between TRH responsiveness and tumor volume (r = -0.341; P < 0.01). The difference between cytokeratin staining patterns was also significant: sparsely granulated-type adenomas were found in only 13% of TRH responders but in 64% of nonresponders (P < 0.0005). TRH responders showed higher GH suppression rates in the octreotide test compared with nonresponders (86 vs. 68%, P < 0.01). CONCLUSION The present data suggest that the responsiveness of serum GH level to TRH reflects significant tumor biological characteristics.

Sitagliptin Significantly Decreases the Ratio of Glycated Albumin to HbA1c in Patients with Type 2 Diabetes Mellitus

Background: Since glycated albumin (GA) is a glycemic control marker which reflects more postprandial plasma glucose (PPPG) and/or glycemic excursions than HbA1c, the GA/HbA1c ratio is a useful indicator for PPPG and/or glycemic excursions. In this study, we investigated the clinical significance of the GA/HbA1c ratio by administration of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in patients with type 2 diabetes mellitus. Methods: Sitagliptin (50 mg/day) was administered for 24 weeks to 69 patients with type 2 diabetes mellitus with stable glycemic control. Results: With sitagliptin administration, both HbA1c and GA significantly decreased from baseline to the periods of week 4 and week 24. The GA/HbA1c ratio also significantly decreased (baseline 2.72 ± 0.42 vs. 24 weeks 2.60 ± 0.38, P<0.0001). The change in the GA/HbA1c ratio with the sitagliptin administration for 24 weeks was inversely correlated with baseline GA (R=-0.425, P<0.001) and baseline GA/HbA1c ratio (R=-0.354, P=0.003), but not with baseline HbA1c (R=-0.222, P=0.066). By tertile analysis based on the baseline GA/HbA1c ratio, the GA/HbA1c ratios were significantly associated with GA (P<0.0001), but not fasting plasma glucose (FPG) and HbA1c. Furthermore, changes in GA (P=0.010), but not FPG and HbA1c, were significantly correlated with the baseline GA/HbA1c ratio. Conclusions: Sitagliptin significantly decreased the GA/HbA1c ratio and this effect was more pronounced in patients with the higher baseline GA/HbA1c ratio. Our findings suggest that the effect of sitagliptin on the GA/HbA1c ratio might reflect improvement of PPPG levels and/or glycemic excursion.