Embryonic stem (ES) cells are pluripotent cells collected from the inner cell mass of blastocysts. Induced pluripotent stem cells exhibit characteristics and pluripotency similar to ES cells, even though they were generated from adult somatic cells. We have been investigating the vascular differentiation kinetics of human pluripotent stem cells (PSCs) and their application to human vascular research and clinical medicine. In this review, we present an overview of recent vascular research using human PSCs, focusing on the role of humoral factors and their receptors. We also discuss possible future application of human PSCs to translational research on human vascular disorders.

View full abstract

Beckwith-Wiedemann syndrome (BWS) is the most common congenital overgrowth syndrome involving tumor predisposition. BWS is caused by various epigenetic or genetic alterations that disrupt the imprinted genes on chromosome 11p15.5 and the clinical findings of BWS are highly variable. Hyperinsulinemic hypoglycemia is reported in about half of all babies with BWS. We identified an infant with diazoxide-unresponsive congenital hyperinsulinism (HI) without any apparent clinical features suggestive of BWS, but diagnosed BWS by molecular testing. The patient developed severe hyperinsulinemic hypoglycemia within a few hours after birth, with macrosomia and mild hydronephrosis. We excluded mutations in the K_ATP channel genes on chromosome 11p15.1, but found a rare homozygous single nucleotide polymorphism (SNP) of ABCC8. Parental SNP pattern suggested paternal uniparetal disomy in this region. By microsatellite marker analysis on chromosome 11p15, we could diagnose BWS due to the mosaic of paternal uniparental disomy. Our case suggests that some HI of unknown genetic etiology could involve undiagnosed BWS with no apparent clinical features, which might be diagnosed only by molecular testing.

View full abstract

Glycated albumin (GA) reflects shorter term glycemic control state than HbA1c. This study evaluated whether GA is useful for early detection of deterioration of glycemic control state after discharge from educational admission. Among the patients with educational admission, this study included 21 diabetic patients who were followed for at least 10 weeks after discharge from educational admission. Deterioration was defined that GA after discharge increased by ≥0.6% compared to the previous GA. Thirteen patients without deterioration up to 10 weeks after discharge were used as controls. In 8 patients with deterioration within 10 weeks after discharge, their HbA1c and GA at the time of admission and the decrease in HbA1c and GA during hospitalization were not significantly different from the control patients. At the time of deterioration, GA in the patients with deterioration increased significantly from 18.7 ± 2.7% to 21.0 ± 2.5%, whereas HbA1c decreased significantly from 9.1 ± 0.7% to 8.3 ± 0.6%. Subsequently, HbA1c increased significantly to 9.0 ± 0.8% together with GA. Thus, GA is useful for early detection of deterioration of glycemic control state after discharge from educational admission.

View full abstract

In patients with papillary thyroid carcinoma (PTC), detectable serum thyroglobulin (Tg) after total thyroidectomy implies biochemically persistent disease (BPD). We reported that the thyroglobulin-doubling time (Tg-DT) was a potent prognostic indicator in patients with BPD. To identify factors that are related to BPD and Tg-DT, we performed new analyses on the data gathered in our previous study. Using the data of 426 patients with PTC in whom the Tg-DT was computed after total thyroidectomy, multivariate logistic analyses for BPD and Tg-DT were performed. Postoperatively, 142 (33%) patients had BPD. The percentages of BPD patients were significantly higher among the young (<40 years) and elderly (≥60 years) patients compared to the middle-aged patients (41%, 41%, and 27%, respectively). Multivariate analysis showed that cN1b, tumor size ≥4 cm, and Ex2 were significantly associated with BPD. The percentage of patients with Tg-DT <2 years among the BPD patients increased with age: 6% in the young, 15% in the middle-aged, and 47% in the elderly patients. Multivariate analysis of the BPD patients revealed that Tg-DT was associated only with the age at surgery. The current analyses indicate that BPD is significantly correlated with the extent of disease status and that Tg-DT correlates only with patient age at surgery. Although our results clearly indicate that the biological behavior of PTC is age-related, the underlying reason for this remains to be established.

View full abstract

A 46 year-old male presented with persistently high level of serum parathyroid hormone (PTH), despite successful resection of an oxyphilic cell parathyroid adenoma of the left lower gland. Renal function and serum calcium were normal, leading to vitamin D deficiency being considered. Tc99m-sestamibi parathyroid scintigraphy showed no capitation, but a cervical ultrasound demonstrated an increase in the lower parathyroids. Surgery confirmed that the right gland was normal but the left corresponded to parathyroid carcinoma. The patient developed severe hypocalcemia, with PTH values being consistent with hypoparathyroidism for a few months. However, a progressive increase in calcium and PTH serum levels indicated recurrence of disease. Tc99m-sestamibi scintigraphy demonstrated hyperfixation in topography of the left inferior parathyroid and the patient was subjected to a third and more extensive surgery, with removal of lymph nodes and adjacent thyroid tissue. Serum calcium and PTH remained elevated, requiring loop diuretics and intravenous bisphosphonates to control hypercalcemia. Cervical radiotherapy was implemented as adjuvant therapy. After two months the patient complained of dyspnea, and a CT scan of the chest demonstrated areas of parenchymal condensation, suggestive of actinic pneumonitis. At the 2-year follow-up no major issues were evident.

View full abstract

Acarbose was administered at 300 mg/day to patients with type 2 diabetes mellitus (T2DM) who had been taking 25 mg/day of alogliptin, and levels of blood glucose were analyzed by continuous glucose monitoring (CGM) for 3 days. The mean blood glucose level with acarbose (136.4 ± 30.7 mg/dL) did not differ significantly from that without acarbose (141.7 ± 28.3 mg/dL). However, in the condition of the combination therapy, there were significant decreases in the standard deviation of the mean blood glucose levels for the 24-hour period (27.6 ± 9.1 vs. 16.2 ± 6.9 mg/dL, p<0.001) and mean amplitude of glycemic excursions (MAGE) (65.8 ± 26.1 vs. 38.8 ± 19.2 mg/dL, p=0.010). In addition, a meal tolerance test was conducted to monitor changes in insulin secretion and active GLP-1 and total GIP values. Ten subjects (5 males, 5 females) of 54.9 ± 6.9 years with BMI 25.9 ± 5.2 kg/m² and HbAlc 9.2 ± 1.2% were enrolled. In the meal tolerance test, active GLP-1 values before and after acarbose administration were 17.0 ± 5.8 and 24.1 ± 9.3 pmol·hr/mL (p=0.054), respectively, showing an increasing tendency, and total GIP_AUC0-180 values were 685.9 ± 209.7 and 404.4 ± 173.7 pmol·hr/mL, respectively, showing a significant decrease (p=0.010). The results indicate that the combined administration of both inhibitors is effective not only in decreasing blood glucose fluctuations and preventing postprandial insulin secretion. The beneficial effects may also protect the endocrine pancreas and inhibit body weight gain.

View full abstract

Recently, many studies have investigated the association of allelic variants of Wolfram syndrome gene (WFS1) with insulin secretion, insulin sensitivity and the risk of hyperglycemia and type 2 diabetes (T2D). Although it is clear that WFS1 mutations cause diabetes, the genetic basis of the association of common WFS1 variants with T2D is still unclear. To date, many case-control studies have been carried out to investigate the role of the WFS1 gene polymorphism in the development of T2D. However, these studies are controversial and individual studies may have insufficient power to reach a comprehensive and reliable conclusion. The aim of this study was to investigate association of WFS1 genes polymorphisms (rs734312 and rs10010131) with T2D by conducting a meta-analysis. Seven studies with 6705 T2D cases and 11144 controls were enrolled in the meta-analysis of the association between rs734312 polymorphism and T2D, and 12 studies with 16304 T2D cases and 22004 controls were enrolled in the meta-analysis of rs10010131 polymorphism. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed and random-effects models. Heterogeneity among studies was evaluated using the I² and Begg’s test was used to evaluate publication bias. Sensitivity analysis was also performed. Our results suggested that the G allele of rs734312 polymorphism [dominant: FEM OR 0.873, 95%CI (0.810 − 0.940), recessive: FEM OR 0.876, 95% CI (0.800 − 0.959)] and A allele of rs10010131 polymorphism [dominant:FEM OR 0.853, 95% CI (0.817 − 0.892), recessive:REM OR 0.833, 95% CI (0.756 − 0.917)] in WFS1 gene had significant protective effects on risk of T2D.

View full abstract

We previously reported that serum interleukin-18 (IL-18) levels were significantly increased in hyperthyroid Graves’ disease patients. The development of insulin resistance in hyperthyroidism has been documented. We investigated the relationship between IL-18 and insulin resistance in patients with hyperthyroid Graves’ disease and in experimental hyperthyroid mice. Then, we examined whether IL-18 induces insulin resistance in mice injected with IL-18 for a week. A significant positive correlation was observed between serum IL-18 levels and parameters such as thyroid functions and homeostasis model assessment for insulin resistance in hyperthyroid Graves’ disease. In experimental hyperthyroid mice, IL-18 was significantly elevated. Insulin resistance increased in experimental hyperthyroid mice and IL-18-injected mice. These findings suggest IL-18 to be an important factor inducing insulin resistance in hyperthyroidism.

View full abstract

It is possible that myeloperoxidase (MPO) contributes to the pathogenesis of diabetic nephropathy through the production of reactive oxygen species and HOCl/OCl^-. In this study, we examined the relationship between renal damage and MPO G-463A gene polymorphism that is associated with its transcription activity in diabetic patients. We evaluated the association between MPO G-463A polymorphism and the prevalence of proteinuria and estimated GFR (eGFR) in 1448 Japanese type 2 diabetic subjects. The prevalence of macroalbuminuria was higher as the number of G alleles increased (GG (7.6%), GA (3.8%), AA (0.0%), p for trend=0.0269). The number of G alleles was significantly associated with macroalbuminuria (odds ratio 2.12, 95%CI 1.06-4.24, p=0.0344) even after adjustment for conventional risk factors. Inversely, eGFR was lower as the number of G alleles increased (GG (76.7±20.7 mL/min/1.73m²), GA (81.0±22.8 mL/min/1.73m²), AA (92.0±23.1 mL/min/1.73m²), p for trend=0.0025) and the number of G allele was an independent risk factor for a low eGFR (β=-0.072, p=0.003). We also examined the association between MPO expression and several stages of renal damage in a high-fat diet-induced diabetic mouse model. The proteinuria-induced increase in MPO expression was markedly enhanced in diabetic mice, and MPO expression was significantly correlated with the severity of kidney damage. In conclusion, it is likely that the G allele of the MPO G-476T polymorphism is a susceptibility allele for renal injury in type 2 diabetic patients.

View full abstract

Whether glucose-6-phosphate (G6P) or xylulose-5-phosphate (X5P) is the signaling molecule for carbohydrate response element binding protein (ChREBP) transactivation has been controversial. In this study, we tested the role of G6P and X5P in the regulation of ChREBP transactivation in the pancreatic β cell line, INS-1E. In contrast to glucose, which can be converted into both G6P and X5P, 2DG is only converted into 2DG6P. The potency of 2-deoxy-glucose (2DG) to induce Chrebp target mRNA was weaker and less persistent than that of glucose. Moreover, the results from siRNA knockdown of ChREBP, a reporter assay involving the pGL3 promoter with carbohydrate response element (ChoRE), and a ChIP assay with an anti-ChREBP antibody revealed that 2DG does not increase ChREBP transactivity in INS-1E cells. In accordance with these results, transfection of siRNA against Chrebp tended to reduce glucose-stimulated, but not 2DG-stimulated, expression of ChREBP target genes. Conversely, the expression of xylulokinase (Xylb), which converts xylitol to X5P, was much lower than in primary hepatocytes. In INS-1E cells infected by adenovirus bearing Xylb cDNA, xylitol increased expression of ChREBP target genes, although with a weaker potency than glucose. Finally, X5P partly induced ChREBP transactivity in INS-1E cells overexpressing Xylb cDNA. In conclusion, G6P and X5P can activate ChREBP transactivity, but their potencies to induce ChREBP transactivity were much lower than that of glucose, suggesting that other factors such as fructose 2,6-bisphosphate may be needed for full activation of glucose-induced gene expression.

View full abstract

To assess the effect of adiponectin on the circadian rhythm disturbances associated with metabolic syndrome, we generated a KK/Ta mouse line expressing the human adiponectin transgene in the liver. Locomotor activity of control C57BL/6 mice was highest during the beginning of the dark period and low during the light period. Under constant darkness, the length of locomotor activity rhythm of control mice was slightly shorter than 24 h. In KK/Ta mice the peak of locomotor activity was blunted and significant activity was observed during the light period. Furthermore, KK/Ta mice showed shorter average period length of free-running locomotor activity rhythm when compared with control mice. However, the transgenic expression of adiponectin in the liver significantly altered the circadian rhythm of locomotor activity and the length of free-running rhythm of KK/Ta mice towards those of C57BL/6 mice. In the liver and skeletal muscles from control mice, mRNA levels of Arntl and Cry1 were increased during the dark period, whereas those of Dbp, Cry2, Per1 and Per2 were elevated during the light period. KK/Ta mice exhibited phase advances in circadian rhythms of Arntl, Dbp, Cry2 and Per2 in both tissues. The phase shifts of the circadian clock gene expression in the liver were attenuated in adiponectin-transgenic mice. These results suggest that adiponectin is a peripheral regulator of the circadian clocks in the brain and peripheral organs, and may be a novel target for the treatment of obesity-associated disorders of circadian rhythms.

View full abstract

Mosapride citrate, a selective agonist of the 5-hydroxytryptaine (5-HT)₄ receptor, is typically used to treat heartburn, nausea, and vomiting associated with chronic gastritis or to prepare for a barium enema X-ray examination. Mosapride citrate reportedly improves insulin sensitivity in patients with type 2 diabetes. As mosapride citrate activates the motility of the gastrointestinal tract, we hypothesized that mosapride citrate affects incretin secretion. We examined the effect of the administration of mosapride citrate on the plasma glucose, serum insulin, plasma glucagon, and plasma incretin levels before breakfast and at 60, 120, and 180 min after breakfast in men with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) to exclude gastropathy. Mosapride citrate was administered according to two different intake schedules (C: control (no drug), M: mosapride citrate 20 mg) in each of the subject groups. The area under the curve (AUC) of the plasma glucose levels was smaller in the M group than in the C group. The time profiles for the serum insulin levels at 60 and 120 min after treatment with mosapride citrate tended to be higher, although the difference was not statistically significant. The AUCs of the plasma active and total glucagon-like peptide-1 (GLP-1) levels were significantly larger in the M group than in the C group. No significant difference in the AUC of the plasma glucose-dependent insulinotropic polypeptide (GIP) level was observed between the two groups. Our results suggest that mosapride citrate may have an antidiabetic effect by increasing GLP-1 secretion.

View full abstract

We have made a cross-sectional investigation of men in the Japanese military for the presence of thyroid abnormalities and thyroid cancer to document the prevalence of thyroid disease in these persons. Six thousand, four hundred and twenty-two Japanese military men and women were screened for thyroid disease by history, physical examination and ultrasound examination. Among them, 6,182 were men 50 years of age, 47 were women 50 years of age, and 149 were men 40 years of age and 44 were women 40 years of age. Among the 50 years old men, thyroid nodules were found in 924 men (14.9%): Nineteen individuals (0.31%) had thyroid cancers ranging from 1 mm to 30 mm in diameter (12.5 mm in mean), pathological TNM staging revealed 7 cases of stage I, 2 cases of stage II and 9 cases of stage III. There was a significant increase in thyroid nodules in 50 years old men compared to that in 40 year old men, but there was no significant difference between men and women (p>0.05). Our data document that the detection rate of thyroid cancer in 50 years old men was 0.31%, and the rate of thyroid nodules increased with age in men, but the frequency of thyroid nodules were similar in men and women of the same age.

View full abstract

Although somatostatin analogues are effective medical therapy for acromegaly, the serum insulin-like growth factor-I (IGF-I) levels remain uncontrolled in 35% of patients. Combined therapy with octreotide LAR and cabergoline has been reported to normalize IGF-I levels in 42-56% of Caucasian patients with acromegaly. However, it remains to be clarified whether combination therapy is effective in Japanese patients and on tumor shrinkage. We conducted a retrospective study on combined therapy in patients with octreotide-resistant acromegaly. Ten patients with acromegaly who showed octreotide-resistance were enrolled in this study. Cabergoline was added in doses of 0.25-2.0mg/week. Serum GH and IGF-I levels and tumor volume were assessed before and after treatment, and factors correlated with effect of the combined therapy were analyzed. Although serum GH levels did not decrease, serum IGF-I levels significantly decreased by 20% after 6 months of combined therapy compared with baseline (p < 0.05). As a result, serum IGF-I levels normalized in 30% of the patients. Tumor volume after combined therapy also significantly decreased (p < 0.01). There were no correlations between the decrease of serum IGF-I levels during combined therapy and the response of GH in a bromocriptine test, random GH, IGF-I, and PRL levels, the tumor volume, and the expression of PRL and dopamine D2 receptor in the tumor. In conclusion, we demonstrated that the addition of cabergoline to octreotide LAR is a beneficial option in Japanese patients with octreotide-resistant acromegaly, irrespective of serum PRL levels and the response of GH levels in a bromocriptine test.

View full abstract

The aim of this study was to clarify the association between C-peptide immunoreactivity (CPR), a marker of beta cell function, and future glycemic control in patients with type 2 diabetes. We conducted a retrospective analysis of 513 consecutive patients with type 2 diabetes who were admitted to our hospital between 2000 and 2007 and followed up for 2 years. Serum and urinary CPR levels were measured during admission, and CPR index was calculated as the ratio of CPR to plasma glucose. The associations between these markers at baseline and glycemic control after 2 years were assessed by means of logistic regression models. After 2 years, 167 patients (32.6%) showed good glycemic control (HbA1c <6.9%). Baseline serum and urinary CPR indices were significantly associated with good glycemic control after 2 years, and the postprandial CPR to plasma glucose ratio (postprandial CPR index) showed the strongest association (odds ratio (OR) 1.29, 95% confidence interval (CI) 1.12-1.50, P = 0.001) among CPR indices. Multivariate analyses showed consistent results (OR 1.23, 95%CI 1.03-1.48, P = 0.021). In conclusion, preserved beta cell function at baseline was associated with better glycemic control thereafter in patients with type 2 diabetes.

View full abstract

The liver plays an important role in maintaining glucose homeostasis in the body. In the prandial state, some of the glucose which is absorbed by the gastrointestinal tract is converted into glycogen and stored in the liver. In contrast, the liver produces glucose by glycogenolysis and gluconeogenesis while fasting. Thus, the liver contributes to maintaining blood glucose level within normoglycemic range. Glycogenesis and glycogenolysis are regulated by various mechanisms including hormones, the sympathetic and parasympathetic nervous systems and the hepatic glucose content. In this study, we examined a rat model in which the celiac superior mesenteric ganglion (CSMG) was resected. We attempted to elucidate how the celiac sympathetic nervous system is involved in regulating glucose homeostasis by assessing the effects of CSMG resection on glucose excursion during an oral glucose tolerance test, and by examining hepatic glycogen content and hepatic glycogen phosphorylase (GP) activity. On the oral glucose tolerance test, CSMG-resected rats demonstrated improved glucose tolerance and significantly increased GP activity compared with sham-operated rats, whereas there were no significant differences in insulin, glucagon or catecholamine levels between the 2 groups. These results suggest that the celiac sympathetic nervous system is involved in regulating the rate of glycogen consumption through GP activity. In conclusion, the examined rat model showed that the celiac sympathetic nervous system regulates hepatic glucose metabolism in conjunction with vagal nerve innervations and is a critical component in the maintenance of blood glucose homeostasis.

View full abstract

The aim of this study is to investigate glucose metabolism longitudinally during pregnancy to explore mechanisms underlying gestational diabetes mellitus (GDM). We reviewed a total of 62 pregnant Japanese women who underwent a 75g oral glucose tolerance test (OGTT) twice during pregnancy (median: early, 13; late, 28 weeks’ gestation) because of positive GDM screening. All showed normal OGTT results in early pregnancy. Based on late OGTT, 15 had GDM (late-onset GDM) and 47 normal glucose tolerance (NGT). In early pregnancy, there were no significant differences in insulin sensitivity (insulin sensitivity index derived from OGTT [IS_OGTT] and homeostasis model assessment for insulin resistance [HOMA-IR]) and insulin secretion (a ratio of the total area-under-the-insulin-curve to the total area-under-the-glucose-curve [AUC_ins/glu] and insulinogenic index [IGI]) between the NGT and late-onset GDM groups. In each group, insulin sensitivity significantly decreased from early to late pregnancy, most in the late-onset GDM group (each p < 0.05). The insulin secretion showed no significant changes with advancing pregnancy in both of the groups, although late-onset GDM showed significantly lower IGI compared with NGT in late OGTT (p < 0.05). When assessed beta cell function by OGTT-derived disposition index (i.e. Insulin Secretion-Sensitivity Index-2 and IGI/fasting insulin), the indices significantly decreased from early to late pregnancy in the both groups (each p < 0.05). Women with late-onset GDM showed significantly lower indices compared with NGT (each p < 0.05). The failure of beta cell to compensate for decreased insulin sensitivity could contribute to the development of the late-onset GDM.

View full abstract

There is a typographical error in the authors’ names.

View full abstract