Peroxisome proliferator-activated receptor (PPAR) γ is a nuclear hormone receptor that is trans-activated by its ligands including insulin-sensitizing thiazolidinediones. PPARγ has recently been reported to demonstrate pleiotropic beneficial effects in the vasculatures, independent of its blood glucose-lowering effects. Firstly, PPARγ ligands have been shown to lower blood pressure in both animals and human. The effect may possibly be mediated via the PPARγ-mediated inhibition of the angiotensin (Ang) II type 1 receptor expression as well as Ang II-mediated signaling pathways, which may result in the suppression of the renin-angiotensin system (RAS). Secondly, the progression of atherosclerosis was also prevented by PPARγ ligands in both animals and human. In addition to the PPARγ-mediated suppression of the RAS and the thromboxane A₂ system, protective effects of PPARγ ligands on endothelial function may also be involved. Thirdly, reno-protective effects of PPARγ ligands, especially on reducing urinary albumin, have been observed in both animals and human not only in diabetic nephropathy but also in non-diabetic renal diseases. The reno-protective effects may be mediated, at least in part, via the PPARγ ligand-induced blood pressure-lowering effects, protective effects on endothelial function, and vasodilating effects on the glomerular efferent arterioles. Additionally, anti-cancer effects of PPARγ ligands have recently been reported. Taken together, usefulness and effectiveness of PPARγ ligands on lifestyle related diseases will be increasingly appreciated.

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The aim of this study was to demonstrate that the addition of orbital magnetic resonance (MR) imaging can provide improvement in sensitivity of detection of active disease and the prediction of the response to intravenous glucocorticoid therapy (ivGC), over clinical activity score (CAS) alone. A prospective case series was studied at our institution. Forty eight patients were examined by CAS and orbital MR imaging. The maximum of T2 relaxation times of extraocular muscles (maxT2RT) and other parameters were evaluated by MR imaging. Thirty five of 48 patients underwent ivGC. Twenty of 35 patients, whose CAS was 2 points or less, were evaluated for the response to ivGC. The correlation between CAS and maxT2RT was evaluated. Differentiation of active and inactive GO was performed by CAS and orbital MR imaging. The response to ivGC was evaluated by CAS, orbital MR imaging and ophthalmic parameters. As a result, CAS and maxT2RT showed significant positive correlation (r=0.58, p<0.0001), and 15 patients were positive by CAS and orbital MR imaging. However, 20 patients were positive by only MR imaging. In those 20 patients, there was significant improvement after ivGC. We concluded that orbital MR imaging combined with CAS could improve the sensitivity of detection of active disease and the prediction of the response to ivGC. In addition, even if only one parameter of CAS is positive, further examination with orbital MR imaging is advised.

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2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) reduces ovulation rate in rats. The present study was to investigate whether TCDD alters the progression of cell cycle, and thus resulting in the blockade of ovulation in gonadotropin-primed, immature rats. The ovulation rate and ovarian weight were reduced in intact rats given TCDD (32 μg/kg BW in corn oil) by gavage one day before pregnant mare’s serum gonadotropin (PMSG; 5 IU/rat) injection. Flow cytometry demonstrated that the percentage of granulosa cells in S-phase was increased at 24 h following PMSG treatment, but declined at 8 h following hCG treatment in corn oil-treated rats. Interestingly, the number of S-phase cells in TCDD-treated rats was reduced 24 and 48 h following PMSG treatment. TCDD, however, increased the percentage of cells in G2/M-phase at 24 h following PMSG treatment. TCDD inhibited the mRNA levels of Cdk2 at 0 h and 24 h, and cyclin D2 at 24 h and 48 h following PMSG treatment. Protein levels of aryl hydrocarbon receptor in granulosa cells were elevated in TCDD-treated rats at 12 h and 24 h following PMSG treatment. The present study indicates that TCDD reduces S-phase cells and inhibits levels of Cdk2 and cyclin D2 at 24 h following PMSG treatment, implying the ovulation-inhibiting action of TCDD may be exerted through the attenuation of cell cycle progression via AhR-mediated cascade.

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Sunitinib is a multi-targeted tyrosine kinase inhibitor that is effective for advanced renal cell carcinoma. However, sunitinib often causes hypothyroidism. In this study, we report eight cases with thyroid dysfunction that occurred during sunitinib treatment for advanced renal cell carcinoma. In seven cases, mild hypothyroidism developed early in the first treatment cycle, and recovered spontaneously. Transient hyperthyroidism was observed during the second or third treatment cycles and was preceded by a rapid increase in thyroglobulin levels. ^99mTc scintigraphy in the hyperthyroid state showed decreased thyroidal uptake of ^99mTcO₄^-, suggesting destructive thyroiditis. Hypothyroidism subsequently developed, requiring levothyroxine replacement therapy. Ultrasonography showed a hypoechogenic pattern of the parenchyma and decreased intrathyroidal blood flow. The thyroid glands ultimately became atrophic, which may progress to permanent hypothyroidism. These findings suggest that sunitinib-induced hypothyroidism may occur frequently and may be a consequence of thyroiditis with transient thyrotoxicosis. The marked decrease in thyroid size due to reduced capillary blood flow induced by VEGF receptor inhibition may cause delayed and/or permanent hypothyroidism. Therefore, thyroid function should be monitored in all patients treated with sunitinib.

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The “lipotoxicity” hypothesis holds that fat-induced hepatic insulin resistance (FIHIR) may play a major role in the pathogenesis of type 2 diabetes. Berberine has been reported to have antidiabetic properties. However, the molecular mechanisms for this action are not fully clarified. Therefore, we will investigate the gene expression alterations involved in the therapeutic effect of berberine on FIHIR in diabetic hamsters and possible mechanisms. In this study, type 2 diabetic hamsters were induced by high-fat diet with streptozotocin injection. After 9 weeks of berberine-treatment, the gene expression alterations involved in the therapeutic molecular mechanisms of berberine on FIHIR will be studied by microarray technology and real time RT-PCR. Our study demonstrates berberine significantly improved fat-induced insulin resistance and diabetic phenotype in type 2 diabetic hamsters. The alterations of certain metabolism related genes and their main regulators: Liver X receptor (LXR) α, Peroxisome proliferator-activated receptor (PPAR) α and Sterol regulatory element-binding protein (SREBPs) are observed in the liver of treated and untreated diabetic hamsters. Compared with diabetic hamsters, the increased mRNA levels of LXRα and PPARα and the decreased mRNA levels of SREBPs are observed in berberine-treated diabetic hamster. The statistical significance of the expression of hepatic LXRα, SREBPs and PPARα and their certain target genes is found between treated and untreated diabetic hamsters. These results suggest that altered hepatic SREBPs, LXRα and PPARα transcriptional programs possibly involve in the therapeutic mechanisms of berberine on FIHIR in type 2 diabetic hamsters.

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The purposes of this study are to set the Elecsys TRAb cutoff value by which GD and PT can be accurately diagnosed simply; and to investigate the usefulness of the vascularity index (VI) obtained from power Doppler sonography (PDS). Using 109 normal controls, 186 GD patients, and 109 PT patients who were diagnosed through Tc-99m uptake, we set the cutoff value by conducting ROC analysis on the Elecsys TRAb values. The cutoff value as a result of the ROC analysis on the Elecsys TRAb values of the normal controls and GD patients was 0.8 IU/L with 100% of sensitivity and specificity. Because all 89 cases (81.6% of the entire PT cases) with Elecsys TRAb =<0.8 IU/L are PT, the cutoff =<0.8IU/L can thus be diagnosed as PT. In contrast, because all 166 cases (88.7% of the entire GD) with Elecsys TRAb >=3.0 IU/L except for one case of PT are GD, the cutoff >=3.0 IU/L can be diagnosed as GD. So Elecsys TRAb between 0.8-3.0 IU/L was dubbed gray zone (GZ). Finally, the cutoff value of 1.5 IU/L from the ROC on the PT and GD cases was chosen as the cutoff with 96.2% of sensitivity and 94.6 of specificity. All PDS VI >=80% were GD including 4 of 6 cases with GZ and all PDS VI <50% plus Elecsys TRAb-negative cases were PT including 4 of 5 cases with GZ. In conclusion, Elecsys TRAb cutoff and VI value for differential diagnosis between GD and PT has been set successfully.

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To date, there are very few clinical reports that have compared the effects of ezetimibe on lipid parameters between hypercholesterolemic patients with and without type 2 diabetes mellitus (T2DM). In this study, we recruited patients for hypercholesterolemic groups with T2DM (n = 42; men/women = 24/18; HbA1c = 6.7 ± 5.4%) and without T2DM (n = 21; men/women = 7/14; HbA1c = 5.3 ± 0.4%). Patients were prescribed ezetimibe at a dose of 10 mg/daily for the course of the 12-week study. At baseline and after 12 weeks of treatment, several lipid parameters, including serum low-density-lipoprotein cholesterol (LDL-C), non-high-density-lipoprotein cholesterol (non-HDL-C), high-sensitivity C-reactive protein (hs-CRP), and cholesterol synthesis/absorption-related markers, were measured. Compared with those at the baseline, the levels of LDL-C, non-HDL-C, campesterol, and sitosterol were significantly reduced after 12 weeks of ezetimibe treatment in both groups. After adjusting for confounding factors, such as age, gender, smoking, and BMI, the levels of LDL-C and non-HDL-C displayed significantly greater reductions in the patients with T2DM (-25.1 ± 13.6% in LDL-C, -20.5 ± 11.2% in non-HDL-C) than those without T2DM (-20.5 ± 7.8% in LDL-C, P < 0.05; -17.4 ± 7.6% in non-HDL-C, P < 0.05). The reduction of the level of cholestanol was significantly and positively correlated with those of LDL-C and non-HDL-C in the patients with T2DM. Taken together, these findings indicate that ezetimibe could reduce the levels of atherogenic lipoproteins to a greater extent in hypercholesterolemic patients with T2DM than in those without T2DM.

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The gonadal function of patients with Turner syndrome (TS) is variable. Individuals with mosaicism characterized by 45,X/46,XX or 45,X/47,XXX are more likely to experience spontaneous menarche compared with other karyotypes. Prepubertal gonadotropins of TS patients with spontaneous menarche are reportedly normal or significantly lower than those of patients with induced menarche. The present study investigated an index of spontaneous and cyclical menstruation at 10-12 years old in TS. Subjects comprised 50 patients with TS, divided into three groups: Group A (n=7), with spontaneous menarche before 16 years old and regular menstruation for at least 1 year and 6 months; Group B (n=6), with irregular menstruation since menarche leading to secondary amenorrhea despite spontaneous menarche before 16 years old; and Group C (n=37), without spontaneous breast budding before 14 years old or without spontaneous menarche before 16 years old. Karyotype, LH and FSH concentrations at 10 and 12 years old were analyzed retrospectively. Spontaneous and cyclical menstruation was more frequently observed in TS with mosaicism characterized by 45,X/46,XX or 45,X/47,XXX than in TS with other karyotypes, as previously described. Spontaneous and cyclical menstruation in TS was observed when serum FSH level was <10 mIU/mL at 12 years old, suggesting this FSH level as an index of spontaneous and cyclical menstruation in TS.

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Understanding the interplay between sleep duration and quality, diet and hormones of obesity may help design effective lifestyle intervention strategies. Here we studied such associations in lean and obese teen-aged Saudi girls. In this cross-sectional observational study, 126 girls (62 lean and 64 obese) aged 14 -18 years (16.5 ± 1.5) were evaluated. A general questionnaire, which included sleep and diet questions, was obtained and anthropometric measurements and overnight fasting blood samples for determination of glucose, lipid profile and serum levels of leptin, adiponectin, resistin and ghrelin were collected. Subjects that slept < 5 hours/day had a higher percent of carbohydrate intake (p = 0.04) than those who slept > 7 hours/day. Adiponectin levels were higher in the lean than the obese group and increased in proportion to hours of sleep. Ghrelin had an inverse association with subjective sleep duration (p = 0.04), while resistin levels were directly proportional to it. Thus, the duration and quality of sleep influenced diet composition and the circulating levels of adipocytokines and ghrelin in adolescent girls. Long and uninterrupted sleep was associated with a better diet and a more favorable hormonal profile.

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Ageing is associated with an increase in visceral obesity in men and women. Although wild-type mice with a C57Bl/6 genetic background are extensively used in studies on obesity and metabolism, little information is available on age-associated changes in their adipose tissues. We have evaluated development and composition of subcutaneous (SC) and gonadal (GON) adipose tissue in male C57Bl/6 mice at the ages of 10 weeks, 12 months or 24 months, while kept on normal chow. Total body weight as well as SC and GON fat mass significantly increased between 10 weeks and 12 months, but markedly decreased again up to 24 months of age. Adipocyte size in both fat depots and blood vessel size in GON fat followed this trend. Plasma leptin levels correlated positively with body weight and SC or GON fat mass. Both 12 and 24 months old mice displayed better insulin sensitivity as compared to 10 weeks old counterparts, reflected by significantly decreased plasma levels of insulin and/or glucose. Thus, ageing of C57Bl/6 male mice is associated with a biphasic pattern (increase up to 12 months followed by a decrease up to 24 months) of body weight, SC and GON fat mass, adipocyte and blood vessel size.

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Type 2 diabetes is characterized by progressive β-cell dysfunction. Family history of type 2 diabetes has been known to be associated with an increased risk for the development of the disease. However, few studies have evaluated the effects of family history of diabetes on residual β-cell function in type 2 diabetic patients. We investigated associations among family histories, clinical characteristics and plasma C-peptide levels in type 2 diabetic patients. A total of 1,350 patients with type 2 diabetes were recruited. The patients with a family history of type 2 diabetes had younger age at onset of diabetes, longer diabetes duration, higher LDL-cholesterol, and lower fasting C-peptide levels than the patients without family history. When divided according to the tertiles of diabetes duration, patients with a family history of type 2 diabetes had more decreased concentrations of fasting C-peptide as duration of diabetes increased, but patients without a family history did not. Multiple regression models were used to determine the association between fasting plasma C-peptide levels and a family history of type 2 diabetes mellitus. With adjustments for age and sex, glycated hemoglobin (HbA_1C), fasting plasma glucose, free fatty acids, body mass index and diabetes mellitus (DM) duration, there was a significant association (P < 0.01). Our results showed that a family history of diabetes was significantly associated with the progressive decline of fasting plasma C-peptide levels in Korean type 2 diabetes mellitus.

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