Low serum albumin, aspartate aminotransferase, and body mass are risk factors for frailty in elderly people with diabetes-a cross-sectional study.

BACKGROUND: Frailty is broadly characterized by vulnerability and decline in physical, mental and social activities and is more common in elderly patients with type 2 diabetes mellitus (T2DM). Frailty is closely associated with nutrition, muscle strength, inflammation, and hormones etc. In hormones, dehydroepiandrosterone sulfate (DHEA-S) and cortisol are suggested to be such candidates affecting frailty. Little investigation has been performed using a wider range of measures of frailty to clarify risk factors for frailty including the above two hormones. METHODS: We performed a cross-sectional study to investigate the risk factors for frailty in elderly T2DM patients (n = 148; ≥65 years), using a broad assessment, the clinical frailty scale. We compared parameters between the non-frail and frail groups using the unpaired t and Mann-Whitney U tests. The Jonckheere-Therpstra test was used to identify relationships with the severity of frailty, and risk factors were identified using binary regression analysis. RESULTS: Simple regression analysis identified a number of significant risk factors for frailty, including DHEAS < 70 µg/dL and cortisol/DHEA-S ratio ≥ 0.2. Multiple regression analysis showed that low albumin (< 4.0 g/dl) (odds ratio [OR] = 5.79, p < 0.001), low aspartate aminotransferase (AST) activity (< 25 IU/L) (OR = 4.34, p = 0.009), and low body mass (BM) (< 53 kg) (OR = 3.85, p = 0.012) were independent risk factors for frailty. A significant decrease in DHEA-S and a significant increase in the cortisol/DHEA-S ratio occurred alongside increases in the severity of frailty. DHEA-S concentration positively correlated with both serum albumin and BM. CONCLUSIONS: Hypoalbuminemia, low AST, and low BM are independent risk factors for frailty in elderly T2DM patients, strongly implying relative malnutrition in these frail patients. DHEA-S may be important for the maintenance of liver function and BM. A decrease in DHEA-S and an increase in the cortisol/DHEAS ratio may be involved in the mechanism of the effect of malnutrition in elderly T2DM patients.

A nationwide survey of adrenal incidentalomas in Japan: the first report of clinical and epidemiological features.

The aim of this study was to reveal clear epidemiologic and clinical characteristics of incidentally discovered adrenal masses, termed adrenal incidentalomas (AIs), and to establish appropriate managemental and therapeutic regimens in Japan. This study had been originally carried out as a project of a research proposed on behalf of the Japanese Ministry of Health, Labour and Welfare, from 1999 to 2004. This nationwide multicenter study on AIs included 3,672 cases with clinically diagnosed AIs, involving 1,874 males and 1,738 females, with mean age 58.1 ± 13.0 years (mean ± SD). In the present study, we focused on the investigation of the real prevalence of various adrenal disorders with AI. The mean nodule size of AI based on computed tomography was 3.0 ± 2.0 cm. Compared to non-functioning adenomas (NFAs), tumor diameters were significantly larger in adrenocortical carcinomas (ACCs), pheochromocytomas, cortisol-producing adenomas (CPAs), myelolipomas, metastatic tumors, cysts, and ganglioneuromas (p < 0.01). Endocrinological evaluations demonstrated that 50.8% of total AIs were non-functioning adenomas, while 10.5%, including 3.6% with subclinical Cushing's syndrome, were reported as CPAs, 8.5% as pheochromocytomas, and 5.1% as aldosterone-producing adenomas. ACCs were accounted for 1.4% (50 cases) among our series of AIs. In conclusion, while almost 50 % of AIs are non-functional adenomas, we must be particularly careful as AIs include pheochromocytomas or adrenal carcinomas, because they may be asymptomatic. To our knowledge, this is the first and the largest investigation of AI, thus providing basic information for the establishment of clinical guidelines for the management of AI.

A High Serum Cortisol/DHEA-S Ratio Is a Risk Factor for Sarcopenia in Elderly Diabetic Patients.

CONTEXT: Elderly patients with type 2 diabetes mellitus (T2DM) have a high prevalence of frailty and/or sarcopenia. Sarcopenia is thought to be related to discordant secretions of the adrenal hormones cortisol and dehydroepiandrosterone (DHEA), as well as the sulfate ester of DHEA (DHEA-S). The current study sought to evaluate the risk factors for sarcopenia in elderly patients with T2DM. DESIGN AND PATIENTS: We enrolled 108 consecutive elderly patients aged ≥65 years with T2DM (mean age, 76.2 ± 7.3 years; 43.5% males). Sarcopenia was assessed and diagnosed based on the Asian version of the diagnostic criteria regarding muscular strength, physical function, and muscle mass. We assessed various physical parameters, blood tests, and atherosclerosis markers and statistically determined the risk factors for sarcopenia. RESULTS: Multiple regression analysis showed that the independent risk factors for sarcopenia were a serum cortisol/DHEA-S ratio ≥0.2, diastolic blood pressure <70 mm Hg, Hb concentration <13 g/dL, and an ankle brachial index <1.0. The strongest risk factor for sarcopenia was a serum cortisol/DHEA-S ratio ≥0.2. An increase in the serum cortisol/DHEA-S ratio reflected higher cortisol values and lower DHEA-S values in patients with sarcopenia compared with those in nonsarcopenic patients. The concentrations of cortisol and DHEA-S, as well as the cortisol/DHEA-S ratio, changed in accordance with the severity of sarcopenia. CONCLUSIONS: A relative increase in cortisol may reflect the presence of stress and stimulate muscle catabolism, whereas a relative decrease in DHEA-S may cause a decrease in the anabolic action of DHEA on muscle; the combination of these factors may lead to sarcopenia.

Selective androgen receptor modulator, S42 has anabolic and anti-catabolic effects on cultured myotubes.

We previously identified a novel selective androgen receptor modulator, S42, that does not stimulate prostate growth but has a beneficial effect on lipid metabolism. S42 also increased muscle weight of the levator ani in orchiectomized Sprague-Dawley rats. These findings prompted us to investigate whether S42 has a direct effect on cultured C2C12 myotubes. S42 significantly lowered expression levels of the skeletal muscle ubiquitin ligase (muscle atrophy-related gene), atrogin1 and Muscle RING-Finger Protein 1(MuRF1) in C2C12 myotubes, as determined by real time PCR. Phosphorylation of p70 S6 kinase (p70S6K), an essential factor for promoting protein synthesis in skeletal muscle, was significantly increased by S42 to almost the same extent as by insulin, but this was significantly prevented by treatment with rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1). However, phosphorylation of Akt, upstream regulator of mTORC1, was not changed by S42. S42 did not increase insulin-like growth factor 1 (Igf1) mRNA levels in C2C12 myotubes. These results suggest that S42 may have an anabolic effect through activation of mTORC1-p70S6K signaling, independent of IGF-1-Akt signaling and may exert an anti-catabolic effect through inhibition of the degradation pathway in cultured C2C12 myotubes.

Selective Androgen Receptor Modulator S42 Suppresses Prostate Cancer Cell Proliferation.

We previously identified the selective androgen receptor (AR) modulator S42, which does not stimulate prostate growth but has a beneficial effect on lipid metabolism. In the prostate cancer (PC) cell line LNCaP, S42 did not induce AR transactivation but antagonized 5α-dihydrotestosterone (DHT)‒induced AR activation. Next, we investigated whether S42 suppresses the growth of PC cell lines. Basal growth of LNCaP cells was significantly suppressed by treatment with S42 compared with vehicle, as determined by cell counting and 5-bromo-2'-deoxyuridine assays. The suppressive effect of S42 on cell growth was evident in the AR-positive PC cells LNCaP and 22Rv1 and was slightly observed even in the AR-negative PC-3 cells. However, S42 did not induce apoptosis as determined by the terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay. S42 had an even greater suppressive effect on DHT-dependent LNCaP cell proliferation than on basal proliferation (P < 0.05). DHT treatment increased the expression of phosphorylated extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK), a major signaling molecule for PC proliferation, and this was significantly inhibited by S42. DHT also significantly upregulated AR, insulinlike growth factor-1 receptor (IGF-1R), and insulin receptor (IR)-ß protein levels, which were similarly reduced by S42 treatment. Importantly, S42 administration to mice attenuated the growth of LNCaP tumors and reduced tumor expression of the prostate-specific antigen, P504S, Ki67, and phosphorylated ERK-MAPK. These data suggest that S42 attenuates LNCaP tumor growth not by inducing apoptosis but by inhibiting the expression of proliferation-related receptors, including IGF-1R, IR, and AR, and by suppressing ERK-MAPK activation. S42 may thus be a feasible candidate for PC treatment.

Frailty in elderly diabetes patients.

Frailty is a state of vulnerability and a consequence of cumulative decline in multiple physiological systems over a lifespan. The occurrence of frailty depends on deterioration in muscle and nerve function, declining cardiopulmonary reserve and loss of executive function. Diabetes mellitus (DM) often causes functional impairment in each of the above systems, thus leading to a loss of whole body homeostasis and deterioration in physical function. Inability of self-management in DM patients may also have considerable impact on the development of sarcopenia/frailty. Thus, there may be positive feedback between the progression of diabetic complications and frailty/sarcopenia. While various factors are involved in this process, insulin resistance or insulin depletion may be an important factor in the progression of frailty in diabetes patients since insulin is well known to be an anabolic hormone in muscle. Interestingly, in our study targeting elderly DM patients, low HbA1c was a significant and independent risk factor for frailty, as assessed using a broad sense frailty scale, the Clinical Frailty Scale (CSF), suggesting that reverse metabolism due to malnutrition in elderly type 2 DM patients might be involved. Therefore, an intervention that includes proper nutrition and exercise training may be essential for the prevention of frailty. The pathogenesis of frailty in DM patients is extensively discussed in this review.

Low glycated hemoglobin level is associated with severity of frailty in Japanese elderly diabetes patients.

AIMS/INTRODUCTION: Previously, a study using a narrowly defined (physical base) frailty scale reported that both good and bad (U-shaped curve) glycated hemoglobin (HbA1c) levels were frailty risk factors in patients with type 2 diabetes mellitus. However, no such studies in Japan have shown this. We aimed to evaluate the frailty risk factors including HbA1c in elderly Japanese patients with type 2 diabetes mellitus using a broadly defined (both physical and psychosocial base) frailty scale, the Clinical Frailty Scale (CFS). MATERIALS AND METHODS: We randomly enrolled 132 elderly patients with type 2 diabetes mellitus (aged ≥65 years) and categorized the patients into nine stages of frailty using CFS. Because no patient had CFS 9, patients with a CFS score of 1-4 and 5-8 were defined as non-frail and frail, respectively. We attempted to identify the risk factors of frailty by investigating the association between CFS stage and various patient factors. RESULTS: Multiple regression analysis showed that an increase in age, low levels of albumin, high-density lipoprotein cholesterol, systolic blood pressure, HbA1c, total cholesterol, and bodyweight were statistically significant and strong independent risk factors for frailty, suggesting that reverse metabolism owing to malnutrition in elderly type 2 diabetes mellitus patients might be involved. CONCLUSIONS: HbA1c level was not a U-shaped risk for frailty, suggesting that relatively good glycemic control might be more important for frailty than poor control in elderly type 2 diabetes mellitus patients.

Comparative study of the correlation between atherosclerosis and osteoporosis in women in Japan and Mongolia.

Objective: Associations between vascular calcification and osteoporosis are well documented, yet effects of lifestyle on atherosclerosis and osteoporosis remain unclear. This study evaluated the relationship between atherosclerosis and osteoporosis of people with different lifestyles living on Uku Island in Japan (rice consumption and fishing lifestyle) and in Ulaanbaatar in Mongolia (meat consumption and nomadic lifestyle), and investigated the differences of lifestyles on atherosclerosis and osteoporosis. Methods: Participants were women aged over 50 years who had undergone a previous medical examination for atherosclerosis and osteoporosis (Uku Island, 104, Ulaanbaatar, 71). Lifestyle habits were obtained by questionnaire. Bone mineral density of the right calcaneus was measured using quantitative ultrasound. Brachial-ankle pulse wave velocity was measured as an index of atherosclerosis. Results: There were no significant differences in bone mineral density and brachial-ankle pulse wave velocity between the two groups, even though meat and dairy intake, number of meals skipped, and number of children were significantly greater in participants from Ulaanbaatar compared with Uku Island. Brachial-ankle pulse wave velocity showed significant positive correlations with age, systolic and diastolic blood pressures, and body mass index and a significant negative correlation with bone mineral density for both groups. With step-wise multiple regression analysis, brachial-ankle pulse wave velocity significantly correlated with age and bone mineral density for both populations. Systolic blood pressure significantly correlated with brachial-ankle pulse wave velocity for the Ulaanbaatar group. Conclusions: Despite significant lifestyle differences, similar relationships between atherosclerosis and osteoporosis were observed in women from Uku Island and Ulaanbaatar. Hypertension was a significant contributing factor for atherosclerosis for the Ulaanbaatar group.

Dehydroepiandrosterone-enhanced dual specificity protein phosphatase (DDSP) prevents diet-induced and genetic obesity.

Dehydroepiandrosterone (DHEA) exerts a wide variety of therapeutic effects against medical disorders, such as diabetes and obesity. However, the molecular basis of DHEA action remains to be clarified. Previously, we reported that DHEA-enhanced dual specificity protein phosphatase, designated DDSP, is one of the target molecules of DHEA. To examine the role of DDSP in DHEA signaling, we generated mice that carry a DDSP transgene in which expression is driven by the CAG promoter (DDSP-Tg). DDSP-Tg mice weighed significantly less than wild-type (WT) control mice when a high fat diet was supplied (p < 0.01). No difference in food-intake or locomotor activity was found between DDSP-Tg and WT mice. Oxygen consumption of DDSP-Tg mice was higher than that of WT mice (p < 0.01), which suggested an increase in basal metabolism in DDSP-Tg mice. To further investigate the role of DDSP in genetic obese mice, DDSP-Tg mice with a db/db background were generated (DDSP-Tg db/db). We observed cancellation of obesity by the db/db mutation and development of a cachexic phenotype in DDSP-Tg db/db mice. In conclusion, our study shows that expression of DDSP leads to prevention of diet-induced and genetic (db/db) obesity. Anti-obese effects of DHEA might be mediated through DDSP, which might be a therapeutic target for intervention of obesity.

Brachial-ankle pulse wave velocity predicts all-cause mortality and cardiovascular events in patients with diabetes: the Kyushu Prevention Study of Atherosclerosis.

OBJECTIVE: Whether brachial-ankle pulse wave velocity (baPWV), a noninvasive marker for arterial stiffness, is a useful predictive maker for cardiovascular events in subjects with diabetes is not established. In the present cohort study, we evaluated the benefit of baPWV for the prediction of cardiovascular morbidity and mortality in subjects with diabetes. RESEARCH DESIGN AND METHODS: A total of 4,272 outpatients with diabetes were enrolled in the Kyushu Prevention Study of Atherosclerosis. Of these, 3,628 subjects, excluding those with an ankle-brachial index of <0.9, were prospectively followed for 3.2 ± 2.2 years. The baPWV at baseline was classified by recursive partitioning (RP) for each end point. We plotted the Kaplan-Meier curves for high- and low-baPWV groups, which were designated based on the cutoff points, and calculated Cox proportional hazards models. RESULTS: The elevation of baPWV quartiles was significantly correlated to the incidence of coronary artery events, cerebrovascular events, and all-cause mortality. RP revealed baPWVs of 14 and 24 m/s as statistically adequate cutoff points for cardiovascular events and mortality, respectively. High-baPWV classes showed significantly low event-free ratios in Kaplan-Meier curves for all end points and remained independent risks for all-cause mortality and cerebrovascular events, but not for coronary artery events after adjustments for age, sex, BMI, hypertension, hyperlipidemia, smoking, and hemoglobin A1c by Cox proportional hazards models. CONCLUSIONS: This large-scale cohort study provided evidence that high baPWV is a useful independent predictor of mortality and cardiovascular morbidity in subjects with diabetes.

Association of borderline ankle-brachial index with mortality and the incidence of peripheral artery disease in diabetic patients.

OBJECTIVE: Peripheral artery disease (PAD) and diabetes mellitus are significant risk factors for all-cause death or cardiovascular death. PAD occurs more frequently in diabetic than in non-diabetic patients. However, the association of ankle-brachial index (ABI), especially borderline ABI, with clinical outcomes has not been fully elucidated in diabetic patients. This study aimed to investigate the association of ABI with mortality and the incidence of PAD in Japanese diabetic patients. METHODS: This observational study included 3981 diabetic patients (61.0 ± 11.8 years of age, 59.4% men), registered in the Kyushu Prevention Study for Atherosclerosis. Patients were divided into 3 groups according to the value of ABI at baseline: ABI ≤0.90 (abnormal ABI:354 patients), 0.91 ≤ ABI ≤ 0.99 (borderline ABI:333 patients), and 1.00 ≤ ABI ≤ 1.40 (normal ABI:3294 patients). RESULTS: Cumulative incidence of all-cause death was significantly higher in patients with abnormal and borderline ABI than in those with normal ABI (34.4% vs. 13.5%, P < 0.0001 and 26.1% vs. 13.5%, P < 0.0001, respectively). In multivariate analysis, the risks for all-cause death in patients with abnormal ABI (HR:2.16; 95%CI:1.46-3.14; P = 0.0002) and borderline ABI (HR:1.78; 95%CI:1.14-2.70; P = 0.01) were significantly higher than in those with normal ABI. The incidence of PAD was remarkably higher in patients with borderline ABI than in those with normal ABI (32.2% vs.9.6%, P < 0.0001). After adjustment, the risk for PAD was significantly higher in patients with borderline ABI than in those with normal ABI (HR:3.10; 95%CI:1.90-4.95; P < 0.0001). CONCLUSIONS: Borderline ABI in diabetic patients was associated with significantly higher risks for mortality and PAD compared with normal ABI.

Roles for corticotropin-releasing factor receptor type 1 in energy homeostasis in mice.

OBJECTIVE: Expression of corticotropin-releasing factor type 1 receptor (CRFR1) has been shown on pancreatic ß cells, and its activation potentiates glucose-stimulated insulin secretion (GSIS). However, the roles of CRFR1 in energy metabolism beyond insulin release remain elusive. MATERIALS/METHODS: We characterized the metabolic phenotypes of mice lacking CRFR1 (CRFR1KO mice) under conditions of energy excess. RESULTS: When fed a normal diet, the glucose profile of CRFR1KO mice in response to a glucose tolerance test was similar to that of wild-type (WT) mice, while serum insulin levels were significantly lower in CRFR1KO mice, reflecting high insulin sensitivity in part due to very low glucocorticoid levels. Histology of the pancreas revealed islet hypoplasia in CRFR1KO mice, suggesting a role of CRFR1 in maintaining the ß cell mass in a manner similar to incretins. In response to a high-fat diet, CRFR1KO mice showed insulin resistance, but serum insulin levels during glucose challenge remained at a low level, indicating defective GSIS. In addition, CRFR1KO mice showed resistance to diet-induced obesity and hepatic steatosis. Although total food intake was not different between CRFR1KO and WT mice, oxygen consumption was significantly increased in CRFR1KO mice. The increased energy expenditure may explain the lean phenotype of CRFR1KO mice under conditions of energy excess. CONCLUSIONS: Our results suggest that CRFR1 plays important roles in whole body energy homeostasis, providing compelling evidence of the close relationship between energy homeostasis and the function of the hypothalamic-pituitary-adrenal axis.

Identification of endocrine disrupting chemicals activating SXR-mediated transactivation of CYP3A and CYP7A1.

Endocrine disrupting chemicals (EDCs) have emerged as a major public health issue because of their potentially disruptive effects on physiological hormonal actions. SXR (steroid xenobiotic receptor), also known as NR1I2, regulates CYP3A expression in response to exogenous chemicals, such as EDCs, after binding to SXRE (SXR response element). In our study, luciferase assay showed that 14 out of 55 EDCs could enhance SXR-mediated rat or human CYP3A gene transcription nearly evenly, and could also activate rat CYP7A1 gene transcription by cross-interaction of SXR and LXRE (LXRα response element). SXR diffused in the nucleus without ligand, whereas intranuclear foci of liganded SXR were produced. Furthermore, endogenous mRNA expression of CYP3A4 gene was enhanced by the 14 positive EDCs. Our results suggested a probable mechanism of EDCs disrupting the steroid or xenobiotic metabolism homeostasis via SXR.

Dihydrotestosterone inhibits lectin-like oxidized-LDL receptor-1 expression in aortic endothelial cells via a NF-κB/AP-1-mediated mechanism.

The mechanisms involved in the antiatherosclerotic effects of androgens are unclear. Although lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells plays critical roles in atherosclerosis, the effects of androgens on endothelial LOX-1 expression has not been examined. Therefore, to investigate the effects of dihydrotestosterone (DHT) on LOX-1 expression in rabbit aortic endothelial cells and cultured human aortic endothelial cells (HAEC), pellets containing DHT or placebo were s.c. implanted into 26 male New Zealand white rabbits at the time of castration or sham operation. The rabbits were then fed a high-cholesterol diet (HCD) for 2 wk. Microscopic examination of the aortic arch revealed that DHT significantly reduced HCD-induced LOX-1 expression in endothelial cells compared with placebo. In cultured HAEC, DHT at concentrations above 10(-9) to 10(-7) mol/liter inhibited TNFα-induced LOX-1 mRNA and protein expression. Deletion and mutation analysis of human LOX-1 promoter-luciferase constructs transfected into HAEC with an androgen receptor (AR) expression plasmid revealed that the 12-O-tetradecanoylphorbol-13-acetate (TPA) response element (TRE; nucleotides -60/-53) contributed to the inhibitory effects of DHT on TNFα-induced LOX-1 expression. Chromatin immunoprecipitation (ChIP) and re-ChIP assays revealed that TNFα- and TPA-dependent enrichment of p65 and phosphorylated c-Jun in the TRE chromatin region was inhibited by DHT-AR. Consistent with these results, DHT also suppressed TPA-induced expression of LOX-1. In conclusion, DHT exerts antiatherosclerotic effects by suppressing endothelial LOX-1 expression. This effect is partly mediated by the suppression of nuclear factor-κB- and activator protein 1-dependent activation of the LOX-1 promoter.

Sex hormone and neuroendocrine aspects of the metabolic syndrome.

We discuss the recent advances in the knowledge that the sex steroids testosterone (T), estradiol and dehydroepiandrosterone sulphate (DHEA-S) are involved in the development of visceral obesity and of the metabolic syndrome. Cross talk between leptin and the androgen receptor (AR) in the hypothalamus as well as the peripheral conversion of DHEA and T to estrone, estradiol and dihydrotestosterone (DHT) in adipocytes and hepatocytes play important roles in the metabolic syndrome in men. Finally, we discuss the development of new drugs, selective AR modulators, for treating the metabolic syndrome in men.

Dihydrotestosterone suppresses foam cell formation and attenuates atherosclerosis development.

The role of testosterone in atherosclerosis remains unclear because it is aromatized to estrogen. We investigated the effect of the nonaromatized natural androgen 5alpha-dihydrotestosterone (DHT) on the rabbit atherogenesis in relation to the proatherogenic molecule lectin-like oxidized-low-density lipoprotein receptor-1 (LOX-1) and its downstream molecules. Thirty-nine male New Zealand white rabbits were divided into four groups: 1) noncastrated group with normal chow diet (n = 6); 2) noncastrated group with high-cholesterol diet (HCD) (n = 10); 3) castrated group with HCD plus sc placebo pellet (n = 11); and 4) castrated group with HCD plus sc 150 mg DHT pellet (n = 12). Implantation of sc DHT or placebo pellet was performed at the time of castration. After castration or sham operation, the rabbits were fed the HCD for 8 wk, and plaque areas were assessed in the entire aorta. The HCD-induced increase in plaque area, which was most aggravated in the castration plus placebo group, was attenuated in the castration plus DHT group. Microscopic examination of the proximal descending aorta revealed that DHT significantly reduced HCD-induced foam cell formation, which was mostly composed of macrophages in the intima layer, compared with the placebo group. The decreased accumulation of foam cells with DHT treatment was accompanied by a marked reduction in the expression of LOX-1 mRNA in these cells. In cultured macrophages prepared from male wild-type mice that express the androgen receptor (AR), 1 x 10(-8) m and 1 x 10(-9) m DHT inhibited the formation of foam cells induced by oxidized low-density lipoprotein. Moreover, the expression of LOX-1 and inflammatory cytokines in the cultured macrophages was significantly suppressed by DHT. Such suppressive effects of DHT on foam cell formation and cytokine expression were not observed in cultured macrophages prepared from male AR-null mice, suggesting an involvement of AR in the mechanism. In conclusion, physiological levels of DHT attenuated the development of atherosclerosis in rabbits through the suppression of intimal foam cell formation of macrophage partly via the suppression of LOX-1 expression.

Impact of metabolic syndrome on the progression of Intima-Media Thickening in Japanese--a follow-up study.

The presence of metabolic syndrome (MetS) and its individual components is related to an increased IMT. MetS and increasing numbers of individual MetS components predicted future progression of IMT. Improvement of MetS was related to smaller increases in IMT, especially in females. These findings may suggest a benefit of intervention for MetS, which needs to be confirmed by prospective studies.

A novel synthetic androgen receptor ligand, S42, works as a selective androgen receptor modulator and possesses metabolic effects with little impact on the prostate.

We identified a novel synthetic steroid, S42, as a promising candidate of selective androgen receptor (AR) modulator. Results of the whole-cell binding assay using COS-7 cells exogenously expressing various steroid receptors indicated that S42 specifically binds to AR and progesterone receptor. When orchiectomized Sprague Dawley rats were administered with S42 for 3 wk, the muscle weight of the levator ani was increased as markedly as that induced by 5alpha-dihydrotestosterone (DHT), but the weight of the prostate was not elevated at any doses in contrast to DHT. The plasma concentrations of gonadotropin and adiponectin, those down-regulated by DHT, were unaffected by S42. In addition, although the plasma triglyceride level was unaffected by DHT, it was significantly reduced by S42. This effect of S42 was associated with suppression of the SRBP-1c-mediated lipogenic and insulin-desensitizing pathway in the liver and visceral fat. Taken together, S42 works as an AR agonist in muscle and as an AR antagonist in the prostate, pituitary gland, and liver, accompanying beneficial potentials on lipid metabolism.

Confirmation of multiple risk Loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population.

OBJECTIVE: To identify novel type 2 diabetes gene variants and confirm previously identified ones, a three-staged genome-wide association study was performed in the Japanese population. RESEARCH DESIGN AND METHODS: In the stage 1 scan, we genotyped 519 case and 503 control subjects with 482,625 single nucleotide polymorphism (SNP) markers; in the stage 2 panel comprising 1,110 case subjects and 1,014 control subjects, we assessed 1,456 SNPs (P < 0.0025, stage 1); additionally to direct genotyping, 964 healthy control subjects formed the in silico control panel. Along with genome-wide exploration, we aimed to replicate the disease association of 17 SNPs from 16 candidate loci previously identified in Europeans. The associated and/or replicated loci (23 SNPs; P < 7 x 10(-5) for genome-wide exploration and P < 0.05 for replication) were examined in the stage 3 panel comprising 4,000 case subjects and 12,569 population-based samples, from which 4,889 nondiabetic control subjects were preselected. The 12,569 subjects were used for overall risk assessment in the general population. RESULTS: Four loci-1 novel with suggestive evidence (PEPD on 19q13, P = 1.4 x 10(-5)) and three previously reported-were identified; the association of CDKAL1, CDKN2A/CDKN2B, and KCNQ1 were confirmed (P < 10(-19)). Moreover, significant associations were replicated in five other candidate loci: TCF7L2, IGF2BP2, SLC30A8, HHEX, and KCNJ11. There was substantial overlap of type 2 diabetes susceptibility genes between the two populations, whereas effect size and explained variance tended to be higher in the Japanese population. CONCLUSIONS: The strength of association was more prominent in the Japanese population than in Europeans for more than half of the confirmed type 2 diabetes loci.