Wei-Shiung Yang

Metabolic Factors and Risk of Hepatocellular Carcinoma by Chronic Hepatitis B/C Infection: A Follow-up Study in Taiwan

BACKGROUND & AIMS This study investigated whether obesity, diabetes, and other metabolic factors are independently associated with hepatocellular carcinoma (HCC), stratified by hepatitis B virus (HBV) and hepatitis C virus (HCV) serostatus, and explored the possible joint influence of obesity/diabetes and HBV/HCV infections on the risk of HCC. METHODS A total of 23,820 residents in Taiwan were recruited and followed up for 14 years. All analyses were stratified by hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) at enrollment, and 218 subjects positive for both seromarkers were excluded. Incident HCC cases were identified via linkage to the national cancer registry. Multivariate-adjusted relative risk (RR(a)) and 95% confidence interval (95% CI) were estimated using Cox proportional hazards models. RESULTS Extreme obesity (body mass index >or=30 kg/m(2)) was independently associated with a 4-fold risk of HCC (RR(a), 4.13; 95% CI, 1.38-12.4) among anti-HCV-seropositive subjects and a 2-fold risk (RR(a), 2.36; 95% CI, 0.91-6.17) in persons without HBV and HCV infections, after controlling for other metabolic components, but not in HBsAg-seropositive subjects (RR(a), 1.36; 95% CI, 0.64-2.89). Diabetes was associated with HCC in all 3 groups, with the highest risk in those with HCV infection (RR(a), 3.52; 95% CI, 1.29-9.24) and lowest in HBV carriers (RR(a), 2.27; 95% CI, 1.10-4.66). We found more than 100-fold increased risk in HBV or HCV carriers with both obesity and diabetes, indicating synergistic effects of metabolic factors and hepatitis. CONCLUSIONS The finding that both obesity and diabetes are predictors of HCC risk, possibly differently depending on HBV and HCV infection status, may shed some light in preventing HCC.

Relationship Between Androgen Levels and Blood Pressure in Young Women With Polycystic Ovary Syndrome

The role of testosterone on the development of hypertension is controversial, especially in women with polycystic ovary syndrome (PCOS) who have higher prevalence of obesity and insulin resistance than women without PCOS. Little is known about the association between serum testosterone level and blood pressure in young women with PCOS. In the 151 young Taiwanese women with PCOS enrolled in this cross-sectional study, we measured the body mass index, waist circumference, blood pressure, fasting glucose, fasting insulin, lipid profile, and hormone profiles. The free androgen index, total testosterone, and sex hormone-binding globulin, but not the level of dehydroepiandrosterone sulfate, significantly correlated with both systolic blood pressure (SBP) and diastolic blood pressure (DBP). In multiple linear regression models adjusted for age, body mass index, and other anthropometric, metabolic, and hormonal variables, the level of serum free androgen index or total testosterone, but not the sex hormone-binding globulin, were independently related to SBP and DBP. The age- and body mass index–adjusted least-square mean of serum-free androgen index levels were significantly different between the highest quartile and other quartiles of the SBP and DBP levels. The high bioavailable testosterone levels (free androgen index: ≥19%) in women with PCOS increased the risk of elevated blood pressure (SBP ≥130 mm Hg and/or DBP ≥85 mm Hg) with an odds ratio of 3.817 (P=0.029; 95% CI: 1.14 to 12.74) after adjustment for age, anthropometric measures, and metabolic profiles. Our results suggest that the characteristic hyperandrogenemia in young women with PCOS was associated with an elevated SBP and DBP independent of age, insulin resistance, obesity, or dyslipidemia.

Sex Differences in high-fat Diet-induced Obesity, Metabolic alterations and Learning, and Synaptic Plasticity Deficits in Mice

Obesity is a potential risk factor for cognitive deficits in the elder humans. Using a high‐fat diet (HFD)–induced obese mouse model, we investigated the impacts of HFD on obesity, metabolic and stress hormones, learning performance, and hippocampal synaptic plasticity. Both male and female C57BL/6J mice fed with HFD (3 weeks to 9–12 months) gained significantly more weights than the sex‐specific control groups. Compared with the obese female mice, the obese males had similar energy intake but developed more weight gains. The obese male mice developed hyperglycemia, hyperinsulinemia, hypercholesterolemia, and hyperleptinemia, but not hypertriglyceridemia. The obese females had less hyperinsulinemia and hypercholesterolemia than the obese males, and no hyperglycemia and hypertriglyceridemia. In the contextual fear conditioning and step‐down passive avoidance tasks, the obese male, but not female, mice showed poorer learning performance than their normal counterparts. These learning deficits were not due to sensorimotor impairment as verified by the open‐field and hot‐plate tests. Although, basal synaptic transmission characteristics (input–output transfer and paired‐pulse facilitation (PPF) ratio) were not significantly different between normal and HFD groups, the magnitudes of synaptic plasticity (long‐term potentiation (LTP) and long‐term depression (LTD)) were lower at the Schaffer collateral‐CA1 synapses of the hippocampal slices isolated from the obese male, but not female, mice, as compared with their sex‐specific controls. Our results suggest that male mice are more vulnerable than the females to the impacts of HFD on weight gains, metabolic alterations and deficits of learning, and hippocampal synaptic plasticity.

The relationship between anti-Müllerian hormone, androgen and insulin resistance on the number of antral follicles in women with polycystic ovary syndrome

BACKGROUND Anti-Müllerian hormone (AMH) is a biomarker that predicts the number of antral follicles and is involved in follicle arrest for women with polycystic ovary syndrome (PCOS). We investigated the association between the characteristic hyperandrogenemia, insulin resistance (IR), AMH, and the morphology and size of ovaries for women with PCOS. METHODS A total of 99 Taiwanese women with PCOS who were willing to undergo vaginal ultrasonography were enrolled in this cross-sectional study. RESULTS The number of antral follicles and the ovarian volume showed a significant correlation with AMH, total testosterone and the free androgen index, but not with age, body mass index (BMI) or the homeostasis model assessment of insulin resistance (HOMA-IR). AMH had a significant negative association with both BMI and HOMA-IR. Multiple stepwise regression analysis demonstrated that AMH, BMI and total testosterone were independently related to the number of antral follicles. AMH and total testosterone were the main determinants for ovarian volume in a stepwise regression model. CONCLUSIONS Our results suggest that not only the AMH level, but also obesity, IR and elevated androgen levels may relate to the development of the large size of antral follicle pool and ovarian volume in women with PCOS. Obesity and IR may enhance the follicular excess through the dysregulation of AMH or through the pathway of hyperandrogenemia. These findings might partly explain why adequate body weight management and improvement in IR can improve the ovulatory function for women with PCOS.

Human genetics of adiponectin in the metabolic syndrome

Adiponectin, an adipose-derived plasma protein, has been well established to be an important biomarker for metabolic syndrome and its complications after exhausted studies in humans. Animal and cell culture experiments also support most claims from human observations of its roles in the metabolic syndrome. Reproducible results of human genetic studies of diverse ethnic origin and by different investigators may provide the evidence for its causative roles in the pathogenesis of the metabolic syndrome and further insight into the genetic constitutions of the metabolic syndrome. Some of the common polymorphisms in the promoter region, exon and intron 2, and the rare nonsynonymous mutations in exon 3 of the human adiponectin gene were repeatedly shown in many studies from many different ethnic populations to associate with the phenotypes related to body weight, glucose metabolism, insulin sensitivity, and risk of type 2 diabetes mellitus and coronary artery disease. The association of adiponectin genetic variations with dyslipidemia and blood pressure was less explored. The common polymorphisms and rare mutations of the human adiponectin gene itself were demonstrated to associate with differential expression of adiponectin at the plasma protein level and mRNA level in adipose tissue. The PPARγ2 Pro12Ala variants were also shown to influence insulin sensitivity in interaction with adiponectin genotype or to influence plasma adiponectin levels. However, the results were not consistent. Three genome-wide scans for the loci that regulate plasma adiponectin concentration suggest further exploration on chromosomes 5, 9, 14, 15, and 18 is required. These human genetic studies on adiponectin and the metabolic syndrome strongly suggest that adiponectin is one of the causative factors in its pathogenesis and provide significant insights into the genetic makeup of the metabolic syndrome. Extension from these studies may accelerate the discovery of new molecular targets for future therapeutic interventions.

Adiponectin: a biomarker of obesity-induced insulin resistance in adipose tissue and beyond

Adiponectin is one of the most thoroughly studied adipocytokines. Low plasma levels of adiponectin are found to associate with obesity, metabolic syndrome, diabetes and many other human diseases. From animal experiments and human studies, adiponectin has been shown to be a key regulator of insulin sensitivity. In this article, we review the evidence and propose that hypo-adiponectinemia is not a major cause of obesity. Instead, it is the result of obesity-induced insulin resistance in the adipose tissue. Hypo-adiponectinemia then mediates the metabolic effects of obesity on the other peripheral tissues, such as liver and skeletal muscle and may also exert some direct effects on end-organ damage. We propose that deciphering the molecular details governing the adiponectin gene expression and protein secretion will lead us to more comprehensive understanding of the mechanisms of insulin resistance in the adipose tissue and provide us new avenues for the therapeutic intervention of obesity and insulin resistance-related human disorders.

Lack of independent relationship between plasma adiponectin, leptin levels and bone density in nondiabetic female adolescents

objectives  Adiponectin has been implicated in the pathophysiology of metabolic syndrome and coronary artery disease in humans. Whether adiponectin is related to bone mineralization remains unclear in adults as well as in adolescents. In this study, we aimed to determine the relationship between plasma adiponectin, leptin concentrations and bone density, including total‐body bone mineral density (BMD) and bone mineral content (BMC) in adolescence.

Genetic epistasis of adiponectin and PPARγ2 genotypes in modulation of insulin sensitivity: a family-based association study

Aims/hypothesisGenetic interactions in modulating the phenotypes of a complex trait, such as insulin sensitivity, were usually taken for granted. However, this has not been commonly shown. Previous studies have suggested that both PPARγ2 and adiponectin genes could influence insulin sensitivity. Therefore it is likely that they could modulate insulin sensitivity through gene to gene interactions.MethodsWe genotyped 1793 subjects of Chinese and Japanese descendents from 601 hypertensive families recruited in Sapphire study for a T94G in the adiponectin gene exon 2 and the PPARγ2 Pro12Ala polymorphisms. Serum insulin concentrations and insulin resistance index (HOMAIR) were used as the markers of insulin sensitivity.ResultsWe found that the T allele of adiponectin gene was associated with a higher Ins60 and higher area under curve of insulin (AUCi) in OGTT utilizing all subjects in a mixed model that corrected for family effects. Important interactions between adiponectin and PPARγ2 genotypes were found in fasting insulin concentrations (Ins0), insulin concentrations at 2-h (Ins120) in OGTT and insulin resistance index (HOMAIR). The main effects of the PPARγ2 genotypes were in the plasma glucose concentrations in OGTT. In contrast, the main effects of adiponectin genotypes were in every insulin variable, including Ins0, Ins60, Ins120, AUCi and HOMAIR. The subjects carrying the adiponectinG allele and the PPARγ2Ala12 allele seemed to be more insulin sensitive.Conclusion/interpretationThese results showed that adiponectin is a genetic factor associated with insulin sensitivity. Interactions with PPARγ2 genotypes modified this association.

Adiponectin as a potential differential marker to distinguish pancreatic cancer and chronic pancreatitis.

Serum adiponectin (ADP) levels are reported inversely related to the risk in breast, endometrial cancer, and gastric cancer. Serum ADP as a potential marker compared with CA-19-9 in pancreatic carcinoma (PC) and chronic pancreatitis (CP) was studied. Adiponectin and CA-19-9 levels were examined at the time of diagnosis in patients with CP and PC. Methods: Serum ADP and CA-19-9 levels were measured by immunoassays in 72 patients with PC and 39 with CP and 290 control subjects. Results: The median levels of ADP for PC were significantly higher than those for CP and control subjects (P = 0.0035). Increasing the upper reference value of ADP allowed for better discrimination between CP and PC. The introduction of 28 ng/mL as a cutoff for ADP significantly improved its specificity. At an elevated cutoff level for ADP (28 ng/mL), a better discrimination between PC and CP was obtained. Conclusions: Adiponectin might be useful in the differential diagnosis of PC and CP with elevated CA-19-9. This gives rise to the possibility that ADP has a potential role in differentiating CP and PC.

Metabolic Syndrome Components Worsen Lower Urinary Tract Symptoms in Women with Type 2 Diabetes

CONTEXT Diabetic women are more susceptible to develop lower urinary tract symptoms (LUTS), especially overactive bladder (OAB). However, data regarding the effect of components of metabolic syndrome (MS) on this association are conflicting. OBJECTIVE The objective of the study was to examine the potential role of MS in the development of LUTS in diabetic women. DESIGN The study was a prevalence study conducted between 2005 and 2007. SETTING The study was conducted in a university hospital. PARTICIPANTS A total of 518 women with type 2 diabetes aged 50-75 yr were included. They were subgrouped as MS (47.5%) and non-MS (52.5%) groups according to whether they fulfilled the criteria of MS. MAIN OUTCOME MEASURE We used American Urological Association Symptom Index (AUA-SI) to evaluate LUTS and Indevus Urgency Severity Scale to evaluate OAB, respectively. RESULTS Women in the MS group had significantly higher storage and total AUA-SI scores as well as a higher prevalence of LUTS and OAB. Most intriguingly, the number of MS components was strongly associated with the LUTS severity because the AUA-SI scores increased in parallel to the number of components were present. Similar results were found between MS and OAB. Multivariate analysis revealed that peripheral neuropathy, but not MS, significantly predicted LUTS in diabetic women after age adjustment. However, MS remained significantly predictive for LUTS and OAB after additional adjustment for neuropathy. CONCLUSIONS Our results suggest that MS may especially influence LUTS and OAB in diabetic women, probably by compounding the effect of peripheral neuropathy.