Hao Chang Hung

Endoplasmic Reticulum Stress Induces the Expression of Fetuin-A to Develop Insulin Resistance

Fetuin-A is a biomarker reported to be important in many metabolic disorders, including obesity, diabetes, and hepatic steatosis. Although it is well known that fetuin-A is increased in diabetes and nonalcoholic fatty liver disease (NAFLD), the levels of fetuin-A in diabetic patients with NAFLD are unknown. Furthermore, the regulation of fetuin-A expression is still obscure. In this study, a total of 180 age- and sex-matched subjects with normal glucose tolerance, NAFLD, newly diagnosed diabetes (NDD), and NDD with NAFLD were recruited. We found that the levels of fetuin-A were significantly increased in NDD with NAFLD as compared with NDD or NAFLD subjects. We further used HepG2 cells to investigate the regulation of fetuin-A. Treatment with endoplasmic reticulum (ER) stress activator, thapsigargin, increased the expression of fetuin-A mRNA and protein in a time- and dose-dependent manner. Pretreatment with ER stress inhibitor, 4-phenylbutyrate, reversed high glucose or palmitate-induced fetuin-A expression. Moreover, treatment with 4-phenylbutyrate in both streptozotocin-induced and high-fat diet-induced diabetic mice not only decreased hepatic fetuin-A levels but also improved hyperglycemia. Taken together, we found that fetuin-A levels were increased in diabetes patients with NAFLD. Moreover, ER stress induced by high glucose and palmitate increased the expression of fetuin-A and further contributed to the development of insulin resistance.

The association between self-reported sleep quality and overweight in a Chinese population.

Sleep quality and obesity are associated with type 2 diabetes, hypertension, and metabolic syndrome. However, there is limited research on the association between sleep quality and obesity, and thus the aim of this study is to investigate this relationship in a Chinese population.

The Association between Self-Reported Sleep Quality and Metabolic Syndrome

Objectives Short and long sleep duration are associated with metabolic syndrome. However, there is limited research on the association between sleep quality and metabolic syndrome, and thus the aim of this study is to investigate this relationship. Materials and Methods The cross-sectional baseline data were collected from the decoded database of the Prevention Health Center of National Cheng Kung University Hospital from 2002 to 2006. The diagnosis of metabolic syndrome was according to the statement of the American Heart Association/National Heart, Lung, and Blood Institute. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). A higher global PSQI score indicates poorer sleep quality, and a global PSQI score greater than five differentiates poor from good sleepers. Results Of the 3,435 subjects recruited, 899 (26.2%) had metabolic syndrome. Subjects with metabolic syndrome had higher PSQI and prevalence of poor sleepers than those without metabolic syndrome. The multivariate lineal regression analysis showed that female gender, metabolic syndrome, sleep duration, snoring, alcohol drinking, and habitual exercise were independent predictors of PSQI. When substituting metabolic syndrome with the five components, hyperglycemia and low high-density lipoprotein cholesterol (HDL-C) were positively associated with PSQI. The multivariate logistic regression analyses showed that female gender, metabolic syndrome, sleep duration, and snoring were independently associated with being poor sleepers. Of the five components, only low HDL-C was an independent predictor of being poor sleepers. Conclusions Subjects with metabolic syndrome have higher global PSQI scores and a higher risk of being poor sleepers. Of the five components of metabolic syndrome, hyperglycemia and low HDL-C are independently associated with the global PSQI scores, while low HDL-C is an independent predictor of being poor sleepers.

The relationship between impaired fasting glucose and self-reported sleep quality in a Chinese population

Decreased sleep quality and duration predicts the development of type 2 diabetes. Prediabetes is an established risk factor for type 2 diabetes and cardiovascular disease. However, there is limited research on the association between prediabetes and sleep quality. The aim of this study is to investigate this relationship in a Chinese population.

Multiple mechanisms of GW-9508, a selective G protein-coupled receptor 40 agonist, in the regulation of glucose homeostasis and insulin sensitivity

Activation of G protein-coupled receptor 40 (GPR40) by agonists increases insulin release in isolated islets, whereas it is inconclusive whether GPR40 antagonists decrease blood glucose and increase insulin sensitivity. Although some clinical trials indicated that administration of a GPR40 agonist shows benefits in the regulation of blood glucose homeostasis, the pharmacological mechanisms of this receptor in the improvement of glycemic control remain unclear. Therefore, we used a selective GPR40 agonist, GW-9508, to clarify the role of GPR40 in the regulation of blood glucose. Bolus intraperitoneal injection of GW-9508 in mice showed a slight decrease in blood glucose, with an increase in plasma insulin levels under glucose stimuli. However, long-term treatment with low doses of GW-9508 in high-fat diet-induced (HFD) diabetic mice decreased blood glucose with decreased plasma insulin significantly and improved glucose intolerance and insulin resistance. Using small interfering ribonucleic acid to delete GPR40 in HepG2 cells, we demonstrated that GW-9508 reversed palmitate-induced insulin signaling impairment through a GPR40-dependent pathway. We also found that GW-9508 activates the Akt/GSK-3β pathway to increase glycogen levels in HepG2 cells. Furthermore, administration of GW-9508 decreased the hepatic expression of fetuin-A in HFD mice significantly and regulated high-glucose- or palmitate-induced fetuin-A expression to increase insulin sensitivity through a GPR40/PLC/PKC pathway in HepG2 cells. Taken together, GW-9508 exerts a partial agonist effect to regulate blood glucose through multiple mechanisms. Investigation of chemicals that act on GPR40 might be a new strategy for the treatment of diabetes.

The role of Hepassocin in the development of non-alcoholic fatty liver disease

BACKGROUND & AIMSnWhile non-alcoholic fatty liver disease (NAFLD) is the most common risk factor of chronic liver disease, the mechanisms that initiate its development are obscure. Hepassocin (HPS) is a hepatokine that has been reported to be involved in liver regeneration. In addition to the mitogenic activity of HPS, HPS expression is decreased in patients with hepatoma. However, the role of HPS in NAFLD is still unknown.nnnMETHODSnA total of 393 subjects with (n=194) or without (n=199) NAFLD were enrolled to evaluate the serum HPS concentration. In order to clarify the causal inference between HPS and NAFLD, we used experimental animal and cell models. Hepatic overexpression or silencing of HPS was achieved by lentiviral vector delivery in mice and lipofectamine transfection in HepG2 cells. Lipogenesis related proteins were detected by Western blots. The expression of inflammatory factors was determined by real-time polymerase chain reaction.nnnRESULTSnSubjects with NAFLD had a higher serum HPS concentration than those without it. Overexpression of HPS increased hepatic lipid accumulation and NAFLD activity scores (NAS), whereas deletion of HPS improved high fat diet-induced hepatic steatosis and decreased NAS in mice. Additionally, oleic acid, a steatogenic reagent, increased HPS expression in hepatocytes. Furthermore, overexpression of HPS in HepG2 cells induced lipid accumulation through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent pathway, whereas deletion of HPS decreased oleic acid-induced lipid accumulation.nnnCONCLUSIONSnThe present study provides evidence that HPS plays an important role in NAFLD and induces hepatic lipid accumulation through an ERK1/2-dependent pathway.

Menopause is associated with self-reported poor sleep quality in women without vasomotor symptoms.

ObjectiveThe aim of this study was to investigate the relationship between menopause and self-reported sleep quality in Chinese women without vasomotor symptoms. MethodsCross-sectional data were collected from a decoded database of the National Cheng Kung University Hospital. Menopause was defined as absence of menses for at least 12 months or a history of hysterectomy and oophorectomy. Self-reported sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). A higher global PSQI score indicates poorer self-reported sleep quality, and a global PSQI score greater than 5 differentiates poor sleepers from good sleepers. ResultsOf the 1,088 women recruited, 353 (32.4%) were in postmenopause status. Postmenopausal women had higher mean (SD) global PSQI scores (8.0 [3.3] vs 6.1 [2.2], P < 0.001) and a greater prevalence of poor sleepers (73.1% vs 60.8%, P < 0.001) compared with premenopausal women. Multivariate linear regression analysis showed that menopause (&bgr; = 1.532; 95% CI, 1.135 to 1.949; P < 0.001) and snoring (&bgr; = 0.764; 95% CI, 0.299 to 1.228; P = 0.001) were positively associated with global PSQI scores, whereas long sleep duration (&bgr; = −0.791; 95% CI, −1.113 to −0.468; P < 0.001) was negatively associated with global PSQI scores. Multivariate logistic regression analyses showed that menopause (odds ratio, 1.453; 95% CI, 1.030 to 2.051; P < 0.05), long sleep duration (odds ratio, 0.545; 95% CI, 0.418 to 0.710; P < 0.001), and snoring (odds ratio, 2.022; 95% CI, 1.312 to 3.116; P = 0.001) were independent predictors of poor sleepers. ConclusionsPostmenopausal women without vasomotor symptoms have significantly higher global PSQI scores and a higher risk of being poor sleepers than premenopausal women. In addition, menopause and snoring are associated with an increased risk of poor self-reported sleep quality independently of cardiometabolic factors and lifestyle, whereas long sleep duration is associated with a decreased risk of poor self-reported sleep quality.

A novel hepatokine, HFREP1, plays a crucial role in the development of insulin resistance and type 2 diabetes

Aims/hypothesisType 2 diabetes is highly correlated with nonalcoholic fatty liver disease (NAFLD). Hepatocyte-derived fibrinogen-related protein 1 (HFREP1) is a hepatokine that mediates NAFLD development; however, the role of HFREP1 in the development of insulin resistance and diabetes remains obscure.MethodsA total of 193 age- and sex-matched participants with normal glucose tolerance, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and newly diagnosed diabetes (NDD) were recruited for a cross-sectional study. Plasma HFREP1 levels were measured and multivariate linear regression analysis was used to evaluate the relationship between HFREP1, IFG, IGT and NDD. The causal relationship between HFREP1 and insulin resistance was then investigated in animal and cell models. Glucose and insulin tolerance tests, and euglycaemic–hyperinsulinaemic clamp, were used to evaluate insulin sensitivity in animals with Hfrep1 overexpression or knockdown in liver by lentiviral vectors. HepG2 cells were used to clarify the possible mechanism of HFREP1-induced insulin resistance.ResultsPlasma HFREP1 concentrations were significantly increased in participants with IFG, IGT and NDD. HFREP1 concentrations were independently associated with fasting plasma glucose levels, insulin resistance, IFG, IGT and NDD. Injection of recombinant HFREP1 or Hfrep1 overexpression induced insulin resistance in mice, and HFREP1 disrupted insulin signalling to induce insulin resistance through an extracellular signal-regulated kinase (ERK)1/2-dependent pathway. Moreover, hepatic knockdown of HFREP1 improved insulin resistance in both mice fed a high-fat diet and ob/ob mice.Conclusions/interpretationThese findings highlight the crucial role of HFREP1 in insulin resistance and diabetes, and provide a potential strategy and biomarker for developing therapeutic approaches to combat these diseases.

In vivo and in vitro anti-tumor effects of fungal extracts

Fungal extracts are extensively used as nutritional supplements in Far-Eastern Asia. In this study, we aimed to evaluate the anti-cancer activities of some different fungal species against different cancer cell lines. The water or ethanol extracts of Fomitopsis pinicola (F. pinicola), Ganoderma sinense, Fomitopsis officinalis, Polyporus melanopus, and Taiwanofungus camphorates were used to evaluate the anti-cancer activities in various cancer cells. We found that all of the fungi ethanol extracts used in this study exert anti-cancer activities in vitro, whereas water extracts show lower inhibitory activities as determined by 3-(4,5-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Among the tested fungi species, F. pinicola ethanol extract exerts the most significant anti-cancer activity (growth inhibitory ratio 82.8%, p < 0.001) by increasing cell apoptosis. Moreover, F. pinicola ethanol extract significantly decreased tumor size (tumor growth inhibitory ratio 54%, p < 0.05) and increased the lifespan in mice bearing sarcoma-180 tumors. Taken together, this is the first study indicating the anti-tumor effect of F. pinicola in vivo and in vitro. F. pinicola ethanol extract induces cell apoptosis to exert a significant anti-tumor activity, with potential to be a new alternative anti-tumor medicine.

Increased cardiotrophin-1 in subjects with impaired glucose tolerance and newly diagnosed diabetes

a Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan b Department of Family Medicine, National Cheng Kung University Hospital, Tainan, Taiwan c College of Medicine, National Cheng Kung University, Tainan, Taiwan d Research Center of Herbal Medicine, New Drugs, and Nutritional Supplements, National Cheng Kung University, Taiwan