High-fat diet-induced increases in glucocorticoids contribute to the development of non-alcoholic fatty liver disease in mice.

This study aimed to investigate the causal relationship between chronic ingestion of a high-fat diet (HFD)-induced secretion of glucocorticoids (GCs) and the development of non-alcoholic fatty liver disease (NAFLD). We have produced a strain of transgenic mice (termed L/L mice) that have normal levels of circulating corticosterone (CORT), the major type of GCs in rodents, but unlike wild-type (WT) mice, their circulating CORT was not affected by HFD. Compared to WT mice, 12-week HFD-induced fatty liver was less pronounced with higher plasma levels of triglycerides in L/L mice. These changes were reversed by CORT supplement to L/L mice. By analyzing a sort of lipid metabolism-related proteins, we found that expressions of the hepatic cluster of differentiation 36 (CD36) were upregulated by HFD-induced CORT and involved in CORT-mediated fatty liver. Dexamethasone, an agonist of the glucocorticoid receptor (GR), upregulated expressions of CD36 in HepG2 hepatocytes and facilitated lipid accumulation in the cells. In conclusion, the fat ingestion-induced release of CORT contributes to NAFLD. This study highlights the pathogenic role of CORT-mediated upregulation of hepatic CD 36 in diet-induced NAFLD.

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

AIMS/HYPOTHESIS: Type 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. METHODS: A 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. RESULTS: Plasma 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/INTERPRETATION: These 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.

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-3ß 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 & AIMS: While 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. METHODS: A 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. RESULTS: Subjects 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. CONCLUSIONS: The present study provides evidence that HPS plays an important role in NAFLD and induces hepatic lipid accumulation through an ERK1/2-dependent pathway.

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

OBJECTIVE: 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. METHODS: Subjects were recruited from the Prevention Health Center of National Cheng Kung University Hospital. Anthropometric data and metabolic parameters were measured. The diagnoses of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and diabetes followed the recommendations of the American Diabetes Association. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: A total of 1805 subjects with normal glucose tolerance (NGT, n = 1217), IFG (n = 118), IGT (n = 287), IFG+IGT (n = 80) and newly diagnosed diabetes (NDD, n = 103) were recruited. The global PSQI scores were 6·07 ± 2·44, 6·74 ± 3·23, 6·91 ± 3·51, 6·74 ± 2·26 and 7·16 ± 3·49 in subjects with NGT, IFG, IGT, IFG+IGT and NDD, respectively. Multivariate linear regression analysis showed that female gender, smoking, IGT, IFG+IGT and NDD, but not IFG, were independent determinants of global PSQI score. Multivariate logistic regression analysis showed that female gender, IGT, IFG+IGT and NDD, but not IFG, were predictors of poor sleepers. CONCLUSIONS: Subjects with prediabetes and NDD had a significantly higher global PSQI score than those with NGT. Furthermore, female gender, smoking, IGT, IFG+IGT and NDD, but not IFG, were significantly associated with poor sleep quality independent of cardiometabolic risk factors in a Chinese population.

Growth differentiation factor-15 is independently associated with metabolic syndrome and hyperglycemia in non-elderly subjects.

Metabolic syndrome (MetS) is a major health issue worldwide accompanied by cardiovascular comorbidities. Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine expressed in cardiomyocytes, adipocytes, macrophages, and endothelial cells. Previous research in elderly subjects revealed that GDF-15 levels were associated with the MetS. However, the association between GDF-15 levels and MetS or its components in the non-elderly subjects remains unclear. In this study, a total of 279 subjects younger than 65-year-old with (n = 84) or without (n = 195) MetS were recruited. MetS was defined according to modified NCEP/ATP III criteria. The GDF-15 levels were measured by an enzyme-linked immunosorbent assay. A multiple linear regression analysis was conducted to identify factors independently associated with GDF-15 levels. Subjects with MetS had higher GDF-15 levels than those without MetS (median (interquartile range), 1.72 ng/mL (1.38, 2.26) vs. 1.63 ng/mL (1.27, 2.07), P = 0.037). With the number of MetS components increased, the GDF-15 levels increased significantly (P for trend = 0.005). Multiple linear regression analysis revealed that the presence of MetS was positively associated with the GDF-15 levels (ß = 0.132, P = 0.037). When substituting MetS with its components, only the presence of hyperglycemia was positively associated with the GDF-15 levels after adjustment for covariates (ß = 0.193, P = 0.003). Taken together, the presence of the MetS in non-elderly was associated with higher GDF-15 levels. Among the MetS components, only hyperglycemia was significantly associated with the GDF-15 levels. Future longitudinal studies will be needed to explore whether GDF-15 has the potential to be a biomarker of gluco-metabolic dysfunction in non-elderly subjects.

Dietary fatty acids differentially affect secretion of pro-inflammatory cytokines in human THP-1 monocytes.

Monocytes are a major population of circulating immune cells that play a crucial role in producing pro-inflammatory cytokines in the body. The actions of monocytes are known to be influenced by the combinations and concentrations of certain fatty acids (FAs) in blood and dietary fats. However, systemic comparisons of the effects of FAs on cytokine secretion by monocytes have not be performed. In this study, we compared how six saturated FAs (SFAs), two monounsaturated FAs (MUFAs), and seven polyunsaturated FAs (PUFAs) modulate human THP-1 monocyte secretion of TNF, IL-1ß, and IL-6 in the absence or presence of lipopolysaccharide. SFAs generally stimulated resting THP-1 cells to secrete pro-inflammatory cytokines, with stearic acid being the most potent species. In contrast, MUFAs and PUFAs inhibited lipopolysaccharide-induced secretion of pro-inflammatory cytokines. Interestingly, the inhibitory potentials of MUFAs and PUFAs followed U-shaped (TNF and IL-1ß) or inverted U-shaped (IL-6) dose-response curves. Among the MUFAs and PUFAs that were analyzed, docosahexaenoic acid (C22:6 n-3) exhibited the largest number of double bonds and was found to be the most potent anti-inflammatory compound. Together, our findings reveal that the chemical compositions and concentrations of dietary FAs are key factors in the intricate regulation of monocyte-mediated inflammation.

A randomized trial on the effect of transcutaneous electrical nerve stimulator on glycemic control in patients with type 2 diabetes.

Transcutaneous electrical nerve stimulator (TENS) has been demonstrated to be beneficial in glycemic control in animal models, but its application in humans has not been well studied. We randomly assigned 160 patients with type 2 diabetes on oral antidiabetic drugs 1:1 to the TENS study device (n = 81) and placebo (n = 79). 147 (92%) randomized participants (mean [SD] age 59 [10] years, 92 men [58%], mean [SD] baseline HbA1c level 8.1% [0.6%]) completed the trial. At week 20, HbA1c decreased from 8.1% to 7.9% in the TENS group (- 0.2% [95% CI - 0.4% to - 0.1%]) and from 8.1% to 7.8% in the placebo group (- 0.3% [95% CI - 0.5% to - 0.2%]) (P = 0.821). Glycemic variability, measured as mean amplitude of glycemic excursion (MAGE) at week 20 were significantly different in the TENS group vs. the placebo group (66 mg/dL [95% CI 58, 73] vs. 79 mg/dL [95% CI 72, 87]) (P = 0.009). Our study provides the clinical evidence for the first time in humans that TENS does not demonstrate a statistically significant HbA1c reduction. However, it is a safe complementary therapy to improve MAGE in patients with type 2 diabetes.

High glucose enhances lipopolysaccharide-induced inflammation in cultured BV2 microglial cell line.

INTRODUCTION: Diabetes mellitus emerges as a global health crisis and is related to the development of neurodegenerative diseases. Microglia, a population of macrophages-like cells, govern immune defense in the central nervous system. Activated microglia are known to play active roles in the pathogenesis of neurodegenerative diseases. METHODS: This study aimed to investigate the effects of high glucose on low-dose lipopolysaccharide (LPS)-induced activations of inflammation-related signaling molecules in cultured BV2 microglial cells. RESULTS: Compared to cells cultured in the normal glucose medium (NGM, 5.5 mM), the LPS-induced activation of NF-κB lasted longer in cells cultured in high glucose medium (HGM, 25 mM). HGM also enhanced the expression of inducible nitric oxide synthase (iNOS). Among the mitogen-activated protein kinases, HGM enhanced the LPS-induced phosphorylation of p38 without affecting the phosphorylation of Erk1/2 or JNK. BV2 cells cultured in HGM expressed higher levels of TLR4 than those cells cultured in NGM. CONCLUSION: High glucose aggravated LPS-induced inflammatory responses of microglia via enhancing the TLR4/p38 pathway and prolonging the activation of NF-κB/iNOS signaling. Controlling blood glucose levels is advised to manage neuroinflammation and related neurodegenerative diseases.

Associations between GDF15 levels and pre-diabetes in non-obese subjects.

Growth differentiation factor 15 (GDF15) is a stress-response cytokine which belongs to the transforming growth factor ß superfamily. Although GDF15 was initially found to have a role in metabolic diseases, the association between GDF15 and dysglycemic status remains inconclusive. Thus, the aim of this study was to examine the relationships between GDF15 and different glycemic statuses in non-obese subjects. We enrolled 502 non-obese subjects, among individuals who had normal glucose tolerance (NGT; n=125), isolated impaired fasting glucose (IFG; n=116), isolated impaired glucose tolerance (IGT; n=106), IFG plus IGT (n=27), and newly diagnosed diabetes (NDD; n=128). A multivariate linear regression analysis of GDF15 levels was used to find independent predictors. The median (IQR) GDF15 levels were 1641.0 (1187.0-1985.5) pg/mL, 1656.1 (1226.8-2379.7) pg/mL, 1487.8 (1145.9-1987.2) pg/mL, 1722.2 (1172.9-1939.0) pg/mL, and 2204.5 (1767.4-2919.1) pg/mL in NGT, IFG, IGT, IFG plus IGT, and NDD groups, respectively. The NDD group had significantly higher GDF15 levels than those with NGT, IFG, IGT, and IFG plus IGT. The IFG group had a significantly higher GDF15 value than the NGT group. In multivariate linear regression analysis, IFG (beta=0.145, 95% CI 192.487 to 740.937, p=0.001), NDD (beta=0.227, 95% CI 390.459 to 888.145, p<0.001), and high-sensitivity C reactive protein (beta=0.105, 95% CI 3.276 to 27.768, p=0.013) were independently associated with GDF15 levels. Non-obese subjects with isolated IFG and NDD had significantly higher GDF15 levels than those with NGT. In addition, A1C was independently associated with GDF15 levels. IFG and NDD, but not isolated IGT or IFG plus IGT, were positively associated with GDF15 levels.

Real-World Comparative Evaluation of Add-On Glucagon-like Peptide 1 Receptor Agonist in Type 2 Diabetes Treated with or without Insulin.

Glucagon-like peptide 1 receptor agonist (GLP-1 RA) is a potent antidiabetic agent with cardiorenal and weight-losing benefits in patients with type 2 diabetes (T2D). The combination of GLP-1 RA with basal insulin has been suggested in several clinical studies as a useful treatment for intensifying insulin therapy in T2D. However, there has been no real-world evidence study comparing the glycemic effects of GLP-1 RAs add-on to background treatment with and without insulin. A retrospective study was performed in 358 patients with T2D who initiated liraglutide or dulaglutide. Among them, 147 patients were prior and concurrent insulin users, and 211 patients were non-insulin users. After 12 months of GLP-1 RA treatment, the changes in hemoglobin A1c (HbA1C) and body weight were evaluated. The effectiveness of GLP-1 RAs on HbA1C reduction was greater in insulin users than non-insulin users at 12 months (−1.17% vs. −0.76%; p = 0.018). There was no significant difference in body weight change between insulin users and non-insulin users at 12 months (−1.42 kg vs. −1.87 kg; p = 0.287). The proportion of responders (decrease of HbA1C > 1%) in insulin users was much higher than that in non-insulin users (48% vs. 37 %; p = 0.04). In insulin users, those who had increased insulin dosage at 12 months had significantly less HbA1C reduction than that of non-increased patients (−0.62% vs. −1.57%; p = 0.001). GLP-1 RAs provide superior glucose-lowering effects in insulin-treated patients compared with non-insulin-treated patients with T2D without significant differences in body weight decrease.

The Serum Concentrations of Hedgehog-Interacting Protein, a Novel Biomarker, Were Decreased in Overweight or Obese Subjects.

Although it was known that obesity is an independent risk factor for metabolic disorders including diabetes, the factors that link these diseases were obscure. The Hedgehog-interacting protein (Hhip) is a negative regulator in tissue remodeling, and inhibits the proliferation of adipocytes, and promotes their differentiation. In addition, Hhip was positively associated with diabetes. However, the relationship between Hhip and obesity in the human body remains unclear. An analysis of the relationship between Hhip and normal weight, overweight, and obesity levels. Participants receiving a physical checkup were recruited. Anthropometric and biochemical data were collected. Serum Hhip levels were determined by enzyme-linked immunosorbent assay (ELISA). Subjects were classified into normal-weight, overweight, and obese groups based on their body mass index (BMI). The association between Hhip and obesity was examined by multivariate linear regression analysis. In total, 294 subjects who were either of a normal weight (n = 166), overweight (n = 90), or obese (n = 38) were enrolled. Hhip concentrations were 6.51 ± 4.86 ng/mL, 5.79 ± 4.33 ng/mL, and 3.97 ± 3.4 ng/mL in normal-weight, overweight, and obese groups, respectively (p for trend = 0.032). Moreover, the regression analysis showed that BMI (ß = -0.144, 95% confidence interval (CI) = -0.397-0.046, p = 0.013) was negatively associated with Hhip concentrations after adjusting for sex and age. Being overweight (ß = -0.181, 95% CI = -3.311-0.400, p = 0.013) and obese (ß = -0.311, 95% CI = -6.393-2.384, p < 0.001) were independently associated with Hhip concentrations after adjusting for sex, age, fasting plasma glucose, the insulin level, and other cardiometabolic risk factors. Our results showed that overweight and obese subjects had lower Hhip concentrations than those of normal weight. Being overweight and obese were negatively associated with Hhip concentrations. Hhip might be a link between obesity and diabetes.

Amiodarone-induced thyrotoxicosis in a patient with autonomously functioning nodular goiter.

OBJECTIVE: To report on adverse reactions associated with amiodarone and propylthiouracil. CASE SUMMARY: A 64-year-old female with atrial fibrillation and nodular goiter progressed to overt thyrotoxicosis after receiving therapy with amiodarone 200 mg/day for less than 12 weeks. Thyroid scan revealed a hyperfunctioning nodule in the left lobe, while immunologic studies were negative for both thyroid peroxidase and thyroglobulin antibodies. The thyroid-stimulating hormone (TSH) receptor antibody level was transiently elevated. Propylthiouracil 100 mg 3 times/day was started after the withdrawal of amiodarone, but the patient developed severe generalized skin rash, fever, and leukocytosis after 4 weeks. Thyroidectomy was performed, and histopathology was compatible with type 1 amiodarone-induced thyrotoxicosis (AIT) associated with toxic nodular goiter. An objective causality assessment revealed that thyrotoxicosis was probably related to use of amiodarone. DISCUSSION: Amiodarone is an antiarrhythmic agent that may cause thyroid dysfunction. Differentiating between the 2 types of AIT is important for implementation of the correct therapeutic strategy. The transient elevation of TSH receptor antibodies in AIT complicated the diagnosis. As a rare subtype, type 1 AIT by nodular goiter may be associated with early AIT. Initiating thyroid function monitoring within 3 months of amiodarone therapy should be considered. CONCLUSIONS: Type 1 AIT caused by nodular goiter is rarely reported. Amiodarone should be avoided in such patients and subtotal thyroidectomy to remove the toxic nodule may be the treatment of choice.

Serum Secretogranin III Concentrations Were Increased in Subjects with Metabolic Syndrome and Independently Associated with Fasting Plasma Glucose Levels.

Secretogranin III (SCG3) plays a crucial role in the biogenesis of secretory granules in endocrine cells, and thus affects glucose homeostasis by regulating insulin secretion by pancreatic beta cells. Insulin resistance and compensatory hyperinsulinemia are hallmarks of metabolic syndrome (MetS). However, the role of SCG3 in MetS remains unclear. Therefore, we investigated the relationship between serum SCG3 levels and metabolic parameters in subjects with and without MetS. This was a case control study, and 295 subjects were recruited. Serum SCG3 concentrations were compared between groups. Associations between SCG3 levels and clinico-metabolic parameters were also examined. We found serum SCG3 levels were higher in the MetS group than non-MetS group (122.6 ± 79.2 vs. 90.6 ± 58.5 nmol/L, p = 0.009). Specifically, elevated SCG3 levels were found in subjects with high fasting plasma glucose (FPG) levels, central obesity, or hypertriglyceridemia. Additionally, MetS was an independent factor of serum SCG3 levels in multivariate linear regression analyses. Moreover, FPG, free fatty acids, and waist circumference were positively associated with serum SCG3 concentrations after adjusting for insulin levels, high-sensitivity C-reactive protein, and cardiovascular risk factors. In conclusion, serum SCG3 concentrations were higher in subjects with MetS and were independently associated with FPG levels.

Elevated Hedgehog-Interacting Protein Levels in Subjects with Prediabetes and Type 2 Diabetes.

BACKGROUND: The prevalence of diabetes is rapidly increasing worldwide and is highly associated with the incidence of cancers. In order to prevent diabetes, early diagnosis of prediabetes is important. However, biomarkers for prediabetes diagnosis are still scarce. The hedgehog-interacting protein (Hhip) is important in embryogenesis and is known to be a biomarker of several cancers. However, Hhip levels in subjects with diabetes are still unknown. METHODS: In total, 314 participants were enrolled and divided into normal glucose tolerance (NGT; n = 75), impaired fasting glucose (IFG; n = 66), impaired glucose tolerance (IGT; n = 86), and newly diagnosed diabetes (NDD; n = 87) groups. Plasma Hhip levels were determined by an ELISA. The association between the Hhip and the presence of diabetes was examined by a multivariate linear regression analysis. RESULTS: There were significant differences in the body mass index, systolic and diastolic blood pressure, fasting plasma glucose (FPG), post-load 2-h glucose, hemoglobin A1c (A1C), C-reactive protein, total cholesterol, triglyceride, and high- and low-density lipoprotein cholesterol levels among the groups. Concentrations of the Hhip were 2.45 ± 2.12, 4.40 ± 3.22, 4.44 ± 3.64, and 6.31 ± 5.35 ng/mL in subjects in the NGT, IFG, IGT, and NDD groups, respectively. In addition, we found that A1C and FPG were independently associated with Hhip concentrations. Using NGT as a reference group, IFG, IGT, and NDD were all independently associated with Hhip concentrations. CONCLUSIONS: Hhip was positively associated with prediabetes and type 2 diabetes mellitus.

Helicobacter pylori eradication improves glycemic control in type 2 diabetes patients with asymptomatic active Helicobacter pylori infection.

AIMS/INTRODUCTION: Helicobacter pylori infection is associated with insulin resistance and glycemia in non-diabetes. However, the relationship between H. pylori infection and glycemia in diabetes remains inconclusive. Therefore, we explored the effect of H. pylori infection status and its eradication on glycemic control and antidiabetic therapy in type 2 diabetes patients. MATERIALS AND METHODS: A total of 549 diabetes patients were recruited for sequential two-step approach (immunoglobulin G [IgG] serology followed by 13 C-urea breath test [UBT]) to discriminate "active" (IgG+ and UBT+) from "non-active" (UBT- or IgG-) H. pylori infection, and "past" (IgG+ but UBT-) from "never/remote" (IgG-) infection. The differences in hemoglobin A1c (A1C) and antidiabetic regimens between groups were compared. In the "active" infection group, the differences in A1C changes between participants with and without 10-day eradication therapy were compared after 3 months. RESULTS: Despite no between-group difference in A1C, the "active" infection group (n = 208) had significantly more prescriptions of oral antidiabetic drug classes (2.1 ± 1.1 vs 1.8 ± 1.1, P = 0.004) and higher percentages of sulfonylurea use (67.3% vs 50.4%, P < 0.001) than the "non-active" infection group (n = 341). There were no differences in A1C and oral antidiabetic drug classes between "past" (n = 111) and "never/remote" infection groups (n = 230). Compared with the non-eradication group (n = 99), the eradication group (n = 98) had significant within-group (-0.17 ± 0.80%, P = 0.036) and between-group (-0.23 ± 0.10%, P = 0.024) improvements in A1C. CONCLUSIONS: Diabetes patients with active H. pylori infection need higher glycemic treatment intensity to achieve comparable glycemia. Furthermore, H. pylori eradication decreases A1C, and thus improves glycemic control.

Tumor-associated Hypercalcemia in a patient with Paget's disease.

Paget's disease of the bone, which is characterized by a focal region of highly exaggerated bone remodeling, is very rare in Asia. Most patients with Paget's disease are asymptomatic; they are normocalcemic and show elevated alkaline phosphatase levels. Hypercalcemia in patients with Paget's disease has rarely been reported. We report one Chinese patient with Paget's disease involving the maxilla bone with an initial presentation of facial cellulitis. Asymptomatic hypercalcemia with a low-normal intact parathyroid hormone level developed 9 years later. After clodronate treatment, the level of alkaline phosphatase normalized, but the hypercalcemia did not respond adequately. After analysis of tumor markers and imaging studies, a clinical diagnosis of pancreatic adenocarcinoma with multiple hepatic and lung metastases with pleural effusion was made. We suggest that malignancy-associated hypercalcemia should be considered as one of the causes of hypercalcemia in patients with Paget's disease.

Unsaturated Fatty Acids Increase the Expression of Hepassocin through a Signal Transducer and Activator of Transcription 3-Dependent Pathway in HepG2 Cells.

Hepassocin (HPS) is a hepatokine that regulates hepatocyte proliferation. It is known that HPS plays an important role in the development of nonalcoholic fatty liver diseases (NAFLD). Fatty acids, such as oleic acid (OLA), exhibit the ability to activate the signal transducer and activator of transcription-3 (STAT3), and the binding site of STAT3 is found in the promoter region of HPS. However, the regulation of HPS by fatty acids is still obscure. To clarify the regulation of HPS, we detected the expression of HPS by western blots. In addition, a hepatic steatosis cell culture model was established by treatment of different fatty acids, including linoleic acid (LNA), oleic acid, palmitic acid, and stearic acid. The intracellular lipid accumulation was confirmed by oil red O staining. Blocking of STAT3 activity was achieved by the pretreatment of the STAT3 inhibitor, stattic. We found that activation of STAT3 by interleukin-6 (IL-6) was mediated in the regulation of HPS expression. Treatment of unsaturated fatty acids significantly induced intracellular lipid accumulation in HepG2 cells. Moreover, the expressions of HPS were increased in unsaturated fatty acid-treated HepG2 cells, as compared with saturated fatty acid-treated groups. Also, the expression of HPS induced by OLA was blocked by the inhibition of STAT3 activity. Furthermore, we found that deletion of HPS by small interfering ribonucleic acid transfection decreased the protective effect of OLA on cell viability. Taken together, we provided evidence that STAT3 plays an important role in the regulation of OLA-induced HPS expression and the increased HPS may further participate in the development of NAFLD. In addition, the increase of HPS might be involved in the protective effect of OLA on cell viability.