The Involvement of GAS6 Signaling in the Development of Obesity and Associated Inflammation.

Growth arrest-specific 6 (GAS6), a vitamin K-dependent protein, plays a role in the survival, proliferation, migration, differentiation, adhesion, and apoptosis of cells. GAS6 is highly expressed during growth arrest, followed by a sharp decrease during differentiation in adipocytes. The functions of GAS6 signaling are limited to TAM (Tyro3, Axl, and Mer) receptors and are dependent on the cell type. While many studies have focused on the role of GAS6 in inflammation and cancer, only few studies focused on its roles of GAS6 in obesity. Accordingly, the participation of GAS6 in the progression of obesity remains controversial. In this review, we summarize the results of current studies from clinical and basic research to elucidate the possible role of GAS6 signaling in obesity and associated disorders. In addition, this summary may offer a direction to develop clinical therapeutic strategies for the prevention and treatment of obesity and related complications.

Cilostazol attenuates the severity of peripheral arterial occlusive disease in patients with type 2 diabetes: the role of plasma soluble receptor for advanced glycation end-products.

Recent studies have demonstrated that the plasma soluble receptor for advanced glycation end-products (sRAGE) play a major role in developing macrovascular complications of type 2 diabetes, including peripheral arterial occlusion disease (PAOD). Cilostazol is an antiplatelet, antithrombotic agent, which has been used for the treatment of PAOD. We hypothesized that cilostazol attenuates the severity of PAOD in patients with type 2 diabetes through the augmentation of plasma sRAGE. Ninety type 2 diabetic patients with PAOD defined as intermittent claudication with ankle-brachial index (ABI) ≦0.9 were recruited for an open-labeled, placebo-controlled study for 52 weeks with oral cilostazol 100 mg twice daily (n = 45) or placebo (n = 45). Fasting plasma sRAGE, endothelial variables of E-selectin, soluble vascular cell adhesion molecule-1 (sVCAM-1), and inflammatory markers of high-sensitivity C-reactive protein (hsCRP) and tumor necrosis factor-α (TNF-α) were determined. After completely the 52-week treatment program, the ABI values were elevated in cilostazol group (P < 0.001). The plasma sRAGE was significantly increased (P = 0.007), and hsCRP, sVCAM, and E-selectin concentrations were significantly decreased (P = 0.028, <0.001 and <0.001, respectively) with cilostazol treatment. In a partial correlation analysis with adjustments for sex and age, the net change of sRAGE significantly correlated with the change of ABI in the cilostazol group (P = 0.043). In a stepwise multiple regression model, only the change with regards to sRAGE was significantly associated with the change of ABI (P = 0.046). Our results suggest that cilostazol may effectively attenuate the severity of PAOD in patients with type 2 diabetes. Plasma sRAGE plays a role as an independent predictor for improving the index of PAOD.

Gender differences in plasma growth arrest-specific protein 6 levels in adult subjects.

BACKGROUND: Growth-arrest-specific 6 (Gas6) is recognized as a secreted vitamin K-dependent protein, as it interacts with receptor tyrosine kinases of the TAM (Tyro-3, Axl, Mer) family. The plasma Gas6 are important to the inflammatory process, and are involved in diverse human diseases. Few studies have shown plasma Gas6 concentration varies with genders. We determined whether plasma Gas6 concentrations are associated with sex hormones in both genders. METHODS: A total of 589 adult subjects, including 361 male and 228 female were recruited. Plasma Gas6 concentration, biochemical, testosterone, estradiol (E2), and sex hormone-binding globulin were assayed. The indices of free androgen (FAI) and free E2 (FEI) were calculated. RESULTS: Significantly higher Gas6 concentrations were observed in adult male rather than female (P<0.05). In univariate regression analysis, plasma Gas6 concentrations were positively associated with FAI in male (ß=0.167, P=0.002) and both E2 and FEI in female (ß=0.384, P<0.001 andß=0.292, P<0.001, respectively). Otherwise, Gas6 concentrations were inversely associated with ages in both genders (ß=-0.234, P<0.001 in male and ß=-0.226, P=0.001 in female, respectively). In multivariate regression analysis, only age in male and E2 in female were independent variables to determine the plasma Gas6 concentrations (ß=-0.231, P=0.002 and ß=0.458, P=0.001). CONCLUSIONS: Plasma Gas6 is associated with sex hormones in female and ages in male, indicating a potential role of sex hormones and ages involving the Gas6/TAM system.

Platelet count can predict metabolic syndrome in older women.

Platelet count (PC) has been found to be related to the metabolic syndrome (MetS). However, the role of PC on MetS remained unclear. In order to evaluate the relationship between PC and MetS components cross-sectionally and determine the optimal cutoff PCs for predicting the subsequent risk of MetS development with sex specificity, two stages included cross-sectional (stage 1) and prospective (stage 2) cohort study were conducted. Stage 1 involved 10 579 subjects aged ≥60 years, of which 7718 subjects advanced to stage 2 with a mean 3.8 year follow-up were enrolled. The MetS components and PC were determined. The PC cutoffs for higher chances of developing MetS in stage 1 were calculated using receiver operating characteristic (ROC) curve analyses. In stage 2, non-MetS subjects were classified into high-PC (HPC) and low-PC (LPC) groups according to the cutoff values from stage 1. We examined the difference of future MetS incidence and calculated the odds ratio (OR) between these two groups. In stage 1, multiple regression showed that age and triglyceride (both sexes) and waist circumstance and high-density lipoprotein cholesterol (only women) were independently correlated with PC. There was significant difference in the area under the ROC curve (AUC) only of HPC women, which exceeded the standard curve (AUC = 0.542, p < 0.001), with a cutoff PC of 223 × 10(3)/µl. HPC women had an OR of 1.287 (95% confidence interval: 1.135-1.461) of developing MetS after 3.8 years. The Kaplan-Meier curve demonstrated a higher incidence of MetS development in HPC women. In conclusion, our results suggest that PC was associated with MetS with sex effects. Most of the MetS components were independent factors for increasing PC, and the risk for subsequent development of MetS was noted when PC >223 × 10(3)/µl in elderly women.

Effect of GAS6 and AXL Gene Polymorphisms on Adiposity, Systemic Inflammation, and Insulin Resistance in Adolescents.

The present study was designed to explore the effects of GAS6 and AXL gene polymorphisms on adiposity, systemic inflammation, and insulin resistance in adolescents. After multistage sampling from the data of the Taipei Children Heart Study-III, we collected 358 boys and 369 girls with an average age of 13.3 years. We genotyped the adolescents' GAS6 rs8191973, GAS6 rs8191974, AXL rs4802113, and AXL rs2304232 polymorphisms. Significantly higher body mass index (BMI), waist circumference (WC), and hsCRP levels were found in boys with the GG genotype of GAS6 rs8191974 than A allele carriers; higher IL-6 and insulin levels and increased HOMA-IR were found in boys with the GG genotype of AXL rs2304232 than the A allele carriers. There was a significant difference in hsCRP levels of boys with the TT, TC, and CC genotypes of AXL rs4802113. Boys with both the GG genotype of GAS6 rs8191973 and the GG genotype of GAS6 rs8191974 exhibited higher BMI, WC, IL-6, and hsCRP levels than the boys carrying both the C allele of the GAS6 rs8191973 and the A allele of the GAS6 rs8191974. In conclusion, GAS6 and AXL polymorphisms are associated with adiposity, systemic inflammation, and insulin resistance in adolescents, especially in boys.

Plasma growth arrest-specific protein 6 levels in premenopausal and postmenopausal women: the role of endogenous estrogen.

Growth arrest-specific 6 (Gas6) is a vitamin K-dependent protein that interacts with receptor tyrosine kinases of the Tyro-3, AXL, Mer (TAM) family. The Gas6/TAM system contributes to the regulation of cell survival and proliferation, cell adhesion and migration, and inflammatory cytokines release. Plasma Gas6 plays an important role in the inflammatory process, and is involved in diverse human diseases. Few studies have investigated gender-specific variations in plasma Gas6 concentration. Hence, the aim of this study was to determine whether plasma Gas6 levels are associated with sex hormones in premenopausal and postmenopausal women. A total of 103 premenopausal and 135 postmenopausal women were recruited. Plasma Gas6 concentration, estradiol (E2), and sex hormone-binding globulin were assayed. The free estrogen index (FEI) was calculated. The results showed significantly lower Gas6 levels in the postmenopausal compared to the premenopausal women (P < 0.005). Plasma Gas6 levels were positively correlated with E2 levels in the pre- and postmenopausal women (r = 0.359, P < 0.001 and r = 0.261, P = 0.002, respectively). Gas6 levels were also correlated with FEI in the pre- and postmenopausal women (r = 0.234, P = 0.017 and r = 0.188, P = 0.029, respectively). After adjusting for confounders, the correlations still remained significant. In multiple stepwise regression analysis, only E2 in premenopausal and both age and E2 in postmenopausal women were independently correlated with the plasma Gas6 levels (all P < 0.001). These results suggest that plasma Gas6 is associated with sex hormones in both pre- and postmenopausal women, indicating a potential role of sex hormones in the Gas6/TAM system.

High glucose induces human endothelial dysfunction through an Axl-dependent mechanism.

BACKGROUND: The receptor tyrosine kinase Axl and its ligand growth arrest-specific protein 6 (Gas6) are involved in the diabetic vascular disease. The aim of this study was to explore the role of Gas6/Axl system in high glucose (HG)-induced endothelial dysfunction. METHODS: We investigated the effect of various glucose concentrations on Axl signaling in human microvascular endothelial cells (HMEC-1 s). RESULTS: Human plasma Gas6 value inversely correlated with glucose status, endothelial markers. HG decreased Gas6/Axl expression and increased intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression in HMEC-1 s. HG significantly decreased HMEC-1 s cell viability and tube formation and promoted monocyte-EC adhesion. Down-regulation of Akt phosphorylation was found in HG culture. Axl transfection significantly reversed HG-induced Akt phosphorylation, VCAM-1 expression and endothelial dysfunction. We also found additive changes in Axl-shRNA-infected HMEC-1 cells in HG culture. Furthermore, Axl overexpression in HMEC-1 s significantly reversed HG-induced vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) expression. In addition, significantly lower Axl and VEGFR2 expression in arteries were found in diabetic patients as compared with non-diabetic patients. CONCLUSIONS: This study demonstrates that HG can alter Gas6/Axl signaling and may through Akt and VEGF/VEGFR2 downstream molecules and suggests that Gas6/Axl may involve in HG-induced EC dysfunction.

The levels of plasma growth arrest-specific protein 6 is associated with insulin sensitivity and inflammation in women.

AIMS: Vitamin K-dependent growth arrest-specific protein 6 (Gas6) and its receptors of the TAM (TYRO-3/Axl/Mer) family are ubiquitously expressed in immune, cardiovascular, and reproductive systems. They play pivotal roles of regulating tissue homeostasis via anti-inflammatory effects. Recent studies show that the Gas6/TAM system is involved in glucose tolerance-related metabolic disorders. Our aim was to investigate the link between Gas6 protein, insulin sensitivity and inflammatory cytokines in men and women. METHODS: A total of 278 adults (126 men and 152 women) were recruited in this study. Plasma Gas6 concentration and various biochemical, proinflammatory and endothelial markers were measured. Insulin sensitivity was estimated by homeostasis model assessment. RESULTS: Waist, fasting and 2h post-load glucose, and glycated hemoglobin (HbA1C) were significantly lower in women than in men. Age, high-density lipoprotein cholesterol, and highly-sensitive C-reactive protein levels were significantly higher in women than in men. Plasma Gas6 levels were negatively correlated with waist (r = -0.187, P = 0.022), HOMA-IR (r = -0.171, P=0.035), interleukin 6 (r = -0.362, P < 0.001), and E-selectin (r = -0.216, P = 0.008), while they were positively correlated with insulin sensitivity (QUICKI) (r = 0.168, P = 0.039) in women, but not in men. Stepwise multiple regression analysis showed that TNF-α was independently correlated with plasma Gas6 levels in both the sexes (P < 0.001). CONCLUSION: Plasma Gas6 is associated with obesity, insulin sensitivity, inflammation, and endothelial dysfunction in women and may be a general marker of inflammatory conditions in women.

Thrombomodulin domain 1 ameliorates diabetic nephropathy in mice via anti-NF-κB/NLRP3 inflammasome-mediated inflammation, enhancement of NRF2 antioxidant activity and inhibition of apoptosis.

AIMS/HYPOTHESIS: Chronic inflammatory processes have been increasingly shown to be involved in the pathogenesis of diabetes and diabetic nephropathy. Recently, we demonstrated that a lectin-like domain of thrombomodulin (THBD), which is known as THBD domain 1 (THBDD1) and which acts independently of protein C activation, neutralised an inflammatory response in a mouse model of sepsis. Here, therapeutic effects of gene therapy with adeno-associated virus (AAV)-carried THBDD1 (AAV-THBDD1) were tested in a mouse model of type 2 diabetic nephropathy. METHODS: To assess the therapeutic potential of THBDD1 and the mechanisms involved, we delivered AAV-THBDD1 (10(11) genome copies) into db/db mice and tested the effects of recombinant THBDD1 on conditionally immortalised podocytes. RESULTS: A single dose of AAV-THBDD1 improved albuminuria, renal interstitial inflammation and glomerular sclerosis, as well as renal function in db/db mice. These effects were closely associated with: (1) inhibited activation of the nuclear factor κB (NF-κB) pathway and the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome; (2) promotion of nuclear factor (erythroid-derived 2)-like 2 (NRF2) nuclear translocation; and (3) suppression of mitochondria-derived apoptosis in the kidney of treated mice. CONCLUSIONS/INTERPRETATION: AAV-THBDD1 gene therapy resulted in improvements in a model of diabetic nephropathy by suppressing the NF-κB-NLRP3 inflammasome-mediated inflammatory process, enhancing the NRF2 antioxidant pathway and inhibiting apoptosis in the kidney.

The adipokines and inflammatory marker in young type 2 diabetics with metabolic syndrome: A pilot study.

OBJECTIVE: The purpose of the metabolic syndrome (MetS) concept was to early identify subjects having risk for developing cardiovascular diseases and diabetes, which of both are involved in low grade inflammation and obesity. We wish to explore the role of adipokines and inflammatory marker in young type 2 diabetics (YDM) with MetS. METHODS: Forty-eight YDM patients were divided to 2 and 3 groups according to the presence of the MetS (MetS+ and MetS-), and the numbers of MetS component (MetS-2 to MetS-4 with 1-2, 3, and 4-5 components) respectively. Plasma adipokines (tumor necrosis factor-α; TNF-α and adiponectin) and C-reactive protein (CRP) were measured and compared among groups. RESULTS: Blood pressure (BP), body mass index (BMI), and plasma triglyceride (TG) levels were higher in the group with MetS+ than that of MetS-. Except for diastolic BP, BMI, waist, and plasma TG levels, which were generally lower in the MetS-2 group, the rest demographic characteristics were not different among these three groups. Finally, the plasma adiponectin, CRP and TNF-αlevels were not different between both groups with or without MetS; and also among these three groups regardless the component numbers they had. CONCLUSION: YDM with MetS might have non-significant lower adiponectin and higher CRP levels compared to subjects without MetS. It needs prospective study with larger scale to explicit the role of cytokines and inflammatory markers in YDM with MetS.

Circulating growth arrest-specific 6 protein is associated with adiposity, systemic inflammation, and insulin resistance among overweight and obese adolescents.

CONTEXT: Growth arrest-specific 6 (Gas6) is a vitamin K-dependent protein secreted by immune cells, endothelial cells, vascular smooth muscle cells, and adipocytes. Preclinical studies indicate that Gas6 and its receptors of the TAM (Tyro-3, Axl, Mer) family may be involved in the pathogenesis of obesity and its complications, including systemic inflammation and insulin resistance. Until now, little has been known about the clinical significance of the Gas6/TAM system in childhood obesity. OBJECTIVES: This study aimed to determine whether circulating Gas6 and soluble Axl (sAxl) levels are associated with adiposity, inflammation, and insulin resistance status among Taiwanese adolescents. METHODS: Cross-sectional analyses using the data from the Taipei Children Heart Study-III were performed. A total of 832 adolescents (average age, 13.3 years) were included; they were divided into 3 groups: lean, overweight, and obese. Circulating Gas6 and sAxl levels, adiposity, inflammatory markers, and insulin resistance status were examined. RESULTS: Levels of circulating Gas6 and sAxl were significantly higher in overweight and obese adolescents than in the lean group (both P < .05). Circulating Gas6 levels were significantly positively correlated with body mass index Z-score (P = .045), waist circumference (P < .001), waist to hip circumference ratio (P < .001), body fat mass (P = .02), serum high-sensitivity C-reactive protein (P = .005), and tumor necrosis factor-α levels (P = .039) among overweight and obese adolescents. The correlations remained significant after adjusting for age, gender, Tanner stage, smoking status, and drinking status. In addition, every 1 ng/mL increase in circulating Gas6 concentration corresponded to a 15% to 19% increase in the risk of developing insulin resistance among overweight and obese adolescents. CONCLUSIONS: Circulating Gas6 levels are strongly associated with adiposity, inflammation, and insulin resistance status among overweight and obese adolescents. The potential role of the Gas6/TAM system in the initiation of childhood obesity and obesity-associated complications deserves further attention.

An occult aldosterone-producing adenoma initially presenting as hyperosmolar hyperglycaemic state.

Aldosterone-producing adenoma (APA), one of the most common causes of primary hyperaldosteronism, is clinically characterized by hypertension, increased sodium retention, increased potassium excretion and altered glucose metabolism. APA can also manifest in the form of hyperosmolar hyperglycaemic state (HHS), which is a life-threatening acute diabetic complication. Infection and inadequate fluid replacement are the common precipitating and predisposing factors for the occurrence of HHS. Here, we report a case of occult APA with the initial presentation of HHS, in which an unusually rapid correction of diabetes was observed after correct diagnosis and surgical resection of the APA. To our knowledge, this is the first case with such manifestations and outcome.

Circulating pro-inflammatory cytokines and adiponectin in young men with type 2 diabetes.

This study was designed to investigate plasma circulating pro-inflammatory cytokines, adiponectin and high-sensitive C-reactive protein (hsCRP) in young men with type 2 diabetes. New-onset young men with type 2 diabetes (young diabetes, YDM; age between 10 and 25) were recruited and divided into a non-obese group (NOYDM, body mass index, BMI ≦ 25 kg/m(2), N = 23) and an obese group (OBYDM, BMI ≧ 25 kg/m(2), N = 24). Twenty-four non-obese non-diabetic young men served as controls. Hemoglobin A1c, fasting glycemic index, lipids, adiponectin, hsCRP, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were determined. Insulin sensitivity and ß-cell function were calculated using the homeostasis model assessment method (HOMA-IR and HOMA-ß, respectively). Compared to controls, significantly greater HOMA-IR (7.9 ± 1.9 and 10.4 ± 2.5 vs. 1.5 ± 0.3, P < 0.001) and fasting insulin (103.3 ± 21.1 and 209.9 ± 24.4 vs. 48.5 ± 6.7 pmol/l, P < 0.01 and P < 0.001, respectively) were observed in NOYDM and OBYDM. There were significantly lower plasma adiponectin and higher hsCRP and TNF-α levels in OBYDM, whereas higher TNF-α and IL-6 were shown in NOYDM. Spearman rank correlation analysis demonstrated significant correlations between BMI and adiponectin (R = -0.44, P < 0.005), CRP (R = 0.28, P < 0.05), TNF-α (R = 0.42, P < 0.005) and IL-6 (R = 0.33, P < 0.01) in all YDM. Among measured cytokines, only adiponectin was significantly correlated with HOMA-IR, this correlation was abolished when adjusted for age and BMI (R = -0.24, P = 0.12). YDM not only exhibits insulin resistance, but also has inflammatory and atherogenic properties. BMI might be a major determinant of those markers.

Baseline forced expiratory volume in the first second as an independent predictor of development of the metabolic syndrome.

A growing body of evidence strongly supports associations between reduced lung function and insulin resistance, type 2 diabetes mellitus, and cardiovascular disease. The present study was undertaken to explore the possibility that reduced lung function is an independent predictor of development of the metabolic syndrome (MetS) and to investigate potential links between reduced lung function and the MetS. A prospective cohort study of reduced lung function as a predictor of subsequent MetS was conducted using 2-year follow-up data for 450 middle-aged adults lacking the MetS at baseline. Data were obtained from the Taipei MJ Health Screening Centers in Taiwan. The MetS was defined according to the modified Adult Treatment Panel III criteria. Over 2 years of follow-up, 26 of the 450 subjects (5.78%) without the MetS at baseline subsequently developed the syndrome. In multiple logistic regression analysis with adjustments for age, sex, body mass index, cigarette smoking, alcohol consumption, and physical activities, reduced forced expiratory volume in the first second (FEV(1)) at baseline remained a predictor of subsequent MetS (relative risk of 4.644, P = .036 for the third [<2.31 L] vs first [>2.88 L] tertile). In Pearson and partial correlation analyses, white blood cell counts and C-reactive protein concentrations were both found to be significantly and negatively correlated with FEV(1). Lower FEV(1) is concluded to serve as an independent predictor of the MetS. Low-grade systemic inflammation is the possible link between reduced lung function and the MetS.