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The
th Annual Meeting of March 21-22, 2015 The Endocrine Society and The Diabetes Association of the R.O.C. (Taiwan)
AP-01
The Studies of Gas6/AxL and Glucose Metabolism, Atherosclerosis, Obestiy and Sex Hormones 1
Yi-Jen Hung, 1Chien-Hsing Lee, 2Yi-Shing Shieh, 1Fone-Ching Hsiao, 1 Chang-Hsun Hsieh 1
Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 2Department of Oral Diagnosis and Pathology, Tri-Service General Hospital, Taipei, Taiwan
Protein growth arrest–specific 6 (Gas6) was the last addition to the family of plasma vitamin K– dependent proteins. Gas6 was cloned and characterized in 1993 and found to be similar to plasma anticoagulant protein S. It was recognized as a growth factor–like molecule, as it interacted with receptor tyrosine kinases of the TAM (Tyro-3, Axl, Mer) family. The Gas6/TAM system regulates an intriguing mix of processes, including cell survival and proliferation, cell adhesion and migration, blood clot stabilization, and inflammatory cytokine release. The role of the Gas6/TAM system has been found to be important in inflammation; hemostasis; autoimmune disease; nervous, reproductive, and vascular systems; and cancer. In our study, plasma Gas6 is associated with altered glucose tolerance, inflammation, and endothelial dysfunction. It may represent a novel independent risk factor of type 2 diabetes and a potential surrogate marker of inflammation and endothelial dysfunction. The Gas6 c.843+7AA genotype and A allele are less prevalent in type 2 diabetes, which may have a protective role for type 2 diabetes. Otherwise, in cellular study, we also found that high glucose can alter Gas6/Axl signaling and may through Akt and VEGF/VEGFR2 downstream molecules and suggests that Gas6/Axl may involve in high glucoSE-induced endothelial cell dysfunction. Gas6 expression is widespread in many tissues, including immune cells, endothelial cells, vascular smooth muscle cells, and adipocytes. Preclinical studies indicate that Gas6 and its receptors of the TAM family may be involved in the pathogenesis of obesity and its complications. Therefore, our data showed that circulating Gas6 and sAxl were significantly higher in overweight and obese adolescents. Circulating Gas6 levels were significantly positively correlated with body mass index Z-score, waist circumference, body fat mass, among overweight and obese adolescents. GAS6 and AXL polymorphisms are associated with adiposity, systemic inflammation, and insulin resistance in adolescents, especially in boys. In addition, we also found that significantly higher Gas6 concentrations were observed in adult male rather than female and lower Gas6 levels in the postmenopausal compared to the premenopausal women. Plasma Gas6 levels were positively correlated with estradiol levels in the pre- and postmenopausal women. 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. How the Gas6/ TAM pathway is regulated by sex hormones or ages in cellular concentrations, whether the activation of GAS6 gene by estrogen and androgen. It still needs further studies to elucidate. 224
