Zemany Laura, Bhanot Sanjay, Peroni Odile D, Murray Susan F, Moraes-Vieira Pedro M, Castoldi Angela, Manchem Prasad, Guo Shuling, Monia Brett P, Kahn Barbara B
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Isis Pharmaceuticals, Carlsbad, CA.
Diabetes. 2015 May;64(5):1603-14. doi: 10.2337/db14-0970. Epub 2014 Dec 18.
Circulating transthyretin (TTR) is a critical determinant of plasma retinol-binding protein 4 (RBP4) levels. Elevated RBP4 levels cause insulin resistance, and the lowering of RBP4 levels improves glucose homeostasis. Since lowering TTR levels increases renal clearance of RBP4, we determined whether decreasing TTR levels with antisense oligonucleotides (ASOs) improves glucose metabolism and insulin sensitivity in obesity. TTR-ASO treatment of mice with genetic or diet-induced obesity resulted in an 80-95% decrease in circulating levels of TTR and RBP4. Treatment with TTR-ASOs, but not control ASOs, decreased insulin levels by 30-60% and improved insulin sensitivity in ob/ob mice and high-fat diet-fed mice as early as after 2 weeks of treatment. The reduced insulin levels were sustained for up to 9 weeks of treatment and were associated with reduced adipose tissue inflammation. Body weight was not changed. TTR-ASO treatment decreased LDL cholesterol in high-fat diet-fed mice. The glucose infusion rate during a hyperinsulinemic-euglycemic clamp was increased by 50% in high-fat diet-fed mice treated with TTR-ASOs, demonstrating improved insulin sensitivity. This was also demonstrated by 20% greater inhibition of hepatic glucose production, a 45-60% increase of glucose uptake into skeletal and cardiac muscle, and a twofold increase in insulin signaling in muscle. These data show that decreasing circulating TTR levels or altering TTR-RBP4 binding could be a potential therapeutic approach for the treatment of type 2 diabetes.
循环甲状腺素运载蛋白（TTR）是血浆视黄醇结合蛋白4（RBP4）水平的关键决定因素。RBP4水平升高会导致胰岛素抵抗，而降低RBP4水平可改善葡萄糖稳态。由于降低TTR水平会增加RBP4的肾脏清除率，我们研究了用反义寡核苷酸（ASO）降低TTR水平是否能改善肥胖症中的葡萄糖代谢和胰岛素敏感性。用TTR-ASO治疗基因或饮食诱导肥胖的小鼠，可使循环中TTR和RBP4水平降低80-95%。用TTR-ASO而非对照ASO治疗，早在治疗2周后就可使ob/ob小鼠和高脂饮食喂养小鼠的胰岛素水平降低30-60%，并改善胰岛素敏感性。胰岛素水平的降低在长达9周的治疗中持续存在，且与脂肪组织炎症减轻有关。体重未发生变化。TTR-ASO治疗可降低高脂饮食喂养小鼠的低密度脂蛋白胆固醇。在用TTR-ASO治疗的高脂饮食喂养小鼠中，高胰岛素-正常血糖钳夹期间的葡萄糖输注率提高了50%，表明胰岛素敏感性得到改善。肝脏葡萄糖生成的抑制增加20%、骨骼肌和心肌葡萄糖摄取增加45-60%以及肌肉中胰岛素信号传导增加两倍也证明了这一点。这些数据表明，降低循环TTR水平或改变TTR-RBP4结合可能是治疗2型糖尿病的一种潜在治疗方法。
