Inhibition of protein tyrosine phosphatase-1B with antisense oligonucleotides improves insulin sensitivity and increases adiponectin concentrations in monkeys.
Inhibition of protein tyrosine phosphatase-1B with antisense oligonucleotides improves insulin sensitivity and increases adiponectin concentrations in monkeys.
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DOI：
10.1210/en.2008-0885
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发表时间：
2009-04
期刊：
影响因子：
4.8
通讯作者：
M. Swarbrick;P. Havel;A. Levin;A. Bremer;K. Stanhope;M. Butler;S. Booten;J. Graham;R. Mckay;S. Murray;L. Watts;B. Monia;S. Bhanot
中科院分区：
文献类型：
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作者：
M. Swarbrick;P. Havel;A. Levin;A. Bremer;K. Stanhope;M. Butler;S. Booten;J. Graham;R. Mckay;S. Murray;L. Watts;B. Monia;S. Bhanot
蛋白酪氨酸磷酸酶（PTP）-1B拮抗胰岛素信号传导，是肥胖和2型糖尿病相关胰岛素抵抗的潜在治疗靶点。迄今为止，PTP-1B的研究受到特定拮抗剂可用性的限制;然而，用针对PTP-1B的反义寡核苷酸（ASO）治疗啮齿动物可改善胰岛素敏感性，抑制脂肪生成基因表达，并减少肝脏和脂肪组织中的甘油三酯积累。在这里，我们研究了ASO介导的PTP-1B抑制灵长类动物。首先，PTP-1B阿索（ISIS 113715）剂量依赖性地抑制猴肝细胞培养物中PTP-1B mRNA和蛋白表达。皮下注射ISIS 113715可使正常体重猴肝脏和脂肪组织中PTP-1B mRNA表达降低40-50%，并在静脉葡萄糖耐量试验（IVGTT）期间改善胰岛素敏感性。在肥胖的胰岛素抵抗恒河猴中，用20 mg/kg ISIS 113715治疗4周降低了胰岛素和葡萄糖的空腹浓度，并降低了IVGTT期间的胰岛素反应。在这些动物中，脂联素浓度也增加了70%，其中大部分是高分子量寡聚体的增加。在接受较低剂量递增方案（1-10 mg/kg，9周）的猴中未观察到这些效应。总体而言，ISIS 113715治疗期间脂联素浓度的增加与IVGTT期间胰岛素反应的降低相关（r =-0.47，P = 0.042）。这些结果表明，用ASO如ISIS 113715抑制PTP-1B可能是治疗和预防肥胖相关的胰岛素抵抗和2型糖尿病的可行方法，因为它们除了改善胰岛素敏感性外还有效地增加脂联素浓度。
Protein tyrosine phosphatase (PTP)-1B antagonizes insulin signaling and is a potential therapeutic target for insulin resistance associated with obesity and type 2 diabetes. To date, studies of PTP-1B have been limited by the availability of specific antagonists; however, treatment of rodents with antisense oligonucleotides (ASOs) directed against PTP-1B improves insulin sensitivity, inhibits lipogenic gene expression, and reduces triglyceride accumulation in liver and adipose tissue. Here we investigated ASO-mediated PTP-1B inhibition in primates. First, PTP-1B ASO (ISIS 113715) dose-dependently inhibited PTP-1B mRNA and protein expression in cultured monkey hepatocytes. Subcutaneous administration of ISIS 113715 reduced PTP-1B mRNA expression in liver and adipose tissue of normal-weight monkeys by 40-50% and improved insulin sensitivity during an iv glucose tolerance test (IVGTT). In obese, insulin-resistant rhesus monkeys, treatment with 20 mg/kg ISIS 113715 for 4 wk reduced fasting concentrations of insulin and glucose and reduced insulin responses during an IVGTT. In these animals, adiponectin concentrations were also increased by 70%, most of which was an increase of high-molecular-weight oligomers. These effects were not observed in monkeys on a lower, dose-escalation regimen (1-10 mg/kg over 9 wk). Overall, the increase of adiponectin concentrations during ISIS 113715 treatment was correlated with the lowering of insulin responses during IVGTT (r = -0.47, P = 0.042). These results indicate that inhibition of PTP-1B with ASOs such as ISIS 113715 may be a viable approach for the treatment and prevention of obesity-associated insulin resistance and type 2 diabetes because they potently increase adiponectin concentrations in addition to improving insulin sensitivity.