Surapongchai Juthamard, Prasannarong Mujalin, Bupha-Intr Tepmanas, Saengsirisuwan Vitoon
Exercise Physiology LaboratoryDepartment of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Department of Physical TherapyFaculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.
J Endocrinol. 2017 Mar;232(3):547-560. doi: 10.1530/JOE-16-0579. Epub 2017 Jan 17.
Angiotensin II (ANGII) is reportedly involved in the development of skeletal muscle insulin resistance. The present investigation evaluated the effects of two ANGII doses on the phenotypic characteristics of insulin resistance syndrome and insulin action and signaling in rat skeletal muscle. Male Sprague-Dawley rats were infused with either saline (SHAM) or ANGII at a commonly used pressor dose (100 ng/kg/min; ANGII-100) or a higher pressor dose (500 ng/kg/min; ANGII-500) via osmotic minipumps for 14 days. We demonstrated that ANGII-100-infused rats exhibited the phenotypic features of non-obese insulin resistance syndrome, including hypertension, impaired glucose tolerance and insulin resistance of glucose uptake in the soleus muscle, whereas ANGII-500-treated rats exhibited diabetes-like symptoms, such as post-prandial hyperglycemia, impaired insulin secretion and hypertriglyceridemia. At the cellular level, insulin-stimulated glucose uptake in the soleus muscle of the ANGII-100 group was 33% lower ( < 0.05) than that in the SHAM group and was associated with increased insulin-stimulated IRS-1 Ser and decreased Akt Ser and AS160 Thr phosphorylation and GLUT-4 expression. However, ANGII-500 infusion did not induce skeletal muscle insulin resistance or impair insulin signaling elements as initially anticipated. Moreover, we found that insulin-stimulated glucose uptake in the ANGII-500 group was accompanied by the enhanced expression of ACE2 and MasR proteins, which are the key elements in the non-classical pathway of the renin-angiotensin system. Collectively, this study demonstrates for the first time that chronic infusion with these two pressor doses of ANGII induced differential metabolic responses at both the systemic and skeletal muscle levels.
据报道，血管紧张素II（ANGII）参与骨骼肌胰岛素抵抗的发展。本研究评估了两种ANGII剂量对胰岛素抵抗综合征的表型特征以及大鼠骨骼肌中胰岛素作用和信号传导的影响。通过渗透微型泵，对雄性Sprague-Dawley大鼠持续输注生理盐水（假手术组，SHAM）、常用升压剂量的ANGII（100 ng/kg/min；ANGII-100）或更高升压剂量的ANGII（500 ng/kg/min；ANGII-500），持续14天。我们发现，输注ANGII-100的大鼠表现出非肥胖胰岛素抵抗综合征的表型特征，包括高血压、葡萄糖耐量受损以及比目鱼肌葡萄糖摄取的胰岛素抵抗，而接受ANGII-500治疗的大鼠表现出类似糖尿病的症状，如餐后高血糖、胰岛素分泌受损和高甘油三酯血症。在细胞水平上，ANGII-100组比目鱼肌中胰岛素刺激的葡萄糖摄取比假手术组低33%（P<0.05），并且与胰岛素刺激的IRS-1丝氨酸增加、Akt丝氨酸和AS160苏氨酸磷酸化以及GLUT-4表达降低有关。然而，输注ANGII-500并未如最初预期的那样诱导骨骼肌胰岛素抵抗或损害胰岛素信号元件。此外，我们发现ANGII-500组中胰岛素刺激的葡萄糖摄取伴随着ACE2和MasR蛋白表达的增强，这两种蛋白是肾素-血管紧张素系统非经典途径的关键元件。总的来说，本研究首次证明，长期输注这两种升压剂量的ANGII在全身和骨骼肌水平上均诱导了不同的代谢反应。
