Dept. of Pharmacology and Therapeutics, Faculty of Medicine, Univ. of Manitoba, Winnipeg, MB R3E0T6, Canada.
J Appl Physiol (1985). 2011 Sep;111(3):704-14. doi: 10.1152/japplphysiol.00057.2011. Epub 2011 May 26.
We have previously demonstrated that progressive development of absence of meal-induced insulin sensitization (AMIS) leads to postprandial hyperglycemia, compensatory hyperinsulinemia, resultant hyperlipidemia, increased oxidative stress, and obesity, progressing to syndrome X in aging rats. The present study tested the hypothesis that progressive development of AMIS in aging rats further resulted in deterioration in cardiac performance. Anesthetized male Sprague-Dawley rats were tested at 9, 26, and 52 wk to determine their dynamic response to insulin and cardiac function. Dynamic insulin sensitivity was determined before and after atropine to quantitate hepatic insulin sensitizing substance (HISS)-dependent and -independent insulin action. Cardiac performance was evaluated using a Millar pressure-volume conductance catheter system. AMIS developed with age, as demonstrated by significant decrease in HISS-dependent insulin action, and this syndrome was increased by sucrose supplementation and inhibited by the antioxidant treatment. Associated with progressive development of AMIS, aging rats showed impaired cardiac performance, including the reduction in cardiac index, heart rate, dP/dt(max), dP/dt(min), ejection fraction and decreased slope of left ventricular end-systolic pressure-volume relationship, and increased relaxation time constant of left ventricular pressure as well as increased left ventricular end-diastolic pressure. Total peripheral vascular resistance also increased with age. Sucrose supplementation and antioxidant treatment, respectively, potentiated and attenuated cardiac dysfunction associated with age. In addition, poor cardiac performance correlated closely with the development of AMIS. These results indicate that AMIS is the first metabolic defect that leads to homeostatic disturbances and dysfunctions, including cardiovascular diseases.
我们之前已经证明，逐渐出现的进食诱导胰岛素敏感性缺失（AMIS）会导致餐后高血糖、代偿性高胰岛素血症、继而引起血脂异常、氧化应激增加和肥胖，最终导致老年大鼠出现综合征 X。本研究检验了这样一个假设，即老年大鼠 AMIS 的逐渐发展会进一步导致心脏功能恶化。在 9、26 和 52 周龄时，对麻醉雄性 Sprague-Dawley 大鼠进行测试，以确定它们对胰岛素的动态反应和心脏功能。在使用阿托品前后测定动态胰岛素敏感性，以定量肝胰岛素敏化物质（HISS）依赖性和非依赖性胰岛素作用。使用 Millar 压力-容积导纳导管系统评估心脏功能。AMIS 随着年龄的增长而发展，这表现为 HISS 依赖性胰岛素作用的显著下降，而这种综合征随着蔗糖补充而增加，并被抗氧化剂治疗所抑制。与 AMIS 的逐渐发展相关的是，老年大鼠表现出心脏功能受损，包括心输出量、心率、dp/dt(max)、dp/dt(min)、射血分数的降低，左心室收缩末期压力-容积关系斜率降低，左心室压力弛豫时间常数增加，以及左心室舒张末期压力增加。总外周血管阻力也随年龄增长而增加。蔗糖补充和抗氧化剂治疗分别增强和减弱了与年龄相关的心脏功能障碍。此外，心脏功能不良与 AMIS 的发展密切相关。这些结果表明，AMIS 是导致稳态紊乱和功能障碍（包括心血管疾病）的第一个代谢缺陷。
