Monti L D, Galluccio E, Lucotti P, Setola E, Costa S, Fontana B, Oldani M, Merante D, Di Blasi P, Bosi E, Piatti P M
Medicine Division, Diabetology and Endocrinology and Metabolic Disease Unit, Scientific Institute San Raffaele, Milan, Italy.
Eur J Clin Invest. 2008 Nov;38(11):849-56. doi: 10.1111/j.1365-2362.2008.02027.x.
The study was performed to determine whether sucrose-induced insulin resistance could increase the expression of cardiac matrix metalloproteinases (MMPs), indices of matrix remodelling, and whether the addition of 1.25 g day(-1) of L-arginine (ARG) to a sucrose diet could prevent both the sucrose-induced metabolic abnormalities and elevated cardiac expression of matrix metalloproteinases in an insulin resistant stage that precedes frank type 2 diabetes.
Experiments were performed on 38 male Sprague-Dawley rats, 16 rats maintained a standard chow diet (ST), 12 rats were switched to a sucrose enriched diet (SU) and 10 rats to a sucrose plus L-arginine (1.25 g day(-1)) enriched diet (SU + ARG) for a period of 8 weeks. After 8 weeks of different diets, an intravenous glucose tolerance test (IVGTT) was performed and samples were drawn for the measurements of insulin, glucose, triglycerides, free fatty acids (FFA), plasma cyclic guanosine-monophosphate (c-GMP) and retroperitoneal, omental, epididymal fat pad and heart were dissected and weighed.
At the end of the study, retroperitoneal fat, heart weight/body weight ratio, fasting plasma glucose, serum insulin, and serum triglyceride levels and integrated insulin area after IVGTT were significantly higher in SU than in SU + ARG and ST. All these parameters were comparable between SU + ARG and ST animals. FFA levels were significantly different among groups, with highest levels in SU and lowest levels in ST. Fasting plasma c-GMP levels and the integrated c-GMP area after IVGTT, an index of nitric oxide activity, were significantly lower in SU than in SU + ARG and ST, the result was similar in SU + ARG and in ST MMP-9 protein expression increased 10.5-fold, MMP-2 protein expression increased 2.4-fold and the expression of tissue inhibitors of metalloproteinase (TIMP-1) increased 1.7-fold in SU rats as compared to ST animals. This was accompanied with a significant increase of cardiac triglyceride concentrations. In contrast, cardiac MMP-9, MMP-2, and TIMP-1 protein expressions were not different between SU + ARG and ST animals. Cardiac triglyceride levels were not significantly different between SU + ARG and ST rats.
SU rats developed insulin resistance and hyperlipidaemia, accompanied with increased fat deposition in the heart and enhanced MMP protein expression. Conversely, ARG supplementation prevents these metabolic abnormalities and restored MMP/TIMP-1 balance.
本研究旨在确定蔗糖诱导的胰岛素抵抗是否会增加心脏基质金属蛋白酶（MMPs）的表达以及基质重塑指标，还旨在确定在蔗糖饮食中添加1.25克/天的L-精氨酸（ARG）是否能预防蔗糖诱导的代谢异常以及在2型糖尿病前期胰岛素抵抗阶段心脏基质金属蛋白酶表达的升高。
对38只雄性Sprague-Dawley大鼠进行实验，16只大鼠维持标准饲料饮食（ST），12只大鼠改为富含蔗糖的饮食（SU），10只大鼠改为富含蔗糖加L-精氨酸（1.25克/天）的饮食（SU + ARG），持续8周。在不同饮食8周后，进行静脉葡萄糖耐量试验（IVGTT），并采集样本测量胰岛素、葡萄糖、甘油三酯、游离脂肪酸（FFA）、血浆环磷酸鸟苷（c-GMP），并解剖分离腹膜后、网膜、附睾脂肪垫和心脏并称重。
在研究结束时，SU组的腹膜后脂肪、心脏重量/体重比、空腹血糖、血清胰岛素、血清甘油三酯水平以及IVGTT后的胰岛素积分面积均显著高于SU + ARG组和ST组。SU + ARG组和ST组动物的所有这些参数相当。FFA水平在各组之间有显著差异，但SU组最高，ST组最低。空腹血浆c-GMP水平以及IVGTT后的c-GMP积分面积（一氧化氮活性指标）在SU组显著低于SU + ARG组和ST组，SU + ARG组和ST组结果相似。与ST组动物相比，SU组大鼠的MMP-9蛋白表达增加了10.5倍，MMP-2蛋白表达增加了2.4倍，金属蛋白酶组织抑制剂（TIMP-1）的表达增加了1.7倍。这伴随着心脏甘油三酯浓度的显著增加。相比之下，SU + ARG组和ST组动物的心脏MMP-9、MMP-2和TIMP-1蛋白表达无差异。SU + ARG组和ST组大鼠的心脏甘油三酯水平无显著差异。
SU组大鼠出现胰岛素抵抗和高脂血症，同时伴有心脏脂肪沉积增加和MMP蛋白表达增强。相反，补充ARG可预防这些代谢异常并恢复MMP/TIMP-1平衡。
