Broderick Tom L, Jankowski Marek, Gutkowska Jolanta
Department of Physiology, Laboratory of Diabetes and Exercise Metabolism, Midwestern University, Glendale, AZ, USA.
Department of Medicine, Laboratory of Cardiovascular Biochemistry, Centre Hospitalier de l'Université de Montréal-Hôtel-Dieu, Montréal, QC, Canada.
Diabetes Metab Syndr Obes. 2017 Jan 11;10:27-36. doi: 10.2147/DMSO.S115453. eCollection 2017.
Regular exercise training (ET) and caloric restriction (CR) are the frontline strategies in the treatment of type 2 diabetes mellitus with the aim at reducing cardiometabolic risk. ET and CR improve body weight and glycemic control, and experimental studies indicate that these paradigms afford cardioprotection. In this study, the effects of combined ET and CR on the cardioprotective oxytocin (OT)-natriuretic peptide (NP) system were determined in the db/db mouse, a model of type 2 diabetes associated with insulin resistance, hyperglycemia, and obesity.
Five-week-old male db/db mice were assigned to the following groups: sedentary, ET, and ET + CR. Nonobese heterozygote littermates served as controls. ET was performed on a treadmill at moderate intensity, and CR was induced by reducing food intake by 30% of that consumed by sedentary db/db mice for a period of 8 weeks.
After 8 weeks, only ET + CR, but not ET, slightly improved body weight compared to sedentary db/db mice. Regardless of the treatment, db/db mice remained hyperglycemic. Hearts from db/db mice demonstrated reduced expression of genes linked to the cardiac OT-NP system. In fact, compared to control mice, mRNA expression of GATA binding protein 4 (GATA4), OT receptor, OT, brain NP, NP receptor type C, and endothelial nitric oxide synthase (eNOS) was decreased in hearts from sedentary db/db mice. Both ET alone and ET + CR increased the mRNA expression of GATA4 compared to sedentary db/db mice. Only ET combined with CR produced increased eNOS mRNA and protein expression.
Our data indicate that enhancement of eNOS by combined ET and CR may improve coronary endothelial vasodilator dysfunction in type 2 diabetes but did not prevent the downregulation of cardiac expression in the OT-NP system, possibly resulting from the sustained hyperglycemia and obesity in diabetic mice.
规律运动训练（ET）和热量限制（CR）是治疗2型糖尿病的一线策略，旨在降低心脏代谢风险。ET和CR可改善体重和血糖控制，实验研究表明这些模式具有心脏保护作用。在本研究中，在db/db小鼠（一种与胰岛素抵抗、高血糖和肥胖相关的2型糖尿病模型）中确定了ET和CR联合对心脏保护催产素（OT）-利钠肽（NP）系统的影响。
将5周龄雄性db/db小鼠分为以下几组：久坐组、ET组和ET + CR组。非肥胖杂合子同窝小鼠作为对照。ET在跑步机上以中等强度进行，CR通过将食物摄入量减少至久坐的db/db小鼠消耗量的30%持续8周来诱导。
8周后，与久坐的db/db小鼠相比，只有ET + CR组，而不是ET组，体重略有改善。无论治疗如何，db/db小鼠仍处于高血糖状态。db/db小鼠的心脏显示与心脏OT-NP系统相关的基因表达降低。事实上，与对照小鼠相比，久坐的db/db小鼠心脏中GATA结合蛋白4（GATA4）、OT受体、OT、脑NP、C型NP受体和内皮型一氧化氮合酶（eNOS）的mRNA表达降低。与久坐的db/db小鼠相比，单独的ET和ET + CR均增加了GATA4的mRNA表达。只有ET与CR联合产生了eNOS mRNA和蛋白表达的增加。
我们的数据表明，ET和CR联合增强eNOS可能改善2型糖尿病中的冠状动脉内皮舒张功能障碍，但不能防止OT-NP系统中心脏表达的下调，这可能是由于糖尿病小鼠持续的高血糖和肥胖所致。
