Scalzo Rebecca L, Knaub Leslie A, Hull Sara E, Keller Amy C, Hunter Kendall, Walker Lori A, Reusch Jane E B
Division of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado.
Department of Medicine, Denver VA Medical Center, University of Colorado School of Medicine, Aurora, Colorado.
Physiol Rep. 2018 Jul;6(13):e13754. doi: 10.14814/phy2.13754.
Cardiorespiratory fitness (CRF) inversely predicts cardiovascular (CV) mortality and CRF is impaired in people with type 2 diabetes (T2D). Aerobic exercise training (ET) improves CRF and is associated with decreased risk of premature death in healthy and diseased populations. Understanding the mechanisms contributing to ET adaptation may identify targets for reducing CV mortality of relevance to people with T2D. The antihyperglycemic hormone glucagon-like peptide-1 (GLP-1) influences many of the same pathways as exercise and may contribute to CV adaptation to ET. We hypothesized that GLP-1 is necessary for adaptation to ET. Twelve-week-old male Wistar rats were randomized (n = 8-12/group) to receive PBS or GLP-1 receptor antagonist (exendin 9-39 (Ex(9-39)) via osmotic pump for 4 weeks ± ET. CRF was greater with ET (P < 0.01). Ex(9-39) treatment blunted CRF in both sedentary and ET rats (P < 0.001). Ex(9-39) attenuated acetylcholine-mediated vasodilation, while this response was maintained with Ex(9-39)+ET (P = 0.04). Aortic stiffness was greater with Ex(9-39) (P = 0.057) and was made worse when Ex(9-39) was combined with ET (P = 0.004). Ex vivo aortic vasoconstriction with potassium and phenylephrine was lower with Ex(9-39) (P < 0.0001). Carotid strain improved with PBS + ET but did not change in the Ex(9-39) rats with ET (P < 0.0001). Left ventricular mitochondrial respiration was elevated with Ex(9-39) (P < 0.02). GLP-1 receptor antagonism impairs CRF with and without ET, attenuates the vascular adaptation to ET, and elevates cardiac mitochondrial respiration. These data suggest that GLP-1 is integral to the adaptive vascular response to ET.
心肺适能（CRF）与心血管（CV）死亡率呈负相关，且2型糖尿病（T2D）患者的CRF受损。有氧运动训练（ET）可改善CRF，并与健康人群和患病群体过早死亡风险的降低相关。了解促成ET适应的机制可能会确定降低与T2D患者相关的CV死亡率的靶点。降糖激素胰高血糖素样肽-1（GLP-1）影响许多与运动相同的途径，可能有助于CV对ET的适应。我们假设GLP-1是ET适应所必需的。将12周龄雄性Wistar大鼠随机分组（每组n = 8 - 12只），通过渗透泵接受PBS或GLP-1受体拮抗剂（艾塞那肽9 - 39（Ex(9 - 39)））4周±ET。ET组的CRF更高（P < 0.01）。Ex(9 - 39)治疗使久坐不动和ET大鼠的CRF均减弱（P < 0.001）。Ex(9 - 39)减弱了乙酰胆碱介导的血管舒张，而Ex(9 - 39)+ET组则维持了这种反应（P = 0.04）。Ex(9 - 39)组的主动脉僵硬度更高（P = 0.057），当Ex(9 - 39)与ET联合时更严重（P = 0.004）。Ex(9 - 39)组离体主动脉对钾和去氧肾上腺素的血管收缩作用较低（P < 0.0001）。PBS + ET组的颈动脉应变得到改善，但Ex(9 - 39) + ET组大鼠未发生变化（P < 0.0001）。Ex(9 - 39)组左心室线粒体呼吸增强（P < 0.02）。GLP-1受体拮抗作用在有或无ET的情况下均损害CRF，减弱对ET的血管适应，并增强心脏线粒体呼吸。这些数据表明，GLP-1是ET适应性血管反应所必需的。
