Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
Molecules. 2019 Feb 7;24(3):586. doi: 10.3390/molecules24030586.
: Diabetic cardiomyopathy (DCM) is an emerging problem worldwide due to an increase in the incidence of type 2 diabetes. Animal studies have indicated that metformin and pioglitazone can prevent DCM partly by normalizing insulin resistance, and partly by other, pleiotropic mechanisms. One clinical study has evidenced the insulin-senzitizing effect of the drug candidate BGP-15, along with additional animal studies that have confirmed its beneficial effects in models of diabetes, muscular dystrophy and heart failure, with the drug affecting chaperones, contractile proteins and mitochondria. Our aim was to investigate whether the inzulin-senzitizer BGP-15 exert any additive cardiovascular effects compared to metformin or pioglitazone, using Goto-Kakizaki (GotoK) rats. : Rats were divided into five groups: (I) healthy control (Wistar), (II) diseased (GotoK), and GotoK rats treated with: (III) BGP-15, (IV) metformin, and (V) pioglitazone, respectively, for 12 weeks. Metabolic parameters and insulin levels were determined at the endpoint. Doppler echocardiography was carried out to estimate diabetes-associated cardiac dysfunction. Thoracotomy was performed after the vascular status of rats was evaluated using an isolated aortic ring method. Furthermore, western blot assays were carried out to determine expression or phosphorylation levels of selected proteins that take part in myocyte relaxation. : BGP-15 restored diastolic parameters (e'/a', E/e', LAP, E and A wave) and improved Tei-index compared to untreated GotoK rats. Vascular status was unaffected by BGP-15. Expression of sarco/endoplasmic reticulum Ca-ATPase (SERCA2a) and phosphodiesterase 9A (PDE9A) were unchanged by the treatments, but the phosphorylation level of vasodilator-stimulated phosphoprotein (VASP) and phospholamban (PLB) increased in BGP-15-treated rats, in comparison to GotoK. : Even though the BGP-15-treatment did not interfere significantly with glucose homeostasis and vascular status, it considerably enhanced diastolic function, by affecting the SERCA/phospholamban pathway in GotoK rats. Although it requires further investigation, BGP-15 may offer a new therapeutic approach in DCM.
糖尿病心肌病（DCM）是由于 2 型糖尿病发病率的增加而在全球范围内出现的一个新问题。动物研究表明，二甲双胍和吡格列酮可以通过纠正胰岛素抵抗，部分通过其他多效机制来预防 DCM。一项临床研究证实了候选药物 BGP-15 的胰岛素增敏作用，此外还有一些动物研究证实了它在糖尿病、肌肉营养不良和心力衰竭模型中的有益作用，该药物影响伴侣蛋白、收缩蛋白和线粒体。我们的目的是研究胰岛素增敏剂 BGP-15 是否与二甲双胍或吡格列酮相比具有任何额外的心血管作用，我们使用 Goto-Kakizaki（GotoK）大鼠进行了研究。
（I）健康对照组（Wistar），（II）患病组（GotoK），以及分别用以下药物治疗的 GotoK 大鼠：（III）BGP-15、（IV）二甲双胍和（V）吡格列酮，治疗 12 周。在终点时测定代谢参数和胰岛素水平。多普勒超声心动图用于评估与糖尿病相关的心脏功能障碍。在使用离体主动脉环方法评估大鼠血管状态后进行开胸手术。此外，进行了 Western blot 测定，以确定参与心肌松弛的选定蛋白质的表达或磷酸化水平。
BGP-15 恢复了未治疗的 GotoK 大鼠的舒张参数（e'/a'、E/e'、LAP、E 和 A 波）并改善了 Tei 指数。BGP-15 对血管状态没有影响。药物处理对肌浆网/内质网 Ca-ATP 酶（SERCA2a）和磷酸二酯酶 9A（PDE9A）的表达没有影响，但 BGP-15 治疗的大鼠中，血管扩张刺激磷蛋白（VASP）和磷酸化肌球蛋白结合蛋白（PLB）的磷酸化水平增加。
尽管 BGP-15 治疗并没有显著影响葡萄糖稳态和血管状态，但它通过影响 GotoK 大鼠的 SERCA/磷酸化肌球蛋白结合蛋白途径，极大地增强了舒张功能。尽管还需要进一步研究，但 BGP-15 可能为 DCM 提供一种新的治疗方法。
