Department of Cardiology, Nantong Third People's Hospital and the Third People's Hospital Affiliated to Nantong University, Nantong, People's Republic of China.
Department of Intensive Care Unit, Tumor Hospital Affiliated to Nantong University, Nantong Tumor Hospital, Nantong, People's Republic of China.
Bioengineered. 2022 Apr;13(4):9184-9196. doi: 10.1080/21655979.2022.2051859.
This study was aimed to evaluate the therapeutic effects and potent mechanisms of a novel GLP-1/GIP dual agonist on hyperglycemia and myocardial injury in diabetic mice. Novel dual-receptor agonists were designed and then evaluated via receptor activation assays. Acute hypoglycemic effects were assessed in diabetic mice induced by intraperitoneal injection of streptozotocin. Chronic effects of dual-receptor agonists on diabetes as well as diabetic cardiomyopathy were investigated in DCM model mice. Effects of the coculture of dual-receptor agonists with or without signaling pathway inhibitors on the cell viability and apoptosis of primary cardiomyocytes under a high-glucose state were assessed via MTT and western blotting methods to investigate the probable mechanism. AP5 exhibited balanced activities of dual-receptor activation and improved hypoglycemic ability in diabetic mice. Moreover, chronic treatment of AP5 achieved the prominently improved efficacy in reversing the deteriorative diabetic disorders and reducing the myocardial injury markers in DCM mice. Moreover, AP5 also inhibited the apoptosis and improved the survival rate of primary cardiomyocytes under a high-glucose state via increasing the expression levels of antiapoptotic proteins and inhibiting the release of apoptotic proteins, respectively, as well as activating the AMPK/PI3K/Akt signaling pathway. In conclusion, the dual GLP-1/GIP receptor agonist, AP5, can effectively improve diabetic symptoms and exert therapeutic effects on DCM via activating the AMPK/PI3K/Akt pathway, reducing the ROS production, oxidative stress and inflammatory markers in the rodent DCM model. Diabetes mellitus, DM; diabetic cardiomyopathy, DCM; streptozotocin, STZ; glucagon-like peptide-1, GLP-1; malondialdehyde, MDA; glucose-dependent insulinotropic polypeptide, GIP; creatine kinase, CK; diabetic cardiomyopathy, DCM; serum superoxide dismutase; SOD; total superoxide disumutase, T-SOD; Methyl Thiazolyl Tetrazolium, MTT; lactate dehydrogenase; LDH; Adenosine Monophosphate-Activated Protein Kinase, AMPK; Dulbecco's modified Eagle medium, DMEM; Fetal Bovine Serum, FBS; Reactive Oxygen Species, ROS; Glyceraldehyde-phosphate dehydrogenase, GAPDH; Surface Plasmon Resonance, SPR; Ethylene Diamine Tetraacetic Acid, EDTA; Interleukin-1β, IL-1β; Phosphoinositol 3-kinase, PI3K; Tumor necrosis factor, TNF-α; Renin-angiotensin-aldosterone system, RAAS; Glucose transporter, GLUT; Dipeptidyl peptidase-IV, DPP-IV; oxygen free radicals, OFR.
本研究旨在评估新型 GLP-1/GIP 双重激动剂对糖尿病小鼠高血糖和心肌损伤的治疗作用和潜在机制。通过受体激活测定法设计并评估了新型双重受体激动剂。通过腹腔注射链脲佐菌素诱导糖尿病小鼠，评估急性低血糖作用。在 DCM 模型小鼠中研究了双重受体激动剂对糖尿病和糖尿病心肌病的慢性作用。通过 MTT 和 Western blot 方法评估双重受体激动剂与或不与信号通路抑制剂共培养对高糖状态下原代心肌细胞活力和凋亡的影响，以探讨可能的机制。AP5 表现出双重受体激活的平衡活性，并提高了糖尿病小鼠的降糖能力。此外，AP5 的慢性治疗在 DCM 小鼠中明显改善了改善糖尿病疾病的疗效，并降低了心肌损伤标志物。此外，AP5 还通过分别增加抗凋亡蛋白的表达水平和抑制凋亡蛋白的释放以及激活 AMPK/PI3K/Akt 信号通路，抑制高糖状态下原代心肌细胞的凋亡并提高其存活率。总之，双重 GLP-1/GIP 受体激动剂 AP5 通过激活 AMPK/PI3K/Akt 通路，减少 ROS 产生、氧化应激和炎症标志物，有效改善糖尿病症状，并在啮齿动物 DCM 模型中发挥对 DCM 的治疗作用。糖尿病，DM；糖尿病心肌病，DCM；链脲佐菌素，STZ；胰高血糖素样肽-1，GLP-1；丙二醛，MDA；葡萄糖依赖性胰岛素促分泌多肽，GIP；肌酸激酶，CK；糖尿病心肌病，DCM；血清超氧化物歧化酶；SOD；总超氧化物歧化酶，T-SOD；噻唑蓝，MTT；乳酸脱氢酶；LDH；腺苷一磷酸激活蛋白激酶，AMPK；改良的 Eagle 培养基，DMEM；胎牛血清，FBS；活性氧，ROS；甘油醛-3-磷酸脱氢酶，GAPDH；表面等离子体共振，SPR；乙二胺四乙酸，EDTA；白细胞介素-1β，IL-1β；磷酸肌醇 3-激酶，PI3K；肿瘤坏死因子，TNF-α；肾素-血管紧张素-醛固酮系统，RAAS；葡萄糖转运蛋白，GLUT；二肽基肽酶-IV，DPP-IV；氧自由基，OFR。
