Novel dual glucagon-like peptide-1/ glucose-dependent insulinotropic polypeptide receptor agonist attenuates diabetes and myocardial injury through inhibiting hyperglycemia, inflammation and oxidative stress in rodent animals

Abstract

ABSTRACT 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 in vitro 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 in vitro 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 in vitro 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.Abbreviation: 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;