Long-Term Activation of Glucagon-like peptide-1 receptor by Dulaglutide Prevents Diabetic Heart Failure and Metabolic Remodeling in Type 2 Diabetes.
Sai-Yang XieMin ZhangWenke ShiYun XingYan HuangWen-Xi FangShi-Qiang LiuMeng-Ya ChenTong ZhangSi ChenXiaofeng ZengShasha WangWei DengQi-Zhu TangPublished in: Journal of the American Heart Association (2022)
Background Mechanistic insights of glucagon-like peptide-1 receptor agonists remain incompletely identified, despite the efficacy in heart failure observed in clinical trials. Here, we evaluated the effects of dulaglutide on heart complications and illuminated its underlying mechanism. Methods and Results We used mice with high-fat diet (HFD)/streptozotocin-induced type 2 diabetes to investigate the effects of dulaglutide upon diabetic cardiac dysfunction. After the onset of diabetes, control and diabetic mice were injected subcutaneously with either dulaglutide (type 2 diabetes-dulaglutide and control-dulaglutide groups) or vehicle (type 2 diabetes-vehicle and control-vehicle groups) for 8 weeks. Subsequently, heart characteristics, cardiometabolic profile and mitochondrial morphology and function were evaluated. Also, we analyzed the effects of dulaglutide on neonatal rat ventricular myocytes treated with high glucose plus palmitic acid. In addition, wild type and AMP-activated protein kinase α2 mutant mice were used to evaluate the underlying mechanism. In type 2 diabetes mouse model, dulaglutide ameliorated insulin resistance, improved glucose tolerance, reduced hyperlipidemia, and promoted fatty acid use in the myocardium. Dulaglutide treatment functionally attenuated cardiac remodeling and dysfunction and promoted metabolic reprogramming in diabetic mice. Furthermore, dulaglutide improved mitochondria fragmentation in myocytes, and simultaneously reinstated mitochondrial morphology and function in diabetic hearts. We also found that dulaglutide preserved AMP-activated protein kinase α2-dependent mitochondrial homeostasis, and the protective effects of dulaglutide on diabetic heart was almost abated by AMP-activated protein kinase α2 knockout. Conclusions Dulaglutide prevents diabetic heart failure and favorably affects myocardial metabolic remodeling by impeding mitochondria fragmentation, and we suggest a potential strategy to develop a long-term activation of glucagon-like peptide-1 receptor-based therapy to treat diabetes associated cardiovascular complications.
Keyphrases
- type diabetes
- heart failure
- high fat diet
- insulin resistance
- protein kinase
- glycemic control
- left ventricular
- oxidative stress
- cardiovascular disease
- wild type
- mouse model
- high glucose
- clinical trial
- adipose tissue
- atrial fibrillation
- cell death
- wound healing
- fatty acid
- metabolic syndrome
- polycystic ovary syndrome
- randomized controlled trial
- climate change
- risk assessment
- study protocol
- preterm birth