Department of Surgery and Cancer, Imperial College London, London, UK; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
Peptides. 2024 Jun;176:171219. doi: 10.1016/j.peptides.2024.171219. Epub 2024 Apr 13.
People with obesity and type 2 diabetes have a high prevalence of metabolic-associated steatotic liver disease, hyperlipidemia and cardiovascular disease. Glucagon increases hepatic glucose production; it also decreases hepatic fat accumulation, improves lipidemia and increases energy expenditure. Pharmaceutical strategies to antagonize the glucagon receptor improve glycemic outcomes in people with diabetes and obesity, but they increase hepatic steatosis and worsen dyslipidemia. Co-agonism of the glucagon and glucagon-like peptide-1 (GLP-1) receptors has emerged as a promising strategy to improve glycemia in people with diabetes and obesity. Addition of glucagon receptor agonism enhances weight loss, reduces liver fat and ameliorates dyslipidemia. Prior to clinical use, however, further studies are needed to investigate the safety and efficacy of glucagon and GLP-1 receptor co-agonists in people with diabetes and obesity and related conditions, with specific concerns regarding a higher prevalence of gastrointestinal side effects, loss of muscle mass and increases in heart rate. Furthermore, co-agonists with differing ratios of glucagon:GLP-1 receptor activity vary in their clinical effect; the optimum balance is yet to be identified.
肥胖和 2 型糖尿病患者中代谢相关脂肪性肝病、血脂异常和心血管疾病的患病率很高。胰高血糖素可增加肝葡萄糖生成；它还可减少肝脂肪堆积，改善血脂异常并增加能量消耗。拮抗胰高血糖素受体的药物治疗策略可改善糖尿病和肥胖患者的血糖控制，但会增加肝脂肪变性并加重血脂异常。胰高血糖素和胰高血糖素样肽-1（GLP-1）受体的共同激动作用已成为改善糖尿病和肥胖患者血糖的一种有前途的策略。添加胰高血糖素受体激动剂可增强减重效果、减少肝脏脂肪并改善血脂异常。然而，在临床应用之前，还需要进一步研究胰高血糖素和 GLP-1 受体共同激动剂在糖尿病和肥胖症及相关疾病患者中的安全性和疗效，具体而言，人们对胃肠道副作用、肌肉质量损失和心率增加的发生率较高表示担忧。此外，具有不同胰高血糖素：GLP-1 受体活性比例的共同激动剂在临床效果上存在差异；最佳平衡仍有待确定。
