Department of Nephrology, Osaka Medical and Pharmaceutical University, Osaka, Japan.
Laboratory of Pharmacology, Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe 610-0395, Kyoto, Japan.
Biomed Pharmacother. 2023 Sep;165:115032. doi: 10.1016/j.biopha.2023.115032. Epub 2023 Jun 16.
Diabetic kidney disease (DKD) is the most common cause of chronic kidney disease (CKD), leading end-stage renal disease. Thus, DKD is one of the most important diabetic complications. Incretin-based therapeutic agents, such as glucagon-like peptide-1 (GLP-1) receptor agonizts and dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to elicit vasotropic actions, suggesting a potential for effecting reduction in DKD. Glucose-dependent insulinotropic polypeptide (GIP) is also classified as an incretin. However, the insulin action after GIP secretion is known to be drastically reduced in patients with type 2 diabetes. Therefore, GIP has been formally considered unsuitable as a treatment for type 2 diabetes in the past. This concept is changing as it has been reported that resistance to GIP can be reversed and its effect restored with improved glycemic control. The development of novel dual- or triple- receptor agonizts that can bind to the receptors, not only for GLP-1 but also to GIP and glucagon receptors, is intended to simultaneously address several metabolic pathways including protein, lipid, and carbohydrate metabolism. These led to the development of GIP receptor agonist-based drugs for type 2 diabetes. The possibility of combined GIP/GLP-1 receptor agonist was also explored. The novel dual GIP and GLP-1 receptor agonist tirzepatide has recently been launched (Mounjaro®, Lilly). We have revealed precise mechanisms of the renoprotective effect of GLP-1 receptor agonizts or DPP-4 inhibitors, while the long-term effect of tirzepatide will need to be determined and its potential effects on kidneys should be properly tested.
糖尿病肾病（DKD）是慢性肾脏病（CKD）的最常见病因，导致终末期肾病。因此，DKD 是最重要的糖尿病并发症之一。肠促胰岛素治疗药物，如胰高血糖素样肽-1（GLP-1）受体激动剂和二肽基肽酶-4（DPP-4）抑制剂，已被报道具有血管活性作用，表明其可能对减少 DKD 有作用。葡萄糖依赖性胰岛素释放肽（GIP）也被归类为肠促胰岛素。然而，已知在 2 型糖尿病患者中，GIP 分泌后的胰岛素作用会大大降低。因此，过去 GIP 被正式认为不适合作为 2 型糖尿病的治疗药物。随着研究的进展，人们发现随着血糖控制的改善，GIP 的抵抗可以被逆转，其作用可以被恢复，这种观念正在发生变化。开发能够与 GLP-1 受体结合的新型双重或三重受体激动剂，同时也能与 GIP 和胰高血糖素受体结合，旨在同时解决包括蛋白质、脂质和碳水化合物代谢在内的几种代谢途径。这导致了用于 2 型糖尿病的 GIP 受体激动剂药物的开发。也探索了联合使用 GIP/GLP-1 受体激动剂的可能性。新型双重 GIP 和 GLP-1 受体激动剂替西帕肽（Mounjaro®，礼来公司）最近已经推出。我们已经揭示了 GLP-1 受体激动剂或 DPP-4 抑制剂的肾保护作用的精确机制，而替西帕肽的长期效果需要确定，其对肾脏的潜在影响需要适当测试。
