Center Laboratories Inc., Taipei, Taiwan, R.O.C.
Lumosa Therapeutics Co., Ltd., Taipei, Taiwan, R.O.C.
PLoS One. 2021 Aug 6;16(8):e0255405. doi: 10.1371/journal.pone.0255405. eCollection 2021.
The global incidence of diabetes mellitus (DM) is increasing. Types 1 and 2 DM are associated with declining β-cell function. Verapamil (50% S-verapamil and 50% R-verapamil) can treat DM by downregulating thioredoxin-interacting protein (TXNIP), which induces islet β-cell apoptosis. However, it may also induce cardiovascular side effects as S-verapamil is negatively inotropic. In contrast, R-verapamil only weakly induces adverse cardiac effects. In this study, we aimed to determine the antidiabetic efficacy and cardiovascular safety of R-verapamil. We examined R- and S-verapamil binding through in vitro studies. Streptozotocin-induced type 1 and db/db type 2 DM mouse models were used to assess the antidiabetic efficacy of verapamil. IL-6, blood glucose (BG), Txnip expression, and β-cells were evaluated in streptozotocin-induced diabetic mice, while body weight, BG, and serum insulin were measured in the db/db mice. In the type 1 DM study, 100 mg/kg/day R-verapamil and racemic verapamil lowered BG, downregulated Txnip expression, and reduced β-cell apoptosis. In the type 2 DM study, the optimal R-verapamil dosage was 60 mg/kg/day and it lowered BG and raised serum insulin. However, efficacy did not increase with R-verapamil dosage. R-verapamil combined with metformin/acarbose improved BG and serum insulin more effectively than metformin/acarbose alone or verapamil combined with acarbose. R-verapamil had weaker cardiovascular side effects than S-verapamil. R-verapamil was 9.0× and 3.4× less effective than S-verapamil at inhibiting atrial inotropy and ileal contractility, respectively. It was also 8.7× weaker than S-verapamil as an agonist of somatostatin receptor type 2 (SSTR2), inhibiting ileal neurogenic contraction. Hence, R-verapamil may be an optimal DM treatment as it is safe, improves glycemic control, and preserves β-cell function both as monotherapy and in combination with metformin or acarbose. R-Verapamil has potential for delaying or arresting DM progression and improving patients' quality of life.
全球糖尿病（DM）发病率正在上升。1 型和 2 型 DM 与β细胞功能下降有关。维拉帕米（50% S-维拉帕米和 50% R-维拉帕米）可通过下调硫氧还蛋白相互作用蛋白（TXNIP）来治疗 DM，后者诱导胰岛β细胞凋亡。然而，由于 S-维拉帕米具有负性肌力作用，它也可能引起心血管副作用。相比之下，R-维拉帕米仅能微弱地诱导不良心脏作用。在这项研究中，我们旨在确定 R-维拉帕米的抗糖尿病疗效和心血管安全性。我们通过体外研究来检测 R-和 S-维拉帕米的结合。我们使用链脲佐菌素诱导的 1 型和 db/db 2 型 DM 小鼠模型来评估维拉帕米的抗糖尿病疗效。我们在链脲佐菌素诱导的糖尿病小鼠中评估了白细胞介素 6、血糖（BG）、Txnip 表达和β细胞，而在 db/db 小鼠中测量了体重、BG 和血清胰岛素。在 1 型 DM 研究中，100mg/kg/天的 R-维拉帕米和外消旋维拉帕米降低了 BG，下调了 Txnip 表达，并减少了β细胞凋亡。在 2 型 DM 研究中，最佳 R-维拉帕米剂量为 60mg/kg/天，可降低 BG 和提高血清胰岛素。然而，疗效并没有随 R-维拉帕米剂量的增加而增加。R-维拉帕米与二甲双胍/阿卡波糖联合使用比二甲双胍/阿卡波糖单独使用或维拉帕米与阿卡波糖联合使用更有效地改善 BG 和血清胰岛素。与 S-维拉帕米相比，R-维拉帕米的心血管副作用较弱。R-维拉帕米抑制心房不应性和回肠收缩性的效力分别比 S-维拉帕米低 9.0 倍和 3.4 倍。作为生长抑素受体 2（SSTR2）激动剂，它也比 S-维拉帕米弱 8.7 倍，抑制回肠神经源性收缩。因此，R-维拉帕米可能是一种安全的 DM 治疗方法，作为单一疗法或与二甲双胍或阿卡波糖联合使用，它可改善血糖控制并保护β细胞功能。R-维拉帕米具有延缓或阻止 DM 进展和提高患者生活质量的潜力。
