Imeglimin preserves islet β-cell mass in Type 2 diabetic ZDF rats.
Imeglimin preserves islet β-cell mass in Type 2 diabetic ZDF rats.
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DOI：
10.1002/edm2.193
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发表时间：
2021-04
影响因子：
--
通讯作者：
Bolze S
中科院分区：
文献类型：
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作者：
Hallakou-Bozec S;Kergoat M;Moller DE;Bolze S
2型糖尿病（T2D）是由进行性功能障碍和胰腺β细胞质量损失驱动的。Imeglimin是一种新型候选药物，可改善临床前模型和患者的血糖和葡萄糖刺激的胰岛素分泌。鉴于有证据表明，在体外，imeglimin可以减轻β细胞功能障碍并保护β细胞，我们假设，在体内，imeglimin也可以发挥更长期的作用，防止胰腺β细胞死亡并保持功能β细胞群。采用标准剂量150 mg/kg或整车灌胃伊米霉素治疗Zucker糖尿病性脂肪（ZDF）雄性大鼠，每天2次，连续5周。治疗结束后，禁食动物进行口服糖耐量试验，然后对胰腺组织切片进行彻底的组织形态测定和免疫组织化学分析，以评估细胞组成和疾病状态。伊米霉素治疗显著改善葡萄糖刺激的胰岛素分泌（胰岛素原指数增加）和改善血糖。伊米霉素也增加了基础胰岛素血症和胰腺胰岛素含量。ZDF对照组大鼠胰岛结构紊乱，β细胞减少；在伊米霉素治疗后，胰岛看起来更健康，形态更正常，胰岛素阳性β细胞显著增加。在细胞凋亡减少的情况下，β细胞质量的增加与β细胞增殖程度的提高有关。出乎意料的是，由于伊米霉素对这种细胞类型具有明显的抗增殖作用，也记录了as α -细胞质量的减少。在雄性ZDF大鼠中，慢性伊米霉素治疗纠正了2型糖尿病进展的一个重要组成部分：功能性β细胞质量的逐渐丧失。此外，依米明还可以调节a细胞的周转，从而进一步改善高血糖。总的来说，这些细胞效应表明，伊米霉素可能提供疾病调节作用，以保持功能性β细胞质量。Imeglimin是一种治疗2型糖尿病的新型候选药物，已经完成了III期试验；其机制涉及增强胰岛β细胞功能的作用。依米霉素治疗ZDF大鼠可改善葡萄糖耐受不良和增加胰岛素血症。慢性伊米霉素治疗后胰岛β细胞质量增加；依米霉素治疗后，β细胞凋亡减少，增殖增加。
Type 2 diabetes (T2D) is driven by progressive dysfunction and loss of pancreatic β‐cell mass. Imeglimin is a first‐in‐class novel drug candidate that improves glycaemia and glucose‐stimulated insulin secretion in preclinical models and patients. Given evidence that imeglimin can attenuate β‐cell dysfunction and protect β cells in vitro, we postulated that imeglimin could also exert longer term effects to prevent pancreatic β‐cell death and preserve functional β‐cell mass in vivo. Zucker diabetic fatty (ZDF) male rats were treated by oral gavage with imeglimin at a standard dose of 150 mg/kg or vehicle, twice daily for five weeks. At treatment completion, oral glucose tolerance tests were performed in fasted animals before a thorough histomorphometry and immunohistochemical analysis was conducted on pancreas tissue slices to assess cellular composition and disease status. Imeglimin treatment significantly improved glucose‐stimulated insulin secretion (augmentation of the insulinogenic index) and improved glycaemia. Both basal insulinaemia and pancreatic insulin content were also increased by imeglimin. In ZDF control rats, islet structure was disordered with few β‐cells; after imeglimin treatment, islets appeared healthier with more normal morphology in association with a significant increase in insulin‐positive β‐cells. The increase in β‐cell mass was associated with a greater degree of β‐cell proliferation in the presence of reduced apoptosis. Unexpectedly, a decrease in as a α‐cell mass was also documented due to an apparent antiproliferative effect of imeglimin on this cell type. In male ZDF rats, chronic imeglimin treatment corrects a paramount component of type 2 diabetes progression: progressive loss of functional β‐cell mass. In addition, imeglimin may also moderate a‐cell turnover to further ameliorate hyperglycaemia. Cumulatively, these cellular effects suggest that imeglimin may provide for disease modifying effects to preserve functional β‐cell mass. Imeglimin is a novel drug candidate for type 2 diabetes, which has completed Phase III trials; its mechanism involves effects to augment islet β‐cell function. Imeglimin treatment of ZDF rats is shown to ameliorate glucose intolerance and increase insulinemia. Islet β‐cell mass is increased after chronic imeglimin treatment; β‐cell apoptosis is reduced, and proliferation is increased in response to imeglimin treatment.