The Sodium Glucose Cotransporter Type 2 Inhibitor Empagliflozin Preserves β-Cell Mass and Restores Glucose Homeostasis in the Male Zucker Diabetic Fatty Rat
The Sodium Glucose Cotransporter Type 2 Inhibitor Empagliflozin Preserves β-Cell Mass and Restores Glucose Homeostasis in the Male Zucker Diabetic Fatty Rat
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DOI：
10.1124/jpet.114.213454
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发表时间：
2014-09-01
影响因子：
3.5
通讯作者：
Mayoux, Eric
中科院分区：
文献类型：
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作者：
Hansen, Henrik H.;Jelsing, Jacob;Mayoux, Eric
2型糖尿病的特征是β细胞功能受损，与胰岛素分泌和β细胞质量的进行性减少有关。显然，在β细胞保护和抗糖尿病功效方面，对更可持续的治疗方法的需求尚未得到满足。通过胰岛素和β细胞不依赖的机制，恩格列净，一种特殊的钠葡萄糖共转运蛋白2 （SGLT-2）抑制剂，可能提供更长的疗效。本研究比较了恩格列净治疗（10 mg/kg p.o）与格列本脲（3 mg/kg p.o）和利拉鲁肽（0.2 mg/kg s.c）对Zucker糖尿病脂肪（ZDF）大鼠葡萄糖稳态缺陷和β细胞功能的抗糖尿病持久性。恩格列净和利拉鲁肽显著改善了饲粮葡萄糖和血红蛋白A1c水平，并阻止了胰岛素水平的逐渐下降。相比之下，格列本脲无效。与第4周相比，利拉鲁肽在治疗第8周的效果不那么明显，而恩格列净的效果在整个研究期间保持稳定。同样，恩格列净在治疗4周和8周后均能改善糖耐量并保持胰岛素分泌。这些作用反映在第4周时恩帕列净或利拉鲁肽对β细胞质量的减少较少，而只有恩帕列净在第8周也显示出β细胞保留作用。虽然本研究不能将不同药物作用机制之间的绝对降糖效果分离开来，但该研究表明，恩格列净对ZDF大鼠的葡萄糖稳态和β细胞保护具有更持久的改善作用。与其他2型糖尿病治疗相比，SGLT-2抑制剂可能通过胰岛素非依赖性途径，从而增强β细胞保护的持久性和降糖效果。
Type 2 diabetes is characterized by impaired beta-cell function associated with progressive reduction of insulin secretion and beta-cell mass. Evidently, there is an unmet need for treatments with greater sustainability in beta-cell protection and antidiabetic efficacy. Through an insulin and beta cell-independent mechanism, empagliflozin, a specific sodium glucose cotransporter type 2 (SGLT-2) inhibitor, may potentially provide longer efficacy. This study compared the antidiabetic durability of empagliflozin treatment (10 mg/kg p.o.) against glibenclamide (3 mg/kg p.o.) and liraglutide (0.2 mg/kg s.c.) on deficient glucose homeostasis and beta-cell function in Zucker diabetic fatty (ZDF) rats. Empagliflozin and liraglutide led to marked improvements in fed glucose and hemoglobin A1c levels, as well as impeding a progressive decline in insulin levels. In contrast, glibenclamide was ineffective. Whereas the effects of liraglutide were less pronounced at week 8 of treatment compared with week 4, those of empagliflozin remained stable throughout the study period. Similarly, empagliflozin improved glucose tolerance and preserved insulin secretion after both 4 and 8 weeks of treatment. These effects were reflected by less reduction in beta-cell mass with empagliflozin or liraglutide at week 4, whereas only empagliflozin showed beta-cell sparing effects also at week 8. Although this study cannot be used to dissociate the absolute antidiabetic efficacy among the different mechanisms of drug action, the study demonstrates that empagliflozin exerts a more sustained improvement of glucose homeostasis and beta-cell protection in the ZDF rat. In comparison with other type 2 diabetic treatments, SGLT-2 inhibitors may through insulin-independent pathways thus enhance durability of beta-cell protection and antidiabetic efficacy.