Early Treatment with Empagliflozin and GABA Improves β-Cell Mass and Glucose Tolerance in Streptozotocin-Treated Mice
Early Treatment with Empagliflozin and GABA Improves β-Cell Mass and Glucose Tolerance in Streptozotocin-Treated Mice
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DOI：
10.1155/2019/2813489
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发表时间：
2019-07-30
影响因子：
4.3
通讯作者：
Lysy, Philippe A.
中科院分区：
文献类型：
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作者：
Daems, Caroline;Welsch, Sophie;Lysy, Philippe A.
虽然T1 D（1型糖尿病）的自身免疫特征受到挑战，但目前公认炎症在其发展中起着关键作用。我们假设葡萄糖毒性可能通过参与胰岛炎症导致β细胞大量破坏。我们评价了恩格列净（EMPA）和GABA（γ-氨基丁酸）在T1 D诊断后保护β细胞群免受葡萄糖毒性和增加β细胞群的潜力。恩格列净是一种SGLT 2（钠依赖性葡萄糖协同转运蛋白）抑制剂，可阻断肾脏对葡萄糖的再捕获，促进葡萄糖经尿液排泄。GABA是一种抑制性神经递质，可刺激α细胞向β细胞的转分化。在链脲佐菌素处理的小鼠中，给予恩格列净和/或GABA 5天或3周。与未处理的T1 D小鼠相比，EMPA处理的T1 D小鼠具有降低的FFA（游离脂肪酸）水平和改善的葡萄糖稳态。EMPA处理的T1 D小鼠具有更高的胰岛密度，与T1 D小鼠相比，具有保留的结构，EMPA处理的T1 D小鼠与T1 D小鼠的不同之处还在于胰岛内完全不存在免疫细胞浸润。来自EMPA处理的小鼠的胰岛也较少经受ER（内质网）应激和炎症，如qPCR分析所示。当T1 D小鼠用GABA和EMPA治疗三周时，与糖尿病对照组相比，葡萄糖稳态参数和胰岛面积/胰腺面积比得到改善。T1 D EMPA+GABA小鼠的胰高血糖素水平高于T1 D小鼠，而胰高血糖素面积/胰岛面积比没有改变。总之，恩格列净和GABA单药治疗链脲佐菌素诱导的糖尿病小鼠，通过对胰岛细胞炎症和ER应激的间接影响，对β细胞质量保持或增殖具有积极作用。必须进行进一步研究，以评价恩格列净和GABA是否可能是新发T1 D后保护β细胞群的潜在治疗靶点。
While the autoimmune character of T1D (type 1 diabetes) is being challenged, it is currently recognized that inflammation plays a key role in its development. We hypothesized that glucotoxicity could contribute to beta-cell mass destruction through participation in islet inflammation. We evaluated the potential of empagliflozin (EMPA) and GABA (gamma-aminobutyric acid) to protect beta-cell mass against glucotoxicity and to increase beta-cell mass after diagnosis of T1D. Empagliflozin is a SGLT2 (sodium-dependent glucose cotransporter) inhibitor which thereby blocks glucose recapture by the kidney and promotes glucose excretion in urine. GABA is an inhibitory neurotransmitter, which stimulates alpha-to-beta cell transdifferentiation. In streptozotocin-treated mice, empagliflozin and/or GABA were delivered for a period of five days or three weeks. As compared to untreated T1D mice, EMPA-treated T1D mice had decreased FFA (free fatty acid) levels and improved glucose homeostasis. EMPA-treated T1D mice had higher islet density, with preserved architecture, compared to T1D mice, and EMPA-treated T1D mice also differed from T1D mice by the total absence of immune cell infiltration within islets. Islets from EMPA-treated mice were also less subjected to ER (endoplasmic reticulum) stress and inflammation, as shown by qPCR analysis. Glucose homeostasis parameters and islet area/pancreas area ratio improved, as compared to diabetic controls, when T1D mice were treated for three weeks with GABA and EMPA. T1D EMPA+GABA mice had higher glucagon levels than T1D mice, without modifications of glucagon area/islet area ratios. In conclusion, empagliflozin and GABA, used in monotherapy in streptozotocin-induced diabetic mice, have positive effects on beta-cell mass preservation or proliferation through an indirect effect on islet cell inflammation and ER stress. Further research is mandatory to evaluate whether empagliflozin and GABA may be a potential therapeutic target for the protection of beta-cell mass after new-onset T1D.