AIMS SGLT2 inhibitors have been proposed as an adjunct to insulin therapy for glycemic control in type 1 diabetes (T1D) patients. However, concern has been raised due to an increase in renin-angiotensin-system (RAS) activity reported in a clinical trial in which an SGLT2 inhibitor was added while insulin dose was reduced in T1D patients. We previously reported that insulin inhibits intrarenal angiotensinogen (Agt) gene transcription and RAS activation. We hypothesized that insulin, rather than SGLT2 inhibition might regulate the intrarenal RAS. METHODS We compared RAS activity in non-diabetic wild type mice, Akita mice (T1D model) and Akita mice treated with insulin or the SGLT2 inhibitor canagliflozin. RESULTS Treatment of Akita mice with insulin or canagliflozin produced similar reductions in blood glucose, whereas insulin, but not canagliflozin, reduced elevated systolic blood pressure. Akita mice exhibited increased renal Agt mRNA/protein expression, which was attenuated by insulin, but not by canagliflozin. Furthermore, insulin was more effective than canagliflozin in lowering kidney weight and albuminuria. CONCLUSIONS Insulin, but not canagliflozin, lowers intrarenal RAS activity in Akita mice. Our findings can be of potential clinical importance, especially for T1D patients who are not on RAS inhibitors at the time of adding SGLT2 inhibitors.

中文翻译：

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胰岛素和SGLT2抑制剂对1型糖尿病小鼠的肾素-血管紧张素系统的作用比较。

已提出将AIMS SGLT2抑制剂作为胰岛素治疗的辅助手段来控制1型糖尿病（T1D）患者的血糖。然而，由于在T1D患者中加入SGLT2抑制剂而降低胰岛素剂量的临床试验中报道的肾素-血管紧张素系统（RAS）活性增加引起了人们的关注。我们以前曾报道过胰岛素抑制肾内血管紧张素原（Agt）基因的转录和RAS激活。我们假设胰岛素而不是SGLT2抑制可能调节肾内RAS。方法我们比较了非糖尿病野生型小鼠，秋田小鼠（T1D模型）和经胰岛素或SGLT2抑制剂卡格列净治疗的秋田小鼠的RAS活性。结果用胰岛素或卡格列净治疗秋田小鼠，血糖降低相似，而胰岛素，但canagliflozin不能降低收缩压升高。秋田小鼠表现出增加的肾脏Agt mRNA /蛋白质表达，这被胰岛素减弱，但卡那列净却不减弱。此外，胰岛素在降低肾脏重量和蛋白尿方面比卡格列净更有效。结论胰岛素而不是canagliflozin可以降低秋田小鼠的肾内RAS活性。我们的发现可能具有潜在的临床重要性，尤其是对于在添加SGLT2抑制剂时未使用RAS抑制剂的T1D患者。降低秋田小鼠的肾内RAS活性。我们的发现可能具有潜在的临床重要性，尤其是对于在添加SGLT2抑制剂时未使用RAS抑制剂的T1D患者。降低秋田小鼠的肾内RAS活性。我们的发现可能具有潜在的临床意义，特别是对于在添加SGLT2抑制剂时未使用RAS抑制剂的T1D患者。