Department of Medicine, Austin Hospital, University of Melbourne, Heidelberg, Victoria, Australia.
Diabetes Obes Metab. 2017 Aug;19(8):1135-1146. doi: 10.1111/dom.12923. Epub 2017 Apr 6.
To determine whether the excretion of glucose improves insulin resistance, impaired insulin secretion or both.
Appropriate methods were used to assess insulin sensitivity (euglycaemic-hyperinsulinaemic clamp) and insulin secretion (hyperglycaemic clamp) in insulin-resistant and hyperglycaemic phosphoenolpyruvate carboxykinase (PEPCK) transgenic rats after treatment with the sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin.
In 14-week-old rats with hyperglycaemia, insulin resistance and glucose intolerance, 6 weeks of dapagliflozin treatment resulted in lower weight gain, plasma glucose and insulin levels, and improved glucose tolerance, associated with enhanced insulin sensitivity (rate of glucose disappearance: 51.6 ± 2.3 vs 110.6 ± 3.9 µmol/min/kg; P < .005) and glucose uptake in muscle (0.9 ± 0.1 vs 1.7 ± 0.3 µmol/min/100 g; P < .05) and fat (0.23 ± 0.04 vs 0.55 ± 0.10 µmol/min/100 g, P < .05). Additionally, adipose tissue GLUT4 protein levels were increased (0.78 ± 0.05 vs 1.20 ± 0.09 arbitrary units; P < .05), adipocyte count was higher (221.4 ± 17.7 vs 302.3 ± 21.7 per mm fat area; P < .05) and adipocyte size was reduced (4631.8 ± 351.5 vs 3397.6 ± 229.4 µm , P < .05). There was no improvement, however, in insulin secretion. To determine whether earlier intervention is necessary, 5-week-old PEPCK transgenic rats were treated with dapagliflozin for 9 weeks and insulin secretion assessed. Dapagliflozin resulted in improved plasma glucose and insulin levels, and lower weight gain but, again, insulin secretion was not improved.
In this transgenic model of low-grade chronic hyperglycaemia, SGLT2 inhibitor treatment resulted in reduced blood glucose and insulin levels and enhanced glucose tolerance, associated with improved muscle and fat insulin resistance but not improved insulin secretory function.
确定葡萄糖的排泄是否改善胰岛素抵抗、受损的胰岛素分泌或两者兼而有之。
在接受钠-葡萄糖协同转运蛋白-2（SGLT2）抑制剂达格列净治疗后，使用适当的方法评估胰岛素抵抗和高血糖磷酸烯醇丙酮酸羧激酶（PEPCK）转基因大鼠的胰岛素敏感性（正常血糖-高胰岛素钳夹）和胰岛素分泌（高血糖钳夹）。
在 14 周龄、高血糖、胰岛素抵抗和葡萄糖耐量受损的大鼠中，6 周的达格列净治疗导致体重增加、血浆葡萄糖和胰岛素水平降低，以及葡萄糖耐量改善，与增强的胰岛素敏感性（葡萄糖清除率：51.6±2.3 对 110.6±3.9 µmol/min/kg；P<.005）和肌肉（0.9±0.1 对 1.7±0.3 µmol/min/100 g；P<.05）和脂肪（0.23±0.04 对 0.55±0.10 µmol/min/100 g，P<.05）中的葡萄糖摄取增加有关。此外，脂肪组织 GLUT4 蛋白水平升高（0.78±0.05 对 1.20±0.09 任意单位；P<.05），脂肪细胞计数更高（221.4±17.7 对 302.3±21.7/脂肪面积 mm ；P<.05），脂肪细胞大小减小（4631.8±351.5 对 3397.6±229.4 µm，P<.05）。然而，胰岛素分泌并没有改善。为了确定是否需要早期干预，对 5 周龄的 PEPCK 转基因大鼠用达格列净治疗 9 周，并评估胰岛素分泌。达格列净导致血糖和胰岛素水平改善，体重增加减少，但胰岛素分泌再次没有改善。
在这种低度慢性高血糖的转基因模型中，SGLT2 抑制剂治疗可降低血糖和胰岛素水平，并改善葡萄糖耐量，与肌肉和脂肪胰岛素抵抗改善相关，但胰岛素分泌功能未改善。
