From the SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK.
From the SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK.
Biochem Pharmacol. 2020 Jul;177:114009. doi: 10.1016/j.bcp.2020.114009. Epub 2020 Apr 30.
Loss of beta cell identity and subsequent transdifferentiation of beta-to-alpha cells is implicated in the pathogenesis of diabetes. In addition, sodium-glucose transport protein 2 (SGLT2) inhibition has been linked to altered alpha-cell function. To investigate these phenomenon, lineage tracing of beta-cells was examined following 10-12 days dapagliflozin (1 or 5 mg/kg, once daily, as appropriate) treatment in multiple low-dose streptozotocin (STZ), high fat fed (HFF) or hydrocortisone (HC) transgenic Ins1/Rosa26-eYFP mouse models of diabetes and insulin resistance. As anticipated, STZ, HFF and HC treated mice developed characteristic features of insulin deficiency or resistance. Dapagliflozin elicited differing beneficial effects depending on the aetiology of syndrome studied. The SGLT2 inhibitor efficiently promoted (P < 0.001) weight loss in HFF and STZ mice, whilst in HC mice it reduced (P < 0.001) energy intake, without an impact on body weight. Despite lacking significant effects on glycaemia, 1 mg/kg dapagliflozin consistently decreased both plasma and pancreatic glucagon. This was associated with increased pancreatic insulin in STZ and HFF mice. In STZ and HFF mice, beta cell proliferation and Pdx1 expression were enhanced by dapagliflozin, with a further increase in overall glucagon staining in HFF islets. Islet, beta- and alpha-cell areas were increased in dapagliflozin treated HC mice, which appeared to be linked to decreased alpha- and beta-cell apoptosis. Although the diabetes-like syndromes induced clear alterations in islet cell transdifferentiation, treatment with dapagliflozin (1 mg/kg) had no significant impact on this process, with 5 mg/kg marginally decreasing loss of beta-cells identity in STZ mice. These data suggest that SGLT2 inhibitors have positive effects on beta cells and decrease plasma and pancreatic glucagon, independent of changes in ambient glucose levels. Our combined data indicate that SGLT2 inhibitors do not directly induce hyperglucagonaemia.
β 细胞特征丧失和随后的β 细胞到α 细胞的转分化与糖尿病的发病机制有关。此外，钠-葡萄糖转运蛋白 2（SGLT2）抑制与α 细胞功能改变有关。为了研究这些现象，在多次低剂量链脲佐菌素（STZ）、高脂肪喂养（HFF）或氢化可的松（HC）转基因 Ins1/Rosa26-eYFP 糖尿病和胰岛素抵抗小鼠模型中，观察了 10-12 天 dapagliflozin（1 或 5mg/kg，每天一次，视情况而定）治疗后β 细胞的谱系追踪。正如预期的那样，STZ、HFF 和 HC 处理的小鼠表现出胰岛素缺乏或抵抗的特征。 dapagliflozin 根据所研究综合征的病因产生不同的有益效果。SGLT2 抑制剂在 HFF 和 STZ 小鼠中有效地促进（P<0.001）体重减轻，而在 HC 小鼠中减少（P<0.001）能量摄入，而对体重没有影响。尽管 dapagliflozin 对血糖没有显著影响，但 1mg/kg 的 dapagliflozin 始终降低血浆和胰腺胰高血糖素。这与 STZ 和 HFF 小鼠中胰腺胰岛素的增加有关。在 STZ 和 HFF 小鼠中，dapagliflozin 增强了β 细胞增殖和 Pdx1 表达，并在 HFF 胰岛中进一步增加了总胰高血糖素染色。在 dapagliflozin 治疗的 HC 小鼠中，胰岛、β 和α 细胞面积增加，这似乎与α 和β 细胞凋亡减少有关。尽管诱导的糖尿病样综合征导致胰岛细胞转分化明显改变，但 dapagliflozin（1mg/kg）治疗对该过程没有显著影响，5mg/kg 略微减少了 STZ 小鼠中β 细胞特征丧失。这些数据表明，SGLT2 抑制剂对β 细胞有积极影响，并降低血浆和胰腺胰高血糖素，而与环境葡萄糖水平的变化无关。我们的综合数据表明，SGLT2 抑制剂不会直接引起高胰高血糖症。
