University of the Ryukyus, Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, Okinawa, Japan.
GenomIdea Incorporated, Okinawa, Japan.
J Diabetes Res. 2020 Dec 27;2020:1682904. doi: 10.1155/2020/1682904. eCollection 2020.
Many blood glucose-lowering drugs cannot be used once patients with type 2 diabetes (T2D) and nonalcoholic fatty liver disease develop nonalcoholic steatohepatitis (NASH). Therefore, such patients often require insulin treatment. We aimed to determine the effect of sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin monotherapy on glucose metabolism in a mouse model of NASH/T2D, with a focus on its diuretic effects. To imitate ascites and to determine its severity by imaging, meglumine sodium amidotrizoate (MSA) was infused into the abdominal cavities of mice. The reduction in ascites induced by dapagliflozin was compared with that induced by furosemide using microcomputed tomography. The effects of each drug on hemodynamics were also compared. A dapagliflozin-related improvement in glucose tolerance was achieved in mice fed a high-fat diet (HFD) or an HFD + methionine-and-choline-deficient diet (MCDD). In dapagliflozin-treated NASH mice, hypoglycemia was not identified during 24-hour casual blood glucose monitoring. In the dapagliflozin and furosemide-treated groups, the time taken for the resolution of artificial ascites was significantly shorter than in the untreated group, and there were no significant differences between these groups. Furosemide significantly reduced the blood pressure and significantly increased the heart rate of the mice. Dapagliflozin caused a mild decrease in systolic, but not diastolic blood pressure, and the heart rate and circulating catecholamine and renin-aldosterone concentrations were unaffected. Dapagliflozin treatment improved glycemic control in the NASH mice versus untreated mice. Thus, dapagliflozin had a prompt diuretic effect but did not adversely affect the hemodynamics of mice with NASH and T2D. Therefore, it may be useful for the treatment of patients with both T2D and liver cirrhosis.
许多降血糖药物不能用于 2 型糖尿病（T2D）和非酒精性脂肪性肝病患者一旦发生非酒精性脂肪性肝炎（NASH）。因此，此类患者通常需要胰岛素治疗。我们旨在确定钠-葡萄糖共转运蛋白 2 抑制剂（SGLT2i）达格列净单药治疗在 NASH/T2D 小鼠模型中对葡萄糖代谢的影响，重点关注其利尿作用。为了模拟腹水并通过成像确定其严重程度，将葡甲胺 amidotrizoate（MSA）注入小鼠腹腔。使用 microCT 比较达格列净和呋塞米诱导的腹水减少。还比较了每种药物对血液动力学的影响。在高脂肪饮食（HFD）或 HFD +蛋氨酸和胆碱缺乏饮食（MCDD）喂养的小鼠中，达格列净相关的葡萄糖耐量得到改善。在达格列净治疗的 NASH 小鼠中，在 24 小时随意血糖监测期间未发现低血糖。在达格列净和呋塞米治疗组中，人工腹水消退所需的时间明显短于未治疗组，且两组之间无显著差异。呋塞米显著降低了小鼠的血压并显著增加了心率。达格列净导致收缩压轻度下降，但舒张压无变化，心率和循环儿茶酚胺和肾素-血管紧张素浓度不受影响。达格列净治疗可改善 NASH 小鼠的血糖控制，而未治疗的小鼠则无改善。因此，达格列净具有迅速的利尿作用，但不会对 NASH 和 T2D 小鼠的血液动力学产生不利影响。因此，它可能对同时患有 T2D 和肝硬化的患者有用。
