达格列净抑制 SGLT2 可减轻 1 型糖尿病小鼠的糖尿病酮症酸中毒。
SGLT2 Inhibition by Dapagliflozin Attenuates Diabetic Ketoacidosis in Mice with Type-1 Diabetes.
机构信息
The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd, BSB 648, Galveston, TX, 77555, USA.
Department of Acupuncture, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
出版信息
Cardiovasc Drugs Ther. 2022 Dec;36(6):1091-1108. doi: 10.1007/s10557-021-07243-6. Epub 2021 Aug 27.
BACKGROUND
SGLT2 inhibitors increase plasma ketone concentrations. It has been suggested that insulinopenia, along with an increase in the counter-regulatory hormones epinephrine, corticosterone, glucagon and growth hormone, can induce ketoacidosis, especially in type-1 diabetes (T1DM). Dehydration precipitates SGLT2 inhibitor-induced ketoacidosis in type-2 diabetes. We studied the effects of dapagliflozin and water deprivation on the development of ketoacidosis and the associated signaling pathways in T1DM mice.
METHODS
C57BL/6 mice were fed a high-fat diet. After 7 days, some mice received intraperitoneal injection of streptozocin + alloxan (STZ/ALX). The treatment groups were control + water at lib; control + dapagloflozin + water at lib; control + dapagloflozin + water deprivation; STZ/ALX + water at lib; STZ/ALX + water deprivation; STZ/ALX + dapagloflozin + water at lib; STZ/ALX + dapagloflozin + water deprivation. Dapagliflozin was given for 7 days. In the morning of day 18, food was removed, and water was removed in the water deprivation groups. ELISA, rt-PCR, and immunoblotting were used to assess blood, heart, liver, white and brown adipose tissues.
RESULTS
The T1DM mice had ketoacidosis even without water deprivation. Water deprivation increased plasma levels of β-hydroxybutyrate, acetoacetate, corticosterone, and epinephrine and reduced the levels of adiponectin in T1DM mice. Interleukin (IL) 1β, IL-6, IL-8, and TNFα were also increased in the T1DM mice with water deprivation. Dapagliflozin attenuated the changes in the T1DM mice without and with water deprivation. Likewise, water deprivation increased the activation of the inflammasome in the heart, liver, and white fat of the T1DM mice and dapagliflozin attenuated these changes. Dapagliflozin reduced the mRNA levels of glucagon receptors in the liver and the increase in GPR109a in white and brown fat. In the liver, dapagliflozin increased AMPK phosphorylation, and attenuated the phosphorylation of TBK1 and the activation of NFκB.
CONCLUSIONS
Dapagliflozin reduced ketone body levels and attenuated the activation of NFκB and the activation of the inflammasome in T1DM mice with ketoacidosis.
背景
SGLT2 抑制剂会增加血浆酮体浓度。有研究表明，胰岛素缺乏以及肾上腺素、皮质酮、胰高血糖素和生长激素等抗调节激素的增加，可诱发酮症酸中毒，尤其是在 1 型糖尿病（T1DM）患者中。在 2 型糖尿病中，脱水会促使 SGLT2 抑制剂诱发酮症酸中毒。我们研究了达格列净和脱水对 T1DM 小鼠酮症酸中毒发展和相关信号通路的影响。
方法
C57BL/6 小鼠给予高脂肪饮食。7 天后，一些小鼠接受链脲佐菌素+别嘌呤醇（STZ/ALX）腹腔注射。对照组给予自由饮水；对照组给予达格列净+自由饮水；对照组给予达格列净+限水；STZ/ALX 组给予自由饮水；STZ/ALX 组限水；STZ/ALX 组给予达格列净+自由饮水；STZ/ALX 组给予达格列净+限水。达格列净治疗 7 天。第 18 天早晨，禁食，限水组限水。采用 ELISA、rt-PCR 和免疫印迹法检测血、心、肝、白、棕色脂肪组织。
结果
即使没有限水，T1DM 小鼠也会发生酮症酸中毒。限水增加了 T1DM 小鼠的β-羟丁酸、乙酰乙酸盐、皮质酮和肾上腺素的血浆水平，并降低了 T1DM 小鼠的脂联素水平。T1DM 小鼠限水后白细胞介素（IL）1β、IL-6、IL-8 和 TNFα也增加。达格列净减弱了 T1DM 小鼠无论是否限水的上述变化。同样，限水增加了 T1DM 小鼠心脏、肝脏和白色脂肪组织中炎症小体的激活，达格列净减弱了这些变化。达格列净降低了肝脏中胰高血糖素受体的 mRNA 水平，并减少了白色和棕色脂肪中 GPR109a 的增加。在肝脏中，达格列净增加 AMPK 磷酸化，减弱了 TBK1 的磷酸化和 NFκB 的激活。
结论
达格列净降低了酮体水平，并减弱了 T1DM 酸中毒小鼠中 NFκB 和炎症小体的激活。
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