Potent Sodium/Glucose Cotransporter SGLT1/2 Dual Inhibition Improves Glycemic Control Without Marked Gastrointestinal Adaptation or Colonic Microbiota Changes in Rodents
Potent Sodium/Glucose Cotransporter SGLT1/2 Dual Inhibition Improves Glycemic Control Without Marked Gastrointestinal Adaptation or Colonic Microbiota Changes in Rodents
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DOI：
10.1124/jpet.118.248575
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发表时间：
2018-06-01
影响因子：
3.5
通讯作者：
Hornby, Pamela J.
中科院分区：
文献类型：
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作者：
Du, Fuyong;Hinke, Simon A.;Hornby, Pamela J.
钠/葡萄糖协同转运蛋白（SGLT1 和 SGLT2）将葡萄糖转运穿过肠刷状缘和肾小管。在 2 型糖尿病患者中，双重 SGLT1/2 抑制比 SGLT2 选择性抑制更能降低高血糖。然而，关于胃肠道(GI)管腔葡萄糖和耐受性改变的问题仍然存在，并且这是在slc5a1(-/-)小鼠中或用强效双重抑制剂(化合物8；SGLT1 K-i = 1.5 +/- 0.5 nM，比根皮苷效力高100倍；SGLT2 K-i = 0.4 +/- 0.2 nM)进行评估。对 slc5a1(-/-) 小鼠和离体大鼠空肠中的 (13)C(6) 葡萄糖摄取进行定量。测量尿葡萄糖排泄 (UGE)、血糖（Sprague-Dawley 大鼠）、胰高血糖素样肽 1 (GLP-1) 和血红蛋白 A1c (HbA1c) 水平（Zucker 糖尿病脂肪大鼠）。对 C57BI/6 小鼠的肠道适应和 rRNA 基因测序进行了分析。在没有 SGLT1 的情况下，血液 C-13(6)-葡萄糖曲线下面积 (AUC) 降低了 75%（野生型小鼠为 245 +/- 6，slc5a1(-/-) 小鼠为 64 +/- 6 mg/dl.h），化合物 8 在离体大鼠空肠中抑制其转运高达 50%。化合物 8 比 SGLT2 选择性抑制更能减少葡萄糖漂移（例如，1 mg/kg 化合物 8 与达格列净相比，AUC = 129 +/- 3 vs. 249 +/- 5 mg/dl-h），具有相似的 UGE，但肾葡萄糖排泄阈值较低。在 Zucker 糖尿病脂肪大鼠中，化合物 8 降低了 HbA1c 并增加了总 GLP-1，但空肠 SGLT1 表达、粘膜重量或绒毛长度没有变化。总体而言，化合物 8（1 mg/kg，持续 6 天）不会增加 C57BL76 小鼠的盲肠葡萄糖浓度或细菌多样性。总之，有效的双重 SGLT1/2 抑制通过降低肠道葡萄糖吸收和肾葡萄糖阈值来降低血糖，但对食物喂养的啮齿动物的肠粘膜或管腔微生物群的影响最小。
The sodium/glucose cotransporters (SGLT1 and SGLT2) transport glucose across the intestinal brush border and kidney tubule. Dual SGLT1/2 inhibition could reduce hyperglycemia more than SGLT2-selective inhibition in patients with type 2 diabetes. However, questions remain about altered gastrointestinal (Gl) luminal glucose and tolerability, and this was evaluated in slc5a1(-/-) mice or with a potent dual inhibitor (compound 8; SGLT1 K-i = 1.5 +/- 0.5 nM 100-fold greater potency than phlorizin; SGLT2 K-i = 0.4 +/- 0.2 nM). (13)C(6)glucose uptake was quantified in slc5a1(-/-) mice and in isolated rat jejunum. Urinary glucose excretion (UGE), blood glucose (Sprague-Dawley rats), glucagon-like peptide 1 (GLP-1), and hemoglobin A1c (HbA1c) levels (Zucker diabetic fatty rats) were measured. Intestinal adaptation and rRNA gene sequencing was analyzed in C57BI/6 mice. The blood C-13(6)-glucose area under the curve (AUC) was reduced in the absence of SGLT1 by 75% (245 +/- 6 vs. 64 +/- 6 mg/dl.h in wild-type vs. slc5a1(-/-) mice) and compound 8 inhibited its transport up to 50% in isolated rat jejunum. Compound 8 reduced glucose excursion more than SGLT2-selective inhibition (e.g., AUC = 129 +/- 3 vs. 249 +/- 5 mg/dl-h for 1 mg/kg compound 8 vs. dapagliflozin) with similar UGE but a lower renal glucose excretion threshold. In Zucker diabetic fatty rats, compound 8 decreased HbA1c and increased total GLP-1 without changes in jejunum SGLT1 expression, mucosal weight, or villus length. Overall, compound 8 (1 mg/kg for 6 days) did not increase cecal glucose concentrations or bacterial diversity in C57BL76 mice. In conclusion, potent dual SGLT1/2 inhibition lowers blood glucose by reducing intestinal glucose absorption and the renal glucose threshold but minimally impacts the intestinal mucosa or luminal microbiota in chow-fed rodents.