High glucose inhibits HCO 3 - and fluid secretion in rat pancreatic ducts
High glucose inhibits HCO 3 - and fluid secretion in rat pancreatic ducts
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DOI：
10.1007/s00424-009-0731-6
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发表时间：
2009-11-01
影响因子：
4.5
通讯作者：
Goto, Hidemi
中科院分区：
文献类型：
--
作者：
Futakuchi, Sachiko;Ishiguro, Hiroshi;Goto, Hidemi
利用从大鼠胰腺分离的小叶间管研究糖尿病患者胰液和电解质分泌损伤的细胞机制。通过监测管腔容积的变化来评估液体分泌。通过酸负荷后细胞内pH值的恢复来估计基底外侧膜的HCO(3)（-）摄取。暴露于高葡萄糖浓度会抑制液体分泌，并降低从正常大鼠分离的分泌素刺激导管中基底外侧HCO(3)（-）的摄取速率。在从链脲佐菌素治疗的糖尿病大鼠分离的导管中，液体分泌和基底外侧HCO(3)（-）摄取也严重受损，但在正常葡萄糖溶液中孵育可以在很大程度上逆转。通过逆转录酶聚合酶链反应在分离的导管中检测钠依赖性葡萄糖共转运蛋白1 （SGLT1）、葡萄糖转运蛋白1 （GLUT）、GLUT2和GLUT8转录本。微灌注导管内腔内葡萄糖浓度升高引起膜电位去极化，这与SGLT1在根尖膜的存在一致。充满高葡萄糖溶液的未受刺激的胰管通过苯根菌素敏感机制失去了管腔液，这表明胰管能够通过SGLT1从管腔重新吸收葡萄糖。在暴露于高葡萄糖浓度的导管中，葡萄糖持续扩散到管腔，并通过SGLT1积极重吸收，导致细胞内Na+浓度升高和顶膜持续去极化。这两个因素往往会抑制Cl-和HCO(3)（-）的基底外侧摄取和根尖外排，因此可以解释糖尿病中观察到的液体和电解质分泌受损的原因。
Cellular mechanisms underlying the impairment of pancreatic fluid and electrolyte secretion in diabetes were examined using interlobular ducts isolated from rat pancreas. Fluid secretion was assessed by monitoring changes in luminal volume. HCO (3) (-) uptake across the basolateral membrane was estimated from the recovery of intracellular pH following an acid load. Exposure to high glucose concentrations inhibited fluid secretion and reduced the rate of basolateral HCO (3) (-) uptake in secretin-stimulated ducts isolated from normal rats. In ducts isolated from streptozotocin-treated diabetic rats, fluid secretion and basolateral HCO (3) (-) uptake were also severely impaired but could be largely reversed by incubation in normal-glucose solutions. Sodium-dependent glucose cotransporter 1 (SGLT1), glucose transporter (GLUT)1, GLUT2, and GLUT8 transcripts were detected by reverse transcriptase polymerase chain reaction in isolated ducts. Raising the luminal glucose concentration in microperfused ducts caused a depolarization of the membrane potential, consistent with the presence of SGLT1 at the apical membrane. Unstimulated ducts filled with high-glucose solutions lost luminal fluid by a phlorizin-sensitive mechanism, indicating that pancreatic ducts are capable of active glucose reabsorption from the lumen via SGLT1. In ducts exposed to high glucose concentrations, continuous glucose diffusion to the lumen and active reabsorption via SGLT1 would lead to elevation of intracellular Na+ concentration and sustained depolarization of the apical membrane. These two factors would tend to inhibit the basolateral uptake and apical efflux of Cl- and HCO (3) (-) and could therefore account for the impaired fluid and electrolyte secretion that is observed in diabetes.