Pal Atanu, Rhoads David B, Tavakkoli Ali
Department of Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, United States of America.
Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, United States of America.
PLoS One. 2016 Nov 2;11(11):e0165592. doi: 10.1371/journal.pone.0165592. eCollection 2016.
The global epidemic of Type-2-Diabetes (T2D) highlights the need for novel therapeutic targets and agents. Roux-en-Y-Gastric-Bypass (RYGB) is the most effective treatment. Studies investigating the mechanisms of RYGB suggest a role for post-operative changes in portal glucose levels. We investigate the impact of stimulating portal glucose sensors on systemic glucose levels in health and T2D, and evaluated the role of sodium-glucose-cotransporter-3 (SGLT3) as the possible sensor.
Systemic glucose and hormone responses to portal stimulation were measured. In Sprague-Dawley (SD) rats, post-prandial state was simulated by infusing glucose into the portal vein. The SGLT3 agonist, alpha-methyl-glucopyranoside (αMG), was then added to further stimulate the portal sensor. To elucidate the neural pathway, vagotomy or portal denervation was followed by αMG+glucose co-infusion. The therapeutic potential of portal glucose sensor stimulation was investigated by αMG-only infusion (vs. saline) in SD and Zucker-Diabetic-Fatty (ZDF) rats. Hepatic mRNA expression was also measured.
αMG+glucose co-infusion reduced peak systemic glucose (vs. glucose alone), and lowered hepatic G6Pase expression. Portal denervation, but not vagotomy, abolished this effect. αMG-only infusion lowered systemic glucose levels. This glucose-lowering effect was more pronounced in ZDF rats, where portal αMG infusion increased insulin, C-peptide and GIP levels compared to saline infusions.
The portal vein is capable of sensing its glucose levels, and responds by altering hepatic glucose handling. The enhanced effect in T2D, mediated through increased GIP and insulin, highlights a therapeutic target that could be amenable to pharmacological modulation or minimally-invasive surgery.
2型糖尿病（T2D）的全球流行凸显了对新型治疗靶点和药物的需求。 Roux-en-Y胃旁路术（RYGB）是最有效的治疗方法。 研究RYGB机制的研究表明门静脉葡萄糖水平的术后变化起作用。 我们研究了刺激门静脉葡萄糖传感器对健康和T2D患者全身葡萄糖水平的影响，并评估了钠葡萄糖协同转运蛋白3（SGLT3）作为可能传感器的作用。
测量全身葡萄糖和激素对门静脉刺激的反应。 在Sprague-Dawley（SD）大鼠中，通过将葡萄糖注入门静脉来模拟餐后状态。 然后添加SGLT3激动剂α-甲基吡喃葡萄糖苷（αMG）以进一步刺激门静脉传感器。 为了阐明神经通路，在迷走神经切断术或门静脉去神经支配后进行αMG +葡萄糖共输注。 通过在SD和Zucker糖尿病脂肪（ZDF）大鼠中仅输注αMG（与盐水相比）来研究门静脉葡萄糖传感器刺激的治疗潜力。 还测量了肝脏mRNA表达。
αMG +葡萄糖共输注降低了全身葡萄糖峰值（与单独葡萄糖相比），并降低了肝脏G6Pase表达。 门静脉去神经支配而非迷走神经切断术消除了这种作用。 仅输注αMG可降低全身葡萄糖水平。 这种降糖作用在ZDF大鼠中更明显，与盐水输注相比，门静脉αMG输注增加了胰岛素、C肽和GIP水平。
门静脉能够感知其葡萄糖水平，并通过改变肝脏葡萄糖处理来做出反应。 通过增加GIP和胰岛素介导的T2D中的增强作用突出了一个可通过药物调节或微创手术治疗的靶点。
