Pal, AtanuRhoads, DavidTavakkoli, Ali2016-12-022016Pal, Atanu, David B. Rhoads, and Ali Tavakkoli. 2016. “Effect of Portal Glucose Sensing on Systemic Glucose Levels in SD and ZDF Rats.” PLoS ONE 11 (11): e0165592. doi:10.1371/journal.pone.0165592. http://dx.doi.org/10.1371/journal.pone.0165592.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:29625975Background: 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. Methods: 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. Results: 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. Conclusions: 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.en-USPhysical SciencesChemistryChemical CompoundsOrganic CompoundsCarbohydratesMonosaccharidesGlucoseOrganic ChemistryMedicine and Health SciencesEndocrinologyDiabetic EndocrinologyInsulinBiology and Life SciencesBiochemistryHormonesSurgical and Invasive Medical ProceduresDenervationAnatomyCardiovascular AnatomyBlood VesselsVeinsPortal VeinsNervous System ProceduresVagotomyEndocrine DisordersDiabetes MellitusMetabolic DisordersGlycobiologyGlycogensNeuroscienceReflexesJournal Article2016-12-0210.1371/journal.pone.0165592