Effect of Portal Glucose Sensing on Systemic Glucose Levels in SD and ZDF Rats.
BACKGROUND
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.
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.
Atanu
A
Pal
Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, United States of America.|Pediatric Endocrine Unit, MassGeneral Hospital for Children, 55 Fruit Street, Boston, MA, 02114, United States of America.
David B
DB
Rhoads
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.|Center for Weight Management and Metabolic Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, United States of America.
Ali
A
Tavakkoli
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000601:surgery; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000601:surgery; D015390:Gastric Bypass; D008297:Male; D008757:Methylglucosides / Q000008:administration & dosage* / Q000494:pharmacology; D009765:Obesity / Q000378:metabolism*; D011169:Portal Vein / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D015398:Signal Transduction; D051247:Sodium-Glucose Transport Proteins / Q000378:metabolism*; D014628:Vagotomy
D001786:Blood Glucose; D008757:Methylglucosides; D051247:Sodium-Glucose Transport Proteins; C027020:methylglucoside