Effect of Portal Glucose Sensing on Systemic Glucose Levels in SD and ZDF Rats

Abstract

BackgroundThe 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.MethodsSystemic 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.ResultsαMG+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.ConclusionsThe 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.

Focused Ultrasound Modulation of Hepatic Neural Plexus Restores Glucose Homeostasis in Diabetes

“…We utilized intrahepatic focused pulsed ultrasound stimulation (pFUS) 1 to modulate the liverbrain neurometabolic pathway [2][3][4][5][6][7][8][9][10][11][12] in several animal models of hyperglycemia and diabetes (Fig. 1A and B; Supplemental Fig.…”

“…Hepatoportal glucose sensing is a well-documented phenomenon in which nerve signals report portal vein-hepatic artery glucose gradients during feeding or fasting, that results in neuronal modulation of the metabolic system. [2][3][4][6][7][8][9][10][11][16][17][18][19][20][21][22] The sensor comprises at least two glucose sensing mechanisms that utilize GLUT2 9,12,23 (for low affinity glucose binding) and SGLT3 7,10,11 (for high affinity glucose binding) and is, therefore, capable of sensing glucose gradients during periods of high or low portal glucose concentration (Supplemental Fig. S1).…”

Vagally Mediated Gut-Brain Relationships in Appetite Control-Insights from Porcine Studies

“…Vagally mediated appetite control is dependent on the integration of glucose-sensing mechanisms located in the brain, portal vein, and intestine [ 72 ]. The impact of obesity and insulin resistance on brain glucose sensing has been investigated extensively [ 73 ], but there is much less information about the hepato-portal sensor [ 74 ] probably, in part, because it is much less accessible.…”

Proceedings of the 2017 ASPEN Research Workshop—Gastric Bypass: Role of the Gut

“…The portal vein delivers the intestinal venous drainage to the liver and as such provides a direct communication between the bowel and the liver. The earlier mentioned studies that show that the portal vein is more than a simple conduit between the bowel and the liver, and the observation that changes in portal vein glucose levels can lead to changes in hepatic pathways involved in glucose homeostasis, 97,99 through a neutrally mediated pathway, highlight an important role for this structure in postoperative glucose improvement.…”