The effect of vagal cooling on canine hepatic glucose metabolism in the presence of hyperglycemia of peripheral origin

DiCostanzo, Catherine A.; Dardevet, Dominique; Williams, P. E. V.; Moore, Mary Courtney; Hastings, Jon R.; Neal, Doss W.; Cherrington, Alan D.

doi:10.1016/j.metabol.2007.01.012

Cited by 7 publications

(5 citation statements)

References 63 publications

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“…Elimination of this effect by portal denervation but not vagotomy indicates signaling from the portal vein through a non-vagal neural pathway, and therefore through the dorsal spinal afferent pathway [20]. This is consistent with work by others which showed the effects of portal glucose sensing on food intake were abolished by portal denervation [7], and that vagal blockade by cooling did not affect net hepatic glucose uptake [21]. …”

Section: Discussionsupporting

confidence: 83%

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

2016

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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.

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Section: Discussionsupporting

confidence: 83%

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

2016

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“…Afferent fibers from the hepatoportal region travel with both the spinal and vagus nerves (35). Data from vagal nerve cooling experiments do not support involvement of vagal afferents in the portal glucose signal because inhibition of vagal firing brought about by cooling the vagus nerves in the conscious dog under hyperglycemic, hyperinsulinemic conditions did not lead to a decrease in NHGU, whether portal glucose delivery was present or not (46,47). The spinal afferent nerves have been shown to function in the detection of hypoglycemia in the portal vein (48), and thus their involvement in the response to a glucose load appears likely, although it has not been examined.…”

Section: Portal Glucose Signalmentioning

confidence: 99%

Regulation of Hepatic Glucose Uptake and Storage In Vivo

Moore

Coate

Winnick

et al. 2012

Advances in Nutrition

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290

224

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In the postprandial state, the liver takes up and stores glucose to minimize the fluctuation of glycemia. Elevated insulin concentrations, an increase in the load of glucose reaching the liver, and the oral/enteral/portal vein route of glucose delivery (compared with the peripheral intravenous route) are factors that increase the rate of net hepatic glucose uptake (NHGU). The entry of glucose into the portal vein stimulates a portal glucose signal that not only enhances NHGU but concomitantly reduces muscle glucose uptake to ensure appropriate partitioning of a glucose load. This coordinated regulation of glucose uptake is likely neurally mediated, at least in part, because it is not observed after total hepatic denervation. Moreover, there is evidence that both the sympathetic and the nitrergic innervation of the liver exert a tonic repression of NHGU that is relieved under feeding conditions. Further, the energy sensor 5'AMP-activated protein kinase appears to be involved in regulation of NHGU and glycogen storage. Consumption of a high-fat and high-fructose diet impairs NHGU and glycogen storage in association with a reduction in glucokinase protein and activity. An understanding of the impact of nutrients themselves and the route of nutrient delivery on liver carbohydrate metabolism is fundamental to the development of therapies for impaired postprandial glucoregulation.

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“…These studies on both man and animal models support a major contribution of the Portal Signal to stimulation of hepatic glucose uptake in hyperinsulineamic conditions [1–3]. The involvement of the parasympathetic innervation in the Portal Signal is supported by the inhibitory effect of atropine, an antagonist of muscarinic receptors [4,9] and by chronic denervation [5–7] though not by acute cooling of the vagal nerve [29,30]. If the contribution of cholinergic mechanisms to the stimulation of hepatic glucose uptake were due to a direct effect of acetylcholine on hepatocytes as opposed to either haemodynamic changes or indirect effects involving release of other neurotransmitters (or incretins), then acetylcholine would be expected to have either a large stimulatory effect on glycogen synthesis in comparison with insulin action or alternatively a synergistic effect with insulin.…”

Section: Discussionmentioning

confidence: 69%

Acetylcholine exerts additive and permissive but not synergistic effects with insulin on glycogen synthesis in hepatocytes

Hampson

Agius

2007

FEBS Letters

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Parasympathetic (cholinergic) innervation is implicated in the stimulation of hepatic glucose uptake by portal vein hyperglycaemia. We determined the direct effects of acetylcholine on hepatocytes. Acute exposure to acetylcholine mimicked insulin action on inactivation of phosphorylase, stimulation of glycogen synthesis and suppression of phosphoenolpyruvate carboxykinase mRNA levels but with lower efficacy and without synergy. Pre-exposure to acetylcholine had a permissive effect on insulin action similar to glucocorticoids and associated with increased glucokinase activity. It is concluded that acetylcholine has a permissive effect on insulin action but cannot fully account for the rapid stimulation of glucose uptake by the portal signal.

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The effect of vagal cooling on canine hepatic glucose metabolism in the presence of hyperglycemia of peripheral origin

Cited by 7 publications

References 63 publications

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

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

Regulation of Hepatic Glucose Uptake and Storage In Vivo

Acetylcholine exerts additive and permissive but not synergistic effects with insulin on glycogen synthesis in hepatocytes

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