Hepatic portal vein denervation impairs oral glucose tolerance but not exenatide’s effect on glycemia

Abstract

The hepatoportal area is an important glucohomeostatic metabolic sensor, sensing hypoglycemia, hyperglycemia, and hormones such as glucagon-like peptide-1 (GLP-1). We have reported previously that activation of hepatoportal sensors by intraportal infusion of glucose and GLP-1 or by subcutaneous administration of GLP-1 receptor activator exenatide and of intraportal glucose improved glycemia independent of corresponding changes in pancreatic hormones. It is not clear whether this effect is mediated via the portal vein (PV) or by direct action on the liver itself. To test whether receptors in the PV mediate exenatide's beneficial effect on glucose tolerance, we performed 1) paired oral glucose tolerance tests (OGTT) with and without exenatide and 2) intravenous glucose tolerance tests before and after PV denervation in canines. Denervation of the portal vein affected oral glucose tolerance; post-denervation (POST-DEN) OGTT glucose and insulin AUC were 50% higher than before denervation (P = 0.01). However, portal denervation did not impair exenatide's effect to improve oral glucose tolerance (exenatide effect: 48 ± 12 mmol·l⁻¹·min before vs. 64 ± 26 mmol·l⁻¹·min after, P = 0.67). There were no changes in insulin sensitivity or secretion during IVGTTs. Portal vein sensing might play a role in controlling oral glucose tolerance during physiological conditions but not in pharmacological activation of GLP-1 receptors by exenatide.

Exenatide improves both hepatic and adipose tissue insulin resistance: A dynamic positron emission tomography study

“…Recently, Ionut et al have shown, in dogs, that portal denervation decreases glucose tolerance by increasing both glucose and insulin concentrations . Surprisingly, portal denervation did not change the capacity of EX to reduce glucose rate of appearance during OGTT …”

“…Although GLP‐1 is able to activate portal receptors even at low concentrations as those observed during fasting, studies in dogs have shown that stimulation of net HGU is independent of portal GLP‐1 receptors, given that both intraportal and peripheral GLP‐1 infusions were able similarly to stimulate HGU . Recently, Ionut et al have shown, in dogs, that portal denervation decreases glucose tolerance by increasing both glucose and insulin concentrations . Surprisingly, portal denervation did not change the capacity of EX to reduce glucose rate of appearance during OGTT …”

“…(39) Recently, Ionut et al have shown, in dogs, that portal denervation decreases glucose tolerance by increasing both glucose and insulin concentrations. (48) Surprisingly, portal denervation did not change the capacity of EX to reduce glucose rate of appearance during OGTT. (48) Consistent with previous studies in humans, (20,36,37) we failed to observe any acute effect of EX on peripheral glucose uptake or glucose clearance.…”

Impaired hepatic counterregulatory response to insulin-induced hypoglycemia in hepatic denervated pigs

“…A recent study by Ionut et al. demonstrated that portal vein denervation impairs hypoglycemic counterregulation due to a suppression of the sympathoadrenal response [19] and impaired glucose tolerance has been observed following portal vein denervation during GLP-1 receptor stimulation [20] . Overall, these experiments support that the portal vein is an important sensing site for hypoglycemia and of hormones such as GLP-1.…”

Exenatide Treatment Alone Improves β-Cell Function in a Canine Model of Pre-Diabetes

“…Glucose 50% was given as a bolus by oral gavage. Blood samples were taken at 15, 30, 45, 60, 90, 120, and 180 min [ 14 ]. Glucose tolerance was measured as the glucose concentration at t = 120 min.…”