Portal glucose infusion-glucose clamp measures hepatic influence on postprandial systemic glucose appearance as well as whole body glucose disposal

Abstract

The full impact of the liver, through both glucose production and uptake, on systemic glucose appearance cannot be readily studied in a classical glucose clamp because hepatic glucose metabolism is regulated not only by portal insulin and glucose levels but also portal glucose delivery (the portal signal). In the present study, we modified the classical glucose clamp by giving exogenous glucose through portal vein, the "portal glucose infusion (PoG)-glucose clamp", to determine the net hepatic effect on postprandial systemic glucose supply along with the measurement of whole body glucose disposal. By comparing systemic rate of glucose appearance (Ra) with portal glucose infusion rate (PoGinf), we quantified "net hepatic glucose addition (NHGA)" in the place of endogenous glucose production determined in a regular clamp. When PoG-glucose clamps (n ϭ 6) were performed in dogs at basal insulinemia and hyperglycemia (ϳ150 mg/dl, portal and systemic), we measured consistently higher Ra than PoGinf (4.2 Ϯ 0.6 vs. 2.9 Ϯ 0.6 mg · kg Ϫ1 · min Ϫ1 at steady state, P Ͻ 0.001) and thus positive NHGA at 1.3 Ϯ 0.1 mg · kg Ϫ1 · min Ϫ1 , identifying net hepatic addition of glucose to portal exogenous glucose. In contrast, when PoG-glucose clamps (n ϭ 6) were performed at hyperinsulinemia (ϳ250 pmol/l) and systemic euglycemia (portal hyperglycemia due to portal glucose infusion), we measured consistently lower Ra than PoGinf (13.1 Ϯ 2.4 vs. 14.3 Ϯ 2.4 mg · kg Ϫ1 · min Ϫ1 , P Ͻ 0.001), and therefore negative NHGA at Ϫ1.1 Ϯ 0.1 mg · kg Ϫ1 · min Ϫ1 , identifying a switch of the liver from net production to net uptake of portal exogenous glucose. Steady-state whole body glucose disposal was 4.1 Ϯ 0.5 and 13.0 Ϯ 2.4 mg · kg Ϫ1 · min Ϫ1 , respectively, determined as in a classical glucose clamp. We conclude that the PoG-glucose clamp, simulating postprandial glucose entry and metabolism, enables simultaneous assessment of the net hepatic effect on postprandial systemic glucose supply as well as whole body glucose disposal in various animal models (rodents, dogs, and pigs) with established portal vein catheterization.net hepatic glucose addition FOLLOWING A MEAL, PLASMA GLUCOSE RISES as the gastrointestinal tract digests and absorbs carbohydrates. A dramatic increase in postprandial glycemia is prevented when the systemic supply of the absorbed glucose is matched to the glucose disposal capacity of the body. Various tissues participate in clearing glucose from the bloodstream, including skeletal muscle, adipose tissue, the liver, and non-insulin-dependent tissues (40,41,46). In contrast, the liver, uniquely situated to receive the absorbed glucose through the portal vein, plays a pivotal role in regulating the systemic glucose supply by adjusting the balance between hepatic glucose production and uptake of newly appearing portal glucose (34). It has been challenging to address both the supply and disposal aspects of postprandial glucose metabolism in a single method, especially the full impact of the liver on systemic glucose appearance...

PAHSAs enhance hepatic and systemic insulin sensitivity through direct and indirect mechanisms

“…kg/min insulin infusion rate (Supplemental Figure 4B). Therefore, we investigated whether hepatic glucose uptake could contribute to the difference in Rd (32). Hepatic glucose uptake cannot be precisely measured with the 2-DOG uptake technique owing to the presence of G6pase in the liver, which regulates both glucose uptake and output so that 2-DOG is not "trapped" in liver as it is in muscle and adipocytes.…”

Metabolic response to high-carbohydrate and low-carbohydrate meals in a nonhuman primate model

“…Accordingly, the ability to sample portal vein blood is important for understanding postprandial metabolic regulation. Several studies conducted in animal models have used portal vein catheterization to evaluate the effect of intraportal nutrient delivery on hepatic and whole body metabolism (11,43,49). However, we are not aware of any studies that have used portal vein catheterization to evaluate the effect of differences in dietary macronutrient composition on the metabolic response to a meal.…”

Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver

“…The insulin-sensitizing effects of Arrdc3 deletion in the liver are associated with increased expression of glucokinase and lower expression of PEPCK, resulting in higher glycogen accumulation and lower glucose output. The liver may also contribute to enhanced glucose disposal given the negative hepatic glucose production, suggesting a switch from net glucose production to net uptake (26). This notion is supported by higher glycogen accumulation in the liver over the transition to the fed state.…”