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 (R(a)) with portal glucose infusion rate (PoG(inf)), we quantified "net hepatic glucose addition (NHGA)" in the place of endogenous glucose production determined in a regular clamp. When PoG-glucose clamps (n = 6) were performed in dogs at basal insulinemia and hyperglycemia ( approximately 150 mg/dl, portal and systemic), we measured consistently higher R(a) than PoG(inf) (4.2 +/- 0.6 vs. 2.9 +/- 0.6 mg x kg(-1) x min(-1) at steady state, P < 0.001) and thus positive NHGA at 1.3 +/- 0.1 mg x kg(-1) x min(-1), identifying net hepatic addition of glucose to portal exogenous glucose. In contrast, when PoG-glucose clamps (n = 6) were performed at hyperinsulinemia ( approximately 250 pmol/l) and systemic euglycemia (portal hyperglycemia due to portal glucose infusion), we measured consistently lower R(a) than PoG(inf) (13.1 +/- 2.4 vs. 14.3 +/- 2.4 mg x kg(-1) x min(-1), P < 0.001), and therefore negative NHGA at -1.1 +/- 0.1 mg x kg(-1) x min(-1), 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 +/- 0.5 and 13.0 +/- 2.4 mg x kg(-1) x min(-1), 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.

Fig. 1.

Portal glucose infusion-glucose clamp. Basal and clamp steady state (SS) indicate the SS during the basal and clamp periods, respectively. Porcine insulin was infused at either 0.15 mU·kg⁻¹·min⁻¹ in the basal insulinemic hyperglycemic clamp study or 0.75 mU·kg⁻¹·min⁻¹ in the hyperinsulinemic euglycemic clamp study. Exogenous glucose was infused via the portal vein to achieve systemic hyperglycemia or maintain systemic euglycemia, respectively, in the 2 studies.

Fig. 2.

A: calculation of net hepatic glucose addition (NHGA) in a portal glucose infusion-glucose clamp. Glucose label indicates the constant and the variable tracer infusions. B: calculation of endogenous glucose production (EGP) in a classical hyperinsulinemic euglycemic clamp. PoG_inf, portal glucose infusion rate; HGU, hepatic glucose uptake; R_a, rate of glucose appearance; R_d, rate of glucose disappearance; G_inf, peripheral glucose infusion rate.

Fig. 3.

Plasma insulin (A), glucose (B), and free fatty acids (FFAs; C) in the basal insulinemic hyperglycemic clamp study (BIHG; ○) and the hyperinsulinemic euglycemic clamp study (HIEG; ●).

Fig. 4.

The time course data of PoG_inf (○) and the R_a (●) in the BIHG (A) and HIEG (B).

Fig. 5.

The time course (left) and clamp SS (right) data of NHGA (A) and the R_a (B) in the BIHG (○) and the HIEG (●).