Effects of physiological hyperinsulinemia on systemic, renal, and hepatic substrate metabolism

Abstract

To determine the effect of physiological hyperinsulinemia on renal and hepatic substrate metabolism, we assessed systemic and renal glucose release and uptake, systemic and renal gluconeogenesis from glutamine, and certain aspects of systemic and renal glutamine and free fatty acid (FFA) metabolism. These were assessed under basal postabsorptive conditions and during 4-h hyperinsulinemic euglycemic clamp experiments in nine normal volunteers using a combination of isotopic techniques and renal balance measurements. Hepatic glucose release (HGR) and glutamine gluconeogenesis were calculated as the difference between systemic and renal measurements. Infusion of insulin suppressed systemic glucose release and glutamine gluconeogenesis by approximately 50% during the last hour of the insulin infusion (P < 0.001). Renal glucose release and glutamine gluconeogenesis decreased from 2.3 +/- 0.4 to 0.9 +/- 0.2 (P < 0.002) and from 0.52 +/- 0.07 to 0.14 +/- 0.03 micromol. kg-1. min-1 (P < 0.001), respectively. HGR and glutamine gluconeogenesis decreased from 8.7 +/- 0.4 to 4.5 +/- 0.5 (P < 0.001) and from 0.35 +/- 0.02 to 0.27 +/- 0.03 micromol. kg-1. min-1 (P < 0.002), respectively. Renal glucose uptake (RGU) increased from 1.61 +/- 0.19 to 2.18 +/- 0.25 micromol. kg-1. min-1 (P = 0.029) but accounted for only approximately 5% of systemic glucose disposal (40.6 +/- 4.3 micromol. kg-1. min-1). Both systemic and renal FFA clearance increased approximately fourfold (P < 0.001 for both). Nevertheless, renal FFA uptake decreased (P = 0.024) and was inversely correlated with RGU (r = -0.582, P = 0.011). Finally, insulin increased systemic glutamine release (P = 0.007), uptake (P < 0.005), and clearance (P < 0.001) but left renal glutamine uptake and release unaffected (P > 0.4 for both).