Relative importance of liver, kidney, and substrates in epinephrine-induced increased gluconeogenesis in humans

Splanchnic and renal net balance measurements indicate that lactate and glycerol may be important precursors for epinephrine-stimulated gluconeogenesis (GNG) in liver and kidney, but the effects of epinephrine on their renal and hepatic conversion to glucose in humans have not yet been reported. We therefore used a combination of renal balance and isotopic techniques in nine postabsorptive volunteers to measure systemic and renal GNG from these precursors before and during a 3-h infusion of epinephrine (270 pmol · kg–1 · min–1) and calculated hepatic GNG as the difference between systemic and renal rates. During infusion of epinephrine, renal and hepatic GNG from lactate increased 4- to 6-fold and accounted for ∼85 and 70% of renal and hepatic glucose release, respectively, at the end of study; renal and hepatic GNG from glycerol increased ∼1.5- to 2-fold and accounted for ∼7–9% of renal and hepatic glucose release at the end of study. The increased renal GNG from lactate and glycerol was due not only to their increased renal uptake (∼3.3- and 1.4-fold, respectively) but also increased renal gluconeogenic efficiency (∼1.8- and 1.5-fold). The increased renal uptake of lactate and glycerol was wholly due to their increased arterial concentrations, since their renal fractional extraction remained unchanged and renal blood flow decreased. We conclude that 1) lactate is the predominant precursor for epinephrine-stimulated GNG in both liver and kidney, 2) hepatic and renal GNG from lactate and glycerol are similarly sensitive to stimulation by epinephrine, and 3) epinephrine increases renal GNG from lactate and glycerol by increasing substrate availability and the gluconeogenic efficiency of the kidney.

Role of human liver, kidney, and skeletal muscle in postprandial glucose homeostasis

Recent studies indicate a role for the kidney in postabsorptive glucose homeostasis. The present studies were undertaken to evaluate the role of the kidney in postprandial glucose homeostasis and to compare its contribution to that of liver and skeletal muscle. Accordingly, we used the double isotope technique along with forearm and renal balance measurements to assess systemic, renal, and hepatic glucose release as well as glucose uptake by kidney, skeletal muscle, and splanchnic tissues in 10 normal volunteers after ingestion of 75 g of glucose. We found that, during the 4.5-h postprandial period, 22 ± 2 g (30 ± 3% of the ingested glucose) were initially extracted by splanchnic tissues. Of the remaining 53 ± 2 g that entered the systemic circulation, 19 ± 3 g were calculated to have been taken up by skeletal muscle and 7.5 ± 1.7 g by the kidney (26 ± 3 and 10 ± 2%, respectively, of the ingested glucose). Endogenous glucose release during the postprandial period (16 ± 2 g), calculated as the difference between overall systemic glucose appearance and the appearance of ingested glucose in the systemic circulation, was suppressed 61 ± 3%. Surprisingly, renal glucose release increased twofold (10.6 ± 2.5 g) and accounted for ∼60% of postprandial endogenous glucose release. Hepatic glucose release (6.7 ± 2.2 g), the difference between endogenous and renal glucose release, was suppressed 82 ± 6%. These results demonstrate a hitherto unappreciated contribution of the kidney to postprandial glucose homeostasis and indicate that postprandial suppression of hepatic glucose release is nearly twofold greater than had been calculated in previous studies (42 ± 4%), which had assumed that there was no renal glucose release. We postulate that increases in postprandial renal glucose release may play a role in facilitating efficient liver glycogen repletion by permitting substantial suppression of hepatic glucose release.

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

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 ∼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 μmol ⋅ 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 μmol ⋅ kg−1 ⋅ min−1( P < 0.002), respectively. Renal glucose uptake (RGU) increased from 1.61 ± 0.19 to 2.18 ± 0.25 μmol ⋅ kg−1 ⋅ min−1( P = 0.029) but accounted for only ∼5% of systemic glucose disposal (40.6 ± 4.3 μmol ⋅ 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).