Release of glucose by liver and kidney are both increased in diabetic animals. Although the overall release of glucose into the circulation is increased in humans with diabetes, excessive release of glucose by either their liver or kidney has not as yet been demonstrated. The present experiments were therefore undertaken to assess the relative contributions of hepatic and renal glucose release to the excessive glucose release found in type 2 diabetes. Using a combination of isotopic and balance techniques to determine total systemic glucose release and renal glucose release in postabsorptive type 2 diabetic subjects and age-weight-matched nondiabetic volunteers, their hepatic glucose release was then calculated as the difference between total systemic glucose release and renal glucose release. Renal glucose release was increased nearly 300% in diabetic subjects (321 Ϯ 36 vs. 125 Ϯ 15 mol/min, P Ͻ 0.001). Hepatic glucose release was increased ‫ف‬ 30% ( P ϭ 0.03), but increments in hepatic and renal glucose release were comparable (2.60 Ϯ 0.70 vs. 2.21 Ϯ 0.32, mol и kg Ϫ 1 и min Ϫ 1 , respectively, P ϭ 0.26). Renal glucose uptake was markedly increased in diabetic subjects (353 Ϯ 48 vs. 103 Ϯ 10 mol/min, P Ͻ 0.001), resulting in net renal glucose uptake in the diabetic subjects (92 Ϯ 50 mol/ min) versus a net output in the nondiabetic subjects (21 Ϯ 14 mol/min, P ϭ 0.043). Renal glucose uptake was inversely correlated with renal FFA uptake ( r ϭ Ϫ 0.51, P Ͻ 0.01), which was reduced by ‫ف‬ 60% in diabetic subjects (10.9 Ϯ 2.7 vs. 27.0 Ϯ 3.3 mol/min, P Ͻ 0.002). We conclude that in type 2 diabetes, both liver and kidney contribute to glucose overproduction and that renal glucose uptake is markedly increased. The latter may suppress renal FFA uptake via a glucose-fatty acid cycle and explain the accumulation of glycogen commonly found in the diabetic kidney. ( J. Clin. Invest. 1998. 102:619-624.)

Summary According to current textbook wisdom the liver is the exclusive site of glucose production in humans in the postabsorptive state. Although many animal and in vitro data have documented that the kidney is capable of gluconeogenesis, production of glucose by the human kidney in the postabsorptive state has generally been regarded as negligible. This traditional view is based on net balance measurements which, other than after a prolonged fast or during metabolic acidosis, showed no significant net renal glucose release. However, recent studies have refuted this view by combining isotopic and balance techniques, which have demonstrated that renal glucose production accounts for 25 % of systemic glucose production. Moreover, these studies indicate that glucose production by the human kidney is stimulated by epinephrine, inhibited by insulin and is excessive in diabetes mellitus. Since renal glucose release is largely, if not exclusively, due to gluconeogenesis, it is likely that the kidney is as important a gluconeogenic organ as the liver. The most important renal gluconeogenic precursors appear to be lactate, glutamine and glycerol. The implications of these recent findings on the understanding of the physiology and pathophysiology of human glucose metabolism are discussed. [Diabetologia (1997) 40: 749-757].

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).

To determine the relationship between free fatty acids (FFA) and glucose uptake by the human kidney, 12 postabsorptive normal volunteers underwent renal vein catheterization and were infused to isotopic steady state with [6-3H]glucose and [9,10-3H]palmitate. Arterial and renal vein palmitate specific activities were not significantly different (3,533 +/- 219 vs. 3,549 +/- 220 dpm/mumol, P = 0.64). Palmitate renal fractional extraction and uptake determined isotopically (7.2 +/- 1.1% and 9.1 +/- 1.4 mumol/min) were not significantly different from those calculated by net balance measurements (8.3 +/- 1.2% and 9.7 +/- 1.2 mumol/min, P > 0.07 and P > 0.7, respectively). Renal palmitate uptake accounted for 8.7 +/- 1.3% of its systemic turnover. Renal linoleate and oleate fractional extraction calculated by net balance measurements (8.0 +/- 0.9 and 7.7 +/- 1.2%, respectively) were not significantly different from each other and that of palmitate (all P > 0.7). Renal uptake of palmitate, linoleate (7.9 +/- 1.0 mumol/min), and oleate (10.9 +/- 2.0 mumol/min) were all directly proportional to their arterial concentrations (r = 0.70, 0.68, and 0.63, respectively, all P < 0.025). Renal glucose uptake (93 +/- 10 mumol/min) accounted for 12.6 +/- 1.5% of its systemic turnover and was inversely related to the sum of palmitate, linoleate, and oleate uptake (r = -0.74, P < 0.01). These data indicate that in postabsorptive humans: 1) the kidney is an important site of FFA and glucose disposal, 2) a renal glucose-fatty acid cycle may exist, and 3) there appears to be little or no release into the circulation of stored renal FFA.

To assess the role of the human kidney in leptin metabolism, we measured renal leptin net balance and urinary leptin excretion in 16 normal postabsorptive volunteers with varying degrees of obesity. Arterial leptin concentrations (11.6 ± 2.7 ng/ml) significantly exceeded renal vein concentrations (10.3 ± 2.5 ng/ml, P < 0.001). Renal leptin fractional extraction averaged 13.1 ± 1.1%, and renal leptin net balance (uptake) averaged 1,070 ± 253 ng/min. Lineweaver-Burk analysis indicated that renal leptin uptake followed saturation kinetics with an apparent Michaelis-Menten constant of 10.9 ng/ml and maximal velocity of 1,730 ng/min. Leptin was generally undetectable in urine. Using literature values for systemic leptin clearance, we calculated that renal leptin uptake could account for ∼80% of all leptin removal from plasma. These data indicate that the human kidney plays a substantial role in leptin removal from plasma by taking up and degrading the peptide.