Horber, Fritz

High-dose glucocorticoid treatment results in protein wasting. To determine whether such therapy affects leucine oxidation in the postabsorptive state and the disposal of dietary amino acids, eight normal subjects were studied twice in random order, once after 5 days of prednisone (20 mg three times daily) and on a second occasion without prednisone as a control. In the postabsorptive state prednisone therapy increased (P less than 0.05) plasma concentrations of leucine, alpha-ketoisocaproate, glucose, insulin, and C-peptide, as well as leucine carbon flux and oxidation calculated by means of isotope dilution techniques and [1-13C]leucine. During infusion of a chemically defined meal, total leucine carbon flux and oxidation increased similarly on both study days, but leucine oxidation was greater (P less than 0.01) during prednisone treatment; net leucine balance became positive on the control day but remained negative or zero on the prednisone study day despite higher (P less than 0.05) plasma insulin concentrations. These studies demonstrate that high-dose glucocorticoid treatment impairs the balance of the essential amino acid leucine in both the postabsorptive and absorptive states in humans.

We previously proposed that, during the infusion of either labeled leucine or its alpha-ketoacid, alpha-ketoisocaproate (KIC), the plasma specific activity (SA) of the transaminated product of the infused tracer ("reciprocal pool SA") may better reflect the intracellular leucine SA than the plasma SA of either infused tracer ("primary pool SA"). To test this hypothesis, 14 dogs were simultaneously infused intravenously with [3H]leucine and [14C]KIC, and blood and tissue compartments were sampled. The ratios of [3H]-leucine to [14C]leucine [( 3H]/[14C]leucine) in mixed tissue proteins and in the intracellular space of striated muscle were the same as the ratio of the isotope infusion rates and similar, although slightly lower (P less than 0.01), than [3H]KIC/[14C]leucine SA (ratio of reciprocal pool SA) in plasma. Plasma [3H]KIC/[14C]leucine SA were essentially identical to the [3H]/[14C] of leucine in 1) mixed liver proteins, 2) intrahepatic free leucine, and 3) fibrin. The [3H]/[14C]leucine in mixed renal proteins and in the intracellular space of kidney and erythrocytes were similar to those of the venous plasma [3H]/[14C]leucine SA. The plasma [3H]KIC and [14C]leucine SA (the reciprocal pool SA) were similar to the SA of [3H]- and [14C]leucine in the intracellular space of all organs investigated with the exception of kidney. Therefore, in postabsorptive dogs, the plasma SA of the transaminated product of the infused labeled KIC or leucine is an excellent predictor of the intracellular leucine SA in all tissues investigated with the exception of kidney.

Human growth hormone (hGH) and prednisone cause insulin resistance and glucose intolerance. However, it is unknown whether hGH and prednisone antagonize insulin action on protein, fat, and carbohydrate metabolism by a common or independent mechanism. Therefore, protein, fat, and carbohydrate metabolism was assessed simultaneously in four groups of eight subjects each after 7 days of placebo, recombinant DNA hGH (rhGH; 0.1 mg · kg−1 · day−1), prednisone (0.8 mg · kg−1 · day−1), or rhGH and prednisone administration after an 18-h fast and during gut infusion of glucose and amino acids (fed state). Fasting plasma glucose concentrations were similar during placebo and rhGH but elevated (P < 0.001) during combined treatment, whereas plasma insulin concentrations were higher (237 ± 57 pmol/ml, P < 0.001) during combined than during placebo, rhGH, or prednisone treatment (34, 52, and 91 pM, respectively). In the fed state, plasma glucose concentrations were elevated only during combined treatment (11.3 ± 2.1 mM, P < 0.001). Plasma insulin concentrations were elevated during therapy with prednisone alone and rhGH alone (667 ± 72 and 564 ± 65 pmol/ml, respectively, P < 0.001) compared with placebo (226 ± 44 pmol/ml) but lower than with the combined rhGH and prednisone treatment (1249 ± 54 pmol/ml, P < 0.01). Protein oxidation ([14C]leucine) increased (P < 0.001) with prednisone therapy, decreased (P < 0.001) with rhGH treatment, and was normal during the combined treatment. By indirect calorimetry, glucose oxidation was similar in all groups; fasting fat oxidation was decreased by prednisone (P < 0.001) and increased by rhGH, although only significantly in the fed state (P < 0.01). In summary, insulin antagonism of rhGH and prednisone are probably caused by independent mechanisms in which rhGH and prednisone may reciprocally regulate the oxidation of protein and fat while decreasing the efficiency of glucose disposal.

To determine the role insulin resistance may play in the catabolic effect of high-dose prednisone therapy, healthy volunteers were studied on four occasions with the hormone-clamp technique at two insulin infusion rates. Subjects were studied after 5 days of prednisone (60 mg/day) or no steroid treatment and were infused with somatostatin, glucagon, growth hormone, [3H]glucose, [14C]leucine, and insulin (0.1 or 0.2 mil · kg1 · min1). At each rate of insulin infusion, the rate of leucine oxidation was increased (P < .001) after steroid treatment. Leucine flux, an indicator of whole-body proteolysis, was similar in the presence or absence of steroid treatment (2.26 ± 0.08 vs. 2.13 ± 0.04 μmol · kg1 · min1 respectively) at the lower rate of insulin infusion but was higher during steroid treatment (2.18 ± 0.06 vs. 1.84 ± 0.13 μmol · kg1 · min1) at the 0.2-mU · kg1 · min1 insulin infusion. Steroid pretreatment had no significant effect on the nonoxidative rates of leucine disappearance. These data provide strong evidence that the protein wasting associated with glucocorticosteroid therapy is in part the result of steroid-induced resistance to the antiproteolytic effect of insulin and an increase in the oxidation (and thus wasting) of one essential amino acid, leucine.