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Insulin-ketone interaction: A possible mechanism for postinjury branched-chain amino acid anticatabolic properties
High doses of tumor necrosis factor (TNF) cause hypotension, metabolic acidosis and, death. At Brigham and Women's Hospital, the effects of a sublethal, 6-hour infusion of TNF (0.57 X 10(5) Units/kg body weight) in twelve anesthetized dogs were studied. The dose caused falls in mean arterial pressure from 153 mmHg to 96 mmHg, pulmonary artery pressure (-4.5 mmHg), central venous pressure (-2.5 mmHg) and pulmonary capillary wedge pressures (-5.25 mmHg). Associated with these responses were a fourfold increase in urine volume (22.4 ml/kg/6 hours as compared to 5.2 ml/kg/6 hours in controls), significant pyrexia (from 38.1 C to 39.5 C, rectal), tachycardia (from 125 to 175 beats/minute), and hypermetabolism. In addition, leukopenia and increased circulating stress hormone concentrations were observed. Blood glucose concentrations fell from 4.68 mM/1 to 3.97 mM/1 (84-71 mg/dl) within 3 hours of TNF infusion, whereas lactate and pyruvate concentrations increased. These alterations occurred in the absence of severe hypotension or acidosis and were similar to changes observed after endotoxin administration or gram-negative septicemia. Pretreatment of the animals with the cyclooxygenase inhibitor ibuprofen abolished most of the hemodynamic changes and attenuated other responses. These findings support the hypothesis that TNF is an important mediator of septic responses and that some of the effects of TNF are mediated via cyclooxygenase pathways.
The influence of growth hormone (GH) on protein metabolism and fuel utilization was investigated in eight paired studies of normal volunteers. GH (10 mg) was given daily during one period, and saline was injected during control studies. For 6 days, subjects received parenteral nutrition that provided adequate dietary nitrogen, vitamin, and minerals, but energy intake varied to provide 30-100% of requirements. On Day 7, the feedings were discontinued and an oral glucose load (100 g) was administered. The level of energy intake did not markedly influence the actions of GH. During nutrient infusions, GH caused positive nitrogen balance (1.0 +/- 0.3 g/m2/day vs. -1.2 +/- 0.3 in controls, p less than 0.001) and increased protein synthesis (16.8 +/- 0.7 g N/m2/day vs. 13.9 +/- 0.8, p less than 0.01). No change in the rate of protein breakdown or excretion of 3-methylhistidine occurred. GH was associated with an increase in insulin and insulin-like growth factor-I concentrations (IGF-I, 9.1 +/- 0.6 IU/ml vs. 3.3 +/- 0.5, p less than 0.001). After discontinuation of the parenteral nutrition and administration of the oral glucose load, glucose concentrations tended to be higher after GH; however, despite a two- to threefold increase in insulin response, muscle glucose uptake was attenuated (1.10 +/- 0.19 g/kg forearm vs. 1.64 +/- 0.30 in controls, p less than 0.05). Compared with control conditions, GH appeared to attenuate the increase in amino acid nitrogen efflux from muscle after the administration of oral glucose. These data demonstrate that the protein anabolic effect of GH, which occurs even during hypocaloric feedings, is related to multiple mechanisms that favor protein synthesis. These include the increase in plasma concentrations of GH, insulin IGF-I and fat utilization. GH administration results in a hormonal-substrate environment that favors nitrogen retention and protein synthesis. GH may be beneficial in promoting protein synthesis in surgical patients, particularly in association with hypocaloric glucose infusions that allow utilization of body fat as an energy source.
Patients undergoing elective abdominal surgery were double-blindly randomized for treatment with growth hormone (GH) 24 IU (n = 9) or placebo (n = 10) the first 5 postoperative days while receiving total parenteral nutrition (nitrogen, 5.7 +/- .1 g/m2; energy, 1,018 +/- 12 kcal/m2, ie, 125% +/- .7% of basal metabolic rate [BMR]). Carbohydrate and fat metabolism were evaluated from indirect calorimetry, daily blood samples, and forearm substrate-flux studies. Hormone levels in plasma or blood were also determined. GH decreased carbohydrate oxidation, increased fat oxidation, and increased resting energy expenditure (REE). Free fatty acids (FFA), glycerol, and beta-hydroxybutyrate (beta-OH-B) levels increased in both arterial and venous plasma, and forearm release of FFA and glycerol increased. GH, insulin-like growth factor 1 (IGF-1), and glucagon levels in venous blood were also increased in GH-treated patients. Thus, GH induced mobilization and utilization of fat, and fat was preferred to glucose for energy requirements in patients after abdominal surgery with nutritional support.
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