Treating hyperglycemia improves skeletal muscle protein metabolism in cancer patients after major surgery.

OBJECTIVE: Cancer and surgical stress interact to aggravate insulin resistance, protein catabolism, and glutamine depletion in skeletal muscle. We compared the effects of insulin-mediated euglycemia and moderate hyperglycemia on kinetics of protein and selected amino acids in skeletal muscle of female cancer patients after major surgery. DESIGN: In each patient, a 24-hr period of insulin-mediated tight euglycemia (mean blood glucose, 5.8 +/- 0.4 mmol/L) preceded or followed a 24-hr control period of moderate hyperglycemia (mean blood glucose, 9.6 +/- 0.6 mmol/L) on the first and second day after surgery, in randomized order, according to a crossover experimental design. SETTING: Intensive care unit, cancer hospital. PATIENTS: Cancer patients after abdominal radical surgery combined with intraoperative radiation therapy. INTERVENTIONS: Intensive (57 +/- 11 units/24 hrs) and conventional (25 +/- 5 units/24 hrs) insulin treatment during total parenteral nutrition. MEASUREMENTS AND MAIN RESULTS: Muscle metabolism was assessed at the end of each 24-hr period of euglycemia and of hyperglycemia by leg arteriovenous catheterization with stable isotopic tracers. We found that euglycemia as compared with hyperglycemia was associated with higher (p < .05) fractional glucose uptake (16% +/- 4% vs. 9% +/- 3%); higher (p < .05) muscle protein synthesis and neutral net protein balance (-3 +/- 3 vs. -11 +/- 3 nmol phenylalanine x 100 mL(-1) x min(-1), respectively); lower (-52% +/- 12%, p < .01) muscle nonprotein leucine disposal (an index of leucine oxidation) and higher (p < .05) plasma leucine concentrations; and higher (3.6 +/- 1.7 times, p < .01) net de novo muscle glutamine synthesis and plasma glutamine concentrations (p < .05). Euglycemia was associated with higher (23% +/- 7%, p < .05) plasma concentrations of arginine but did not affect either arginine release from muscle or plasma concentration and muscle flux of asymmetrical dimethylarginine. Rate of muscle proteolysis correlated (p < .05) with muscle release of asymmetrical dimethylarginine. CONCLUSIONS: Treating hyperglycemia improves skeletal muscle protein and amino acid metabolism in cancer patients after major surgery.

Response of muscle protein and glutamine kinetics to branched-chain-enriched amino acids in intensive care patients after radical cancer surgery.

OBJECTIVE: Patients with cancer are characterized by decreased muscle protein synthesis and glutamine availability that contribute to an impaired immune response. These abnormalities worsen after surgical stress. We tested the hypothesis that pharmacologic doses of branched-chain amino acids would improve the early metabolic response after major cancer surgery. METHODS: By using a crossover experimental design, we compared the metabolic effects of isonitrogenous solutions of balanced and branched-chain-enriched amino acid mixtures infused at the rate of 82 mg x h(-1) x kg(-1) for 3 h in patients with colorectal or cervical cancer on the first and second days after radical surgery combined with intraoperative radiation therapy. The ratios of leucine to total amino acid (grams) in the two mixtures were 0.09 and 0.22, respectively. Muscle protein and glutamine kinetics were determined by using stable isotope of amino acids and the leg arteriovenous balance technique. Glucose and insulin were continuously infused throughout the 2-d study to maintain near euglycemia. RESULTS: Rates of muscle protein synthesis and degradation were not significantly affected by the balanced amino acid infusion. In contrast, the isonitrogenous, branched-chain-enriched amino acid mixture accelerated muscle protein turnover by stimulating (P

Metabolic consequences of physical inactivity.

Physical inactivity is associated with alteration of normal physiologic processes leading to muscle atrophy, reduced exercise capacity, insulin resistance, and altered energy balance. Bed rest studies in human beings using stable isotopes of amino acids indicate that muscle unloading decreases the turnover rates of muscle and whole-body proteins, with a prevailing inhibition of protein synthesis. In the fasting state, muscle and whole-body nitrogen loss was not accelerated during bed rest. In experimental postprandial states, the amino acid-mediated stimulation of protein synthesis was impaired, whereas the ability of combined insulin and glucose infusion to decrease whole-body proteolysis was not affected by muscle inactivity. Thus, an impaired ability of protein/amino acid feeding to stimulate body protein synthesis is the major catabolic mechanism for the effect of bed rest on protein metabolism. This suggests that a protein intake level greater than normal could be required to achieve the same postprandial anabolic effect during muscle inactivity. Metabolic adaptation to muscle inactivity also involves development of resistance to the glucoregulatory action of insulin, decreased energy requirements, and increased insulin and leptin secretion. These alterations may lead to the development of the metabolic syndrome that is defined as the association of hyperinsulinemia, dyslipidemia, hypertension, hyperglycemia, and abdominal obesity. This cluster of metabolic abnormalities is a risk factor for coronary artery disease and stroke. Evidence indicates that exercise training programs may counteract all of these abnormalities both in healthy sedentary subjects and in patients affected by a variety of chronic disease states.