Normal protein anabolic response to hyperaminoacidemia in insulin-resistant patients with lung cancer cachexia

Abstract

Insulin resistance of protein anabolism has been speculated to underlie the skeletal muscle wasting characteristic of cancer cachexia. We tested whether insulin resistance is present in cachectic lung cancer patients and if a sustained, physiological elevation of amino acids with hyperinsulinemia would compensate for it. Whole-body [(13)C]leucine and [(3)H]glucose kinetics were assessed in 10 male non-small cell lung cancer (NSCLC) patients and 10 healthy matched controls during a euglycemic, hyperinsulinemic clamp under conditions of isoaminoacidemia followed by hyperaminoacidemia. Postabsorptive glucose and protein kinetics were comparable between groups. Glucose uptake was significantly lower in NSCLC patients during hyperinsulinemia. During concurrent isoaminoacidemia, protein breakdown was suppressed in both, but rates were elevated in NSCLC; rates of synthesis did not change, resulting in reduced net protein balance (synthesis - breakdown) in response to insulin in NSCLC. With subsequent hyperaminoacidemia, synthesis increased significantly with no further change in breakdown, resulting in similar increase in net balance between groups. NSCLC patients with moderate cachexia showed considerable insulin resistance of glucose and of whole-body protein anabolism. Their anabolic protein response was stimulated normally by hyperaminoacidemia. Thus, ample provision of amino acids is a feasible strategy to overcome the protein anabolic failure of cancer cachexia.