Protein synthesis and breakdown rates associated with the insulin resistance of fibroblasts from patients with leprechaunism.

Postreceptor defects in insulin action have been reported in fibroblasts isolated from two patients with Leprechaunism, Leprechaun/Ark-1 and Leprechaun NC-1. We have extended the published reports on glucose, aminoisobutyric acid, and thymidine uptake in these cells to measurements of protein synthesis and protein breakdown. We found a remarkably consistent pattern of responsiveness between the two Leprechaun fibroblast lines. First, protein synthesis proceeded at a low basal rate that was only slightly stimulated by insulin. Second, basal rates of protein breakdown were significantly higher than in normal skin fibroblasts, with approximately equal inhibitory effects produced by 100 nM insulin. Third, the responses of protein synthesis and protein breakdown to insulin required higher concentrations of the hormone to elicit half-maximal effects. Fourth, both Leprechaun cell lines were slow growing in complete medium, a situation that results from low rates of protein synthesis and high rates of protein breakdown. Fifth, the abnormal rates of protein metabolism in the presence of serum were caused not by the inability of serum to produce anabolic responses but because the unstimulated rates reflect a more catabolic basal state. Taken together with previous published results, our measurements suggest a generalized metabolic defect in Leprechaun fibroblasts that can only partly be explained by the reduced sensitivity of the cells to insulin.