Effects of the rapid-acting insulin analog glulisine on cultured human skeletal muscle cells: Comparisons with insulin and insulin-like growth factor I

Context: The insulin analog Lys(B3), Glu(B29)-insulin (glulisine) displays accelerated in vivo bioavailability compared with native insulin. Objective: Biological properties of this rapid-acting insulin analog were compared with the actions of native insulin and IGF-I. Design: The effects of the hormones on hormone binding, glucose uptake, and thymidine uptake were evaluated in cultured human skeletal muscle cells. Setting: This study was performed at a Veterans Administration hospital for patient characterization and tissue biopsies; in vitro studies were performed in a research laboratory. Patients or Other Participants: Skeletal muscle tissue was obtained from nondiabetic ( n = 13) and type 2 diabetic (n = 14) subjects. Intervention: Cultured skeletal muscle cells were treated acutely (15-90 min) or chronically (16 h) with varying concentrations of hormones. Main Outcome: The main study outcomes were measures of sensitivity I-125] insulin or [I-125]IGF-I bound and sensitivity (EC50) and potency ( maximal response) for hormone binding and biological responses. Results: Insulin and glulisine were comparable in their ability to displace insulin binding. Neither insulin nor glulisine competed efficiently for IGF-I binding. Insulin, glulisine, and IGF-I were equipotent in the stimulation of glucose uptake. Maximal stimulation of phosphorylation of Akt was greatest for IGF-I, whereas sensitivities were similar to those for glucose uptake. Sensitivities were comparable in muscle cells from nondiabetic and type 2 diabetic subjects. Stimulation of [H-3] thymidine uptake was most responsive to IGF-I; insulin and glulisine were equally less effective, with sensitivities approximately 1-2% of that for IGF-I. Stimulation of p42/44 MAPK phosphorylation reflected the behavior of thymidine uptake. Conclusions: Although altered pharmacokinetics of glulisine can have therapeutic advantages, glulisine is indistinguishable from native insulin at the skeletal muscle level.