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 LysB3,GluB29-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 (concentration required to attain 50% displacement of specific [125I]insulin or [125I]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 [3H]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.