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.