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Effects of the Rapid-Acting Insulin Analog Glulisine on Cultured Human Skeletal Muscle Cells: Comparisons with Insulin and Insulin-Like Growth Factor I

Veterans Affairs San Diego HealthCare System (T.P.C., L.C., V.A., S.M., R.R.H.) and Departments of Medicine (T.P.C., L.C., V.A., S.M., R.R.H.) and Pediatrics (S.A.P.), University of California-San Diego, La Jolla, California 92093

Address all correspondence and requests for reprints to: Dr. Theodore P. Ciaraldi, Department of Medicine (9111G), University of California-San Diego, La Jolla, California 92093. E-mail: tciaraldi{at}ucsd.edu.

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 (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.