STIMULATION OF GLUCOSE AND AMINO-ACID-TRANSPORT AND ACTIVATION OF THEINSULIN SIGNALING PATHWAYS BY INSULIN LISPRO IN L6 SKELETAL-MUSCLE CELLS

The monomeric insulin analogue insulin lispro (Lys B28, Pro B29) is a rapid-acting insulin with a shorter duration of activity than human re gular insulin. This compound has the advantage of reducing early postp randial hyperglycemia and the accompanying late hypoglycemia, thereby improving overall blood glucose control. To date, all published studie s of the functional properties of insulin lispro have been conducted i n whole animals. This study aimed to characterize the cellular actions of insulin lispro and the signals it elicits in an insulin-sensitive muscle cell line, L6 cells. Comparing the cellular actions of insulin lispro with those of human regular insulin, a number of observations w ere made. (1) Insulin lispro stimulated glucose and amino acid transpo rt into L6 myotubes with a dose dependency and time course virtually i dentical to those of human regular insulin. (2) Insulin lispro was as effective as human regular insulin in stimulating time-dependent phosp horylation of insulin receptor substrate 1 (IRS-1), p70 ribosomal S6 k inase, and two isoforms of mitogen-activated protein kinase (ERK1 and ERK2). (3) Insulin lispro's ability to induce the association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase was similar to that of human regular insulin. (4) As with human regular insulin, 100 nmol of the fungal metabolite wortmannin completely inhibited insulin lispro stimulation of glucose uptake. We concluded that the cellular a ctions of insulin lispro are similar to those of human regular insulin with respect to glucose and amino acid uptake and that the biochemica l signals elicited are also comparable.