Metabolic effect and receptor signalling profile of a non-metabolisable insulin glargine analogue

Abstract

Context: Insulin glargine (GLA) is rapidly metabolized in vivo to metabolite M1, which has in vitro metabolic and mitogenic profiles comparable with human insulin (HI). Objective: To investigate the pharmacologic and signalling profiles of a non-metabolizable analogue (A21Gly,DiD-Arg) insulin (D-GLA). Methods: Rats were injected s.c. with 1, 12.5 or 200U/kg of GLA or D-GLA; blood glucose and phosphorylation status of the insulin receptor (IR), Akt and IGF-1 receptor (IGF1R) in tissue samples were investigated after 1h. Plasma samples were analysed for insulin by LC-MS/MS. Results: Blood glucose lowering was prolonged with D-GLA. D-GLA comprised 98% of insulin after D-GLA injection; M1 comprised 76-92% after GLA injection. IR and Akt phosphorylation were comparable with GLA and D-GLA. Neither analogue stimulated IGF1R phosphorylation. Conclusions: Suprapharmacological doses of D-GLA did not activate IGF1R in vivo. Mitogenic effects of insulin and insulin analogues might be solely based on IR growth-promoting activity.