effect of insulin analogues on insulinigf1 hybrid receptors increased activation by glargine but not by its metabolites m1 and m2胰岛素类似物对insulinigf1混合受体激活增加了甘精而不是由其代谢物狭义货币供应量m1及广义货币供应量m2.pdfVIP

Effect of Insulin Analogues on Insulin/IGF1 Hybrid Receptors: Increased Activation by Glargine but Not by Its Metabolites M1 and M2 ´ 1,2 1,2 1,2 ´ 1,2 3 Cecile Pierre-Eugene , Patrick Pagesy , Tuyet Thu Nguyen , Marion Neuille , Georg Tschank , Norbert Tennagels3, Cornelia Hampe1,2, Tarik Issad1,2* ´ 1 Institut Cochin, Universite Paris Descartes, CNRS (UMR8104), Paris, France, 2 INSERM, U1016, Paris, France, 3 Sanofi-Aventis, Frankfurt, Germany Abstract Background: In diabetic patients, the pharmacokinetics of injected human insulin does not permit optimal control of glycemia. Fast and slow acting insulin analogues have been developed, but they may have adverse properties, such as increased mitogenic or anti-apoptotic signaling. Insulin/IGF1 hybrid receptors (IR/IGF1R), present in most tissues, have been proposed to transmit biological effects close to those of IGF1R. However, the study of hybrid receptors is difficult because of the presence of IR and IGF1R homodimers. Our objective was to perform the first study on the pharmacological properties of the five marketed insulin analogues towards IR/IGF1R hybrids. Methodology: To study the effect of insulin analogues on IR/IGF1R hybrids, we used our previously developed Bioluminescence Resonance Energy Transfer (BRET) assay that permits specific analysis of the pharmacological properties of hybrid receptors. Moreover, we have developed a new, highly sensitive BRET-based assay to monitor phophatidylinositol-3 phosphate (PIP3) production in living cells. Using this assay, we performed a detailed