title: Insulin glulisine: insulin receptor signaling characteristics in vivo.
abstract: In recent years, recombinant DNA technology has been used to design insulin molecules that overcome the limitations of regular insulin in mealtime supplementation. However, safety issues have been raised with these alternatives, as the alteration of the three-dimensional structure may alter the interaction with the insulin and/or IGF-I receptors and therefore lead to the activation of alternate metabolic as well as mitogenic signaling pathways. It is therefore essential to carefully study acute and long-term effects in a preclinical state, as insulin therapy is meant to be a lifelong treatment. In this study, we determined in vivo the insulin receptor signaling characteristics activated by insulin glulisine (Lys(B3), Glu(B29)) at the level of insulin receptor phosphorylation, insulin receptor substrate phosphorylation, and downstream signaling elements such as phosphatidylinositol (PI) 3-kinase, AKT, and mitogen-activated protein kinase. C57BL/6 mice were injected with insulin glulisine or regular insulin and Western blot analysis was performed for liver and muscle tissue. The extent and time course of insulin receptor phosphorylation and activation of downstream signaling elements after insulin glulisine treatment was similar to that of human regular insulin in vivo. Moreover, insulin signaling in hypothalamic tissue determined by PI 3-kinase activity was comparable. Therefore, insulin glulisine may be a useful tool for diabetes treatment.
authors.affiliation: University of Tuebingen, Department of Internal Medicine IV, D-72076, Tuebingen, Germany.
authors.forename: Anita M
authors.initials: AM
authors.lastname: Hennige
authors.forename: Rainer
authors.initials: R
authors.lastname: Lehmann
authors.forename: Cora
authors.initials: C
authors.lastname: Weigert
authors.forename: Klaus
authors.initials: K
authors.lastname: Moeschel
authors.forename: Myriam
authors.initials: M
authors.lastname: Schäuble
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Metzinger
authors.forename: Reiner
authors.initials: R
authors.lastname: Lammers
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
mesh_terms: D000818:Animals; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007328:Insulin; C479079:insulin glulisine; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin