title: Histopathological nerve and skeletal muscle changes in rats subjected to persistent insulin-induced hypoglycemia.
abstract: New insulin analogues with a longer duration of action and a flatter pharmacodynamic profile are developed to improve convenience and safety for diabetic patients. During the nonclinical development of such analogues, safety studies must be conducted in nondiabetic rats, which consequently are rendered chronically hypoglycemic. A rat comparator model using human insulin would be valuable, as it would enable differentiation between effects related to either persistent insulin-induced hypoglycemia (IIH) or a new analogue per se. Such a model could alleviate the need for an in-study-comparator and thereby reduce the number of animals used during development. Thus, the aims of the present study were i) to develop a preclinical animal model of persistent hypoglycemia in rats using human insulin infusion for four weeks and ii) to investigate histopathological changes in sciatic nerves and quadriceps femoris muscle tissue, as little is known about the response to persistent hypoglycemia in these tissues. Histopathologic changes in insulin-infused animals included axonal degeneration and myofibre degeneration. To our knowledge, this is the first study to show that persistent IIH provokes peripheral nerve and skeletal myofiber degeneration within the same animals. This suggests that the model can serve as a nonclinical comparator model during development of long-acting insulin analogues.
authors.affiliation: Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870 Frederiksberg C, Denmark; Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Maaloev, Denmark.
authors.forename: Vivi Flou Hjorth
authors.initials: VF
authors.lastname: Jensen
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Maaloev, Denmark.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mølck
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Maaloev, Denmark.
authors.forename: Annette
authors.initials: A
authors.lastname: Heydenreich
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Maaloev, Denmark.
authors.forename: Karin Juul
authors.initials: KJ
authors.lastname: Jensen
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Maaloev, Denmark.
authors.forename: Line Olrik
authors.initials: LO
authors.lastname: Bertelsen
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Maaloev, Denmark.
authors.forename: Lene
authors.initials: L
authors.lastname: Alifrangis
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Maaloev, Denmark.
authors.forename: Lene
authors.initials: L
authors.lastname: Andersen
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Maaloev, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Søeborg
authors.affiliation: Huntingdon Life Sciences, Barric Lane, Eye, Suffolk, IP23 7PX, UK.
authors.forename: Melissa
authors.initials: M
authors.lastname: Chapman
authors.affiliation: Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870 Frederiksberg C, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Lykkesfeldt
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Maaloev, Denmark.
authors.forename: Ingrid Brück
authors.initials: IB
authors.lastname: Bøgh
keywords: animal models; human insulin; hypoglycemia; peripheral nerve; rat; skeletal muscle