TY - JOUR

T1 - Histopathological nerve and skeletal muscle changes in rats subjected to persistent insulin-induced hypoglycemia

AU - Jensen, Vivi Flou Hjorth

AU - Mølck, Anne-Marie

AU - Heydenreich, Annette

AU - Jensen, Karin Juul

AU - Bertelsen, Line Olrik

AU - Alifrangis, Lene

AU - Andersen, Lene

AU - Søeborg, Henrik

AU - Chapman, Melissa

AU - Lykkesfeldt, Jens

AU - Bøgh, Ingrid Brück

PY - 2016/1

Y1 - 2016/1

N2 - 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.

AB - 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.

U2 - 10.1293/tox.2015-0041

DO - 10.1293/tox.2015-0041

M3 - Journal article

C2 - 26989298

VL - 29

SP - 17

EP - 30

JO - Toxicologic Pathology

JF - Toxicologic Pathology

SN - 0192-6233

IS - 1

ER -