title: Toxicological Effects during and following Persistent Insulin-Induced Hypoglycaemia in Healthy Euglycaemic Rats.
abstract: New insulin analogues with a longer duration of action and a 'peakless' pharmacokinetic profile have been developed to improve efficacy, safety and convenience for patients with diabetes. During non-clinical development, according to regulatory guidelines, these analogues are tested in healthy euglycaemic rats rendering them persistently hypoglycaemic. Little is known about the effect of persistent (24 hr/day) insulin-induced hypoglycaemia (IIH) in rats, complicating interpretation of results in pre-clinical studies with new longer-acting insulin analogues. In this study, we investigated the effects of persistent IIH and their reversibility in euglycaemic rats. Histopathological changes in insulin-infused animals included partly reversible axonal and reversible myofibre degeneration in peripheral nerve and skeletal muscle tissue, respectively, as well as reversible pancreatic islet atrophy and partly reversible increase in unilocular adipocytes in brown adipose tissue. Additionally, results suggested increased gluconeogenesis. The observed hyperphagia, the pancreatic, peripheral nerve and skeletal muscle changes were considered related to the hypoglycaemia. Cessation of insulin infusion resulted in transient hyperglycaemia, decreased food consumption and body-weight loss before returning to control levels. The implications for the interpretation of non-clinical studies with long-acting insulin analogues are discussed.
authors.affiliation: Department of Veterinary and Animal Sciences, Section for Experimental Animal Models, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Department of Toxicology, Safety Pharm and Pathology, Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: Vivi F H
authors.initials: VFH
authors.lastname: Jensen
authors.affiliation: Department of Toxicology, Safety Pharm and Pathology, Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mølck
authors.affiliation: Department of Toxicology, Safety Pharm and Pathology, Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: Line O
authors.initials: LO
authors.lastname: Berthelsen
authors.affiliation: Department of Development DMPK, Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: Lene
authors.initials: L
authors.lastname: Alifrangis
authors.affiliation: Department of Diabetes Bioanalysis, Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: Lene
authors.initials: L
authors.lastname: Andersen
authors.affiliation: Division of Toxicology, Envigo, Suffolk, UK.
authors.forename: Melissa
authors.initials: M
authors.lastname: Chapman
authors.affiliation: Department of Veterinary and Animal Sciences, Section for Experimental Animal Models, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Lykkesfeldt
authors.affiliation: Department of Toxicology, Safety Pharm and Pathology, Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Bøgh
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D005943:Gluconeogenesis / Q000187:drug effects; D006943:Hyperglycemia / Q000097:blood / Q000209:etiology*; D006963:Hyperphagia / Q000209:etiology; D007003:Hypoglycemia / Q000097:blood / Q000139:chemically induced* / Q000150:complications; D007004:Hypoglycemic Agents / Q000633:toxicity*; D049528:Insulin, Long-Acting / Q000633:toxicity*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D010525:Peripheral Nerves / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015431:Weight Loss / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D049528:Insulin, Long-Acting