381-P: Recurrent Hypoglycemia Alters Endocrine Counterregulation during Insulin-Induced Hypoglycemia in Healthy and Diabetic Göttingen Minipigs

Abstract

Hypoglycemia is a common adverse effect of insulin treatment in people with diabetes and recurrent episodes can alter counter regulation, ultimately increasing the risk of severe hypoglycemic episodes. The aim of this study was to investigate the effect of recurrent hypoglycemia on endocrine counter regulation during insulin-induced hypoglycemia in healthy and diabetic Göttingen Minipigs. Twelve adult, female, intact Göttingen Minipigs with (n=6) and without (n=6) streptozotocin-induced diabetes were included. Three pigs in each group were preconditioned with either hypoglycemia (RH) or normoglycemia (RN) on three consecutive days using a three-hour hyperinsulinemic clamp procedure (16 pmol/kg/min human insulin and variable glucose infusion) targeted a fasted minipig euglycemic level of 63 mg/dL plasma glucose in RN and 27 mg/dL in RH. On day four, all groups were subjected to a four-hour hypoglycemic clamp with 18 mg/dL target. Samples for plasma glucose, glucagon and epinephrine were collected at predefined time points. Influence of diabetes status and preconditioning on endocrine counter regulation during the final clamp were investigated using a repeated measures linear mixed model. Clamp glucose targets were reached in all groups. A blunted glucagon response was seen during the final hypoglycemic clamp in the RH groups (median 26.7 pM (IQR 21.6-33.2)) compared to RN groups (56.3 pM (46.3-63.5) , P=0.008) . Diabetes status did not influence the findings and no significant differences in plasma epinephrine were found between groups. Göttingen Minipigs with and without streptozotocin induced diabetes exhibit blunted glucagon response to hypoglycemia after recurrent hypoglycemia similar to humans, indicating impaired counter regulatory response. Epinephrine response was not significantly affected. Further studies are needed to investigate the effect of RH on epinephrine counter regulation in the Göttingen Minipig. Disclosure M.Lyhne: None. K.Hinz: Employee; Antag Therapeutics, Novo Nordisk. A.Vegge: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. J.Sturis: Employee; Novo Nordisk A/S. J.Kildegaard: Employee; Novo Nordisk A/S. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. L.Olsen: None.