373-P: Recurrent Insulin-Induced Hypoglycaemia Leads to Weight Gain in Association with Increased Adiposity and Reduced Basal Metabolic Rate

Abstract

Intensification of insulin therapy in type 1 diabetes is associated with significant weight gain. Several mechanisms have been proposed to account for this weight gain including reduced glucosuria and suppression of hepatic gluconeogenesis and glucose production however the precise mechanisms responsible for this remain unclear. This study examined the hypothesis that recurrent hypoglycaemia (RH) might contribute, at least in part, to this phenomenon. Male C57BL6J mice (n=12/group) received either RH (1mU/g insulin i.p. 3 per week for 12 weeks to achieve glucose of approximately 2.8mmol/l) or Vehicle (saline i.p in equivalent volume). Body composition and energy homeostasis were assessed using EchoMRI and CLAMS systems respectively. Hypothalamic transcript abundance was assessed using Taqman real time PCR. Data are expressed as mean+/-SEM. RH animals were 43% heavier and had increased fat mass compared to Control animals (8.49+/-0.64 v 16.6+/-1.38% body weight) despite comparable food intake (p=ns). Energy expenditure was significantly lower (53% decrease) in RH animal (0.414+/-0.006 v 0.218+/-0.004 kcal/min; p<0.01) and was associated with a decrease in the respiratory exchange ratio (RER: 0.98+/-0.01 v 0.96+/-0.01;p<0.05). There was no difference in locomotor activity. These changes were associated with suppression of genes involved in thermogenesis, mitochondrial energetics and lipolysis within the brown adipose tissue. Consistent with our hypothesis, RH leads to increased accumulation of fat stored which is associated with reduced energy expenditure and RER. These results suggest that RH induces a state of hypometabolism that may contribute to weight gain observed with intensification of insulin therapy in type 1 diabetes. Disclosure A.D. McNeilly: None. J. Gallagher: None. R.J. McCrimmon: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust. Funding JDRF; Diabetes UK