Hypoglycaemia is common in insulin-treated therapy in the management of type 1 and long duration type 2 diabetes. Hypoglycemia evokes a significant stress response stimulating the release of several inflammatory mediators including interleukin 6 (IL-6). Importantly, glial cells also release IL-6 in response to glucose deprivation. We have previously demonstrated a role for IL-6 in the induction of defective neuronal glucose sensing in vitro. Here we investigate the potential role of IL-6 in the development of defective counter-regulatory response (CRR) to hypoglycaemia in vivo.

IL-6Ra-/- mice were generated by crossing IL-6RaFlx/flx with Nestin-Cre+/-animals. Male IL-6Ra-/- and Cre+/- animals (Control) 18 weeks old, n=10/12 per group) were fed standard laboratory chow for 20 weeks. Hormonal response to hypoglycaemia was assessed in vivo by hyperinsulinaemic-hypoglycaemic clamps. Plasma epinephrine and glucagon were measured by ELISA in response to either acute (single hypo; AH) or recurrent (3 episodes per week for 4 weeks; RH) hypoglycaemia. Data are expressed as mean±SEM.

The epinephrine response to hypoglycaemia was significantly elevated (>3 fold higher) in male IL-6Ra-/- animals following AH when compared to their control counterparts (0.38±0.09 vs. 1.31±0.28 delta; p<0.05). Plasma glucagon levels were comparable between genotypes (p=ns). In contrast, there was a significant suppression of the CRR to hypoglycaemia in both Control and IL-6Ra-/- animals following RH. Indeed, both IL-6Ra-/- and Control animals had suppressed epinephrine (50% and 68% reduction) and glucagon (65% and 44% reduction) responses to following RH when compared to their non-RH counterparts.

These findings highlight an important role for central IL-6 signaling in response to acute hypoglycemia, however, additional mechanisms appear to contribute to the development of defective CRR following RH.


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.


Diabetes UK

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