Endocrine Abstracts (2015) 38 P192 | DOI: 10.1530/endoabs.38.P192

Central IL6 signalling and the development of impaired insulin secretion in type2 diabetes

Adonis Yiannakas, Alison D McNeilly, Jennifer Gallagher, Kathryn Wright & Rory J McCrimmmon

University of Dundee, Dundee, UK.

Obesity and the metabolic syndrome are chronic inflammatory states that are now understood to be involved in the development type 2 Diabetes. Hypothalamic cytokine signalling is thought to influence neuroendocrine networks critical to the dynamic maintenance of glucose homeostasis. Interleukin 6 (IL6) is a cytokine that displays tissue-specificity and is instrumental in the mounting of the acute phase response, as well as in the subsequent resolving and adaptive phase. IL6 is a strong biomarker of disease progression and its receptor displays extensive expression centrally. To examine the role of central IL6 signalling in diabetes, we generated brain-specific receptor knock-down mice (NesCre IL-6R KD) by crossing NesCre1 and IL-6Rflox/flox mice, and proceeded to validate and metabolically phenotype their KD and control offspring on standard chow (SC) and high fat diet (HFD). KD mice on SC exhibited a 15% decrease in body mass compared to their controls and appeared to harbor increased musculature and decreased body fat at 3 and 20 weeks of the study. Unsurprisingly, HFD KDs only displayed significant differences in body fat following 20 weeks. Intriguingly, KD animals on SC were found to be less active in the feeding phase of their cycle, with no significant differences observed in the HFD groups. Similarly, no significant differences in terms of food consumption were observed, however comparison of mean RER over 48 h using the CLAMS monitoring system, revealed a preference to glucose oxidation in KD animals compared to control animals on SC and HFD. Most strikingly, dramatic deficits in basal and glucose-stimulated insulin secretion were observed in both SC and HFD KD mice, while HFD KDs displayed significantly elevated resting blood glucose by 10 weeks of diet. This would suggest central classical IL6 signaling to regulate insulin release in the periphery as well as the adaptive response to HFD via promoting peripheral fat oxidation.

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