Inflammation has become a major mechanism linking obesity to type 2 diabetes (T2D). The pleiotropic cytokine, Interleukin 6 (IL-6) is pro-inflammatory and widely thought to negatively impact on obesity-induced insulin resistance. However, recent evidence challenges this concept. IL-6-deficient (IL-6−/−) mice develop mature onset obesity, glucose intolerance, insulin resistance, and increased liver inflammation in response to a high-fat diet. Here we investigate the CNS role of IL-6 in the manifestation of T2D using a neuronal-specific IL-6 receptor null mouse model.

IL-6Ra-/- mice were generated by crossing IL-6RaFlx/flx with Nestin-Cre+/-animals. Male IL-6Ra-/- and Cre+/- animals (18 weeks, n=12/group) were fed standard laboratory chow for 20 weeks. Body composition and energy homeostasis were assessed using EchoMRI and CLAMS systems. Insulin secretion by glucose-stimulated insulin secretion (GSIS) was measured both in vivo and ex-vivo in isolated β-cell preparations. Circulating insulin was measured by ELISA. Data are expressed as mean±SEM.

Body weight was comparable between IL-6Ra-/- and Cre+/- animals. Fat mass however was significantly reduced (20% reduction; p<0.05) despite animals being hyperphagic (28% increase; p<0.01). Energy expenditure was reduced (12% reduction) and the respiratory exchange ratio were significantly increased (18% increase) in IL-6Ra-/- animals (p<0.01 for both). Glucose and insulin tolerance were comparable. In vivo insulin secretion was markedly diminished in IL-6Ra-/- animals (GSIS AUC; 2.5±0.6 vs. 17.1±5.1, p<0.01). Histological analysis and stimulation of isolated pancreatic islets ex vivo however, showed similar islet morphology and GSIS or glucagon secretion (p=ns for all). Administration of hexamethonium, an Ach receptor blocker to IL-6Ra-/- animals restored GSIS in vivo (p=ns).

These finding suggest that classical IL-6 signaling within the CNS plays an important role in regulating insulin secretion via direct effect on β-cell function in vivo.

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

Diabetes UK

© 2019 by the American Diabetes Association.
2019
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