Differential Glycaemic Effects of Recombinant IL-9 across Species Highlight Translational Challenges for Immunometabolic Phenotypes

In the present study, IL-9 was initially identified as a strong regulator of blood glucose in diabetic db/db mice through a hydrodynamic gene delivery screening effort. IL-9 belongs to the common gamma-chain binding cytokine family and has classically been linked to asthma and type 2 immune responses. Alongside the very clear dosing effects of mouse IL-9 on fasting blood glucose, the more classical effects of IL-9, including IL-5 plasma increases and eosinophilia, were also observed in the db/db mice. An expansion of epididymal white adipose tissue macrophages was shown with IL-9-, but not IL-5 dosing. Inhibition of endogenous IL-5, with an anti-IL5 mAb, attenuated the IL-9 effects on eosinophils but not macrophages. Interestingly, suppression of glucagon levels following IL-9 dosing was a general observation in several diabetic mouse studies. The addition of anti-IL-5 mAb to IL-9 dosing did not affect glucagon levels in the db/db mouse model, and an association between eosinophil/macrophage changes and blood glucose could not be established. To examine the translation of these interesting IL-9 effects to higher species, a recombinant protracted human IL-9 dosed to low streptozotocin induced diabetic mini-pigs (2-week study) , showed increased numbers of circulating eosinophils, but no significantly reduced levels of glucagon or plasma glucose. Finally, an 11-week treatment study in type 2 diabetic cynomolgus monkeys was performed. Eosinophilia was observed as an indicator of IL-9 receptor engagement, but several glycaemic parameters and glucagon levels were unaffected throughout the study. Conclusion: The pronounced glycaemic effects observed for IL-9 in a diabetic mouse model was not found in diabetic minipigs and non-human primates highlighting the complexity and need for further studies of the translation of immuno-metabolic phenotypes. Disclosure T.Guo: Employee; Novo Nordisk A/S. K.S.Frederiksen: Employee; Novo Nordisk A/S. E.Straarup: Employee; Novo Nordisk A/S. J.Lindroos christensen: Employee; Novo Nordisk A/S. G.Bolt: Employee; Novo Nordisk A/S. P.Lisby nørby: Employee; Novo Nordisk A/S. W.Zhe: Employee; Novo Nordisk A/S. T.A.Pedersen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. M.Ferreras: Employee; Novo Nordisk A/S. K.Sass-ørum: Employee; Novo Nordisk A/S.