Hyperglycemia in critical illness is a common complication and a strong independent risk factor for morbidity and death. Intensive insulin therapy decreases this risk by up to 50%. It is unclear to what extent this benefit is due to reversal of glucotoxicity or to a direct effect of insulin, as anti-inflammatory effects of insulin have already been described, but the underlying mechanisms are still poorly understood.

The Insulin receptor (IR) is expressed on resting neutrophils, monocytes and B cells, but not detectable on T cells. However, significant up-regulation of IR expression is observed on activated T cells, which suggests an important role during T cell activation. Exogenous insulin in vitro induced a shift in T cell differentiation toward a T helper cell type 2 (Th2)-type response, decreasing the Th1/Th2 ratio by 36%. This result correlated with a corresponding change in cytokine secretion, the IFN-/IL-4 ratio being decreased by 33%. These changes were associated with increased Th2-promoting ERK phosphorylation in the presence of insulin.

Thus, we demonstrate for the first time that insulin treatment influences T cell differentiation promoting a shift toward a Th2-type response. This effect of insulin in changing T cell polarization may contribute to its anti-inflammatory role not only in sepsis, but also in chronic inflammation associated with obesity and type 2 diabetes.