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Pro-inflammatory cytokines of a T helper-1-signature are known to promote insulin resistance (IR) in obesity, but the physiological role of this mechanism is unclear. It is also unknown whether and how viral infection induces loss of glycemic control in subjects at risk for developing diabetes mellitus type 2 (DM2). We have found in mice and humans that viral infection caused short-term systemic IR. Virally-induced interferon-γ (IFN-γ) directly targeted skeletal muscle to downregulate the insulin receptor but did not cause loss of glycemic control because of a compensatory increase of insulin production. Hyperinsulinemia enhanced antiviral immunity through direct stimulation of CD8+ effector T cell function. In pre-diabetic mice with hepatic IR caused by diet-induced obesity, infection resulted in loss of glycemic control. Thus, upon pathogen encounter, the immune system transiently reduces insulin sensitivity of skeletal muscle to induce hyperinsulinemia and promote antiviral immunity, which derails to glucose intolerance in pre-diabetic obese subjects.Virus-induced IFN-γ downregulates insulin receptor expression of skeletal muscleMuscle insulin resistance results in compensatory hyperinsulinemia to keep euglycemiaInsulin directly boosts anti-viral effector CD8+ T cell responsesIn obese mice with hepatic IR, viral infection causes rapid progression to diabetesIt is unknown how viral infections contribute to the progression of type 2 diabetes. Šestan and colleagues demonstrate that virus-induced interferon-γ increases muscle insulin resistance, which drives hyperinsulinemia to keep euglycemia and to boost anti-viral CD8+ T cell responses. This mechanism in obese subjects with hepatic IR derails glycemic control.