Virus-Induced Interferon-γ Causes Insulin Resistance in Skeletal Muscle and Derails Glycemic Control in Obesity

Abstract

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. VIDEO ABSTRACT.

‘Beauty and the beast’ in infection: How immune–endocrine interactions regulate systemic metabolism in the context of infection

“…Similarly, people with acute mild respiratory infection showed higher insulin levels, but similar blood glucose levels at time of diagnosis compared to a time point three months later . In mice, infection with cytomegalovirus (CMV), lymphochriomeningitis virus (LCMV) or mild influenza, induced systemic insulin resistance, whereas it did not lead to a loss of glycemic control . In lean people and mice, infection‐induced IR is compensated by increased insulin output by the pancreas, which prevents fasting and postprandial hyperglycemia .…”

“…An analysis of patients infected with HIV showed increased insulin levels, whereas fasting plasma glucose levels (FPG) were not different from those of age and gender‐matched controls . Similarly, people with acute mild respiratory infection showed higher insulin levels, but similar blood glucose levels at time of diagnosis compared to a time point three months later . In mice, infection with cytomegalovirus (CMV), lymphochriomeningitis virus (LCMV) or mild influenza, induced systemic insulin resistance, whereas it did not lead to a loss of glycemic control .…”

“…Adipose tissue hormones, which communicate the status of nutrient stock availability, promote or inhibit the responsiveness of immune cells to activating stimuli in cases of nutrient abundance or shortage, respectively . Conversely, cytokines are able to influence processes normally regulated by endocrine hormones, such as hunger, body temperature and glucose uptake, as well as production of endocrine hormones themselves . Conversely, immune cells can respond directly to hormones such as insulin, which regulate systemic metabolism .…”

“…Conversely, cytokines are able to influence processes normally regulated by endocrine hormones, such as hunger, body temperature and glucose uptake, as well as production of endocrine hormones themselves . Conversely, immune cells can respond directly to hormones such as insulin, which regulate systemic metabolism . Immune–endocrine interactions in the context of metabolic disease have been well studied.…”

Crossroads between immune responses and physiological regulation: Metabolic control of resistance versus tolerance against disease

“…Anabolic demands imposed by the induction of resistance mechanisms are mainly satisfied by glucose [14], which is prioritized to immune cells inducing a robust and long-lasting insulin-resistant state in glucose-utilizing pathways of peripheral tissues [15]. Moreover, it has been recently shown that INF-γ released in the course of viral immunity targets skeletal muscle cells to downregulate the insulin receptor, driving compensatory hyperinsulinemia, which boosts glucose uptake by CD8 T cells and sustains antiviral cytotoxic resistance responses [16]. As different parenchymal tissues encounter different types of stress, damage and functional impairment during infection, disease physiology is uniquely context specific and so are the metabolic adaptations that promote tolerance.…”