Glucagon induces the hepatic expression of inflammatory markers in vitro and in vivo

Glucagon exerts multiple hepatic actions, including stimulation of glycogenolysis/gluconeogenesis. The liver plays a crucial role in chronic inflammation by synthesizing proinflammatory molecules, which are thought to contribute to insulin resistance and hyperglycaemia. Whether glucagon affects hepatic expression of proinflammatory cytokines and acute‐phase reactants is unknown. Herein, we report a positive relationship between fasting glucagon levels and circulating interleukin (IL)‐1β (r = 0.252, p = .042), IL‐6 (r = 0.230, p = .026), fibrinogen (r = 0.193, p = .031), complement component 3 (r = 0.227, p = .024) and high sensitivity C‐reactive protein (r = 0.230, p = .012) in individuals without diabetes. In CD1 mice, 4‐week continuous treatment with glucagon induced a significant increase in circulating IL‐1β (p = .02), and IL‐6 (p = .001), which was countered by the contingent administration of the glucagon receptor antagonist, GRA‐II. Consistent with these results, we detected a significant increase in the hepatic activation of inflammatory pathways, such as expression of NLRP3 (p < .02), and the phosphorylation of nuclear factor kappaB (NF‐κB; p < .02) and STAT3 (p < .01). In HepG2 cells, we found that glucagon dose‐dependently stimulated the expression of IL‐1β (p < .002), IL‐6 (p < .002), fibrinogen (p < .01), complement component 3 (p < .01) and C‐reactive protein (p < .01), stimulated the activation of NLRP3 inflammasome (p < .01) and caspase‐1 (p < .05), induced the phosphorylation of TRAF2 (p < .01), NF‐κB (p < .01) and STAT3 (p < .01). Preincubating cells with GRA‐II inhibited the ability of glucagon to induce an inflammatory response. Using HepaRG cells, we confirmed the dose‐dependent ability of glucagon to stimulate the expression of NLRP3, the phosphorylation of NF‐κB and STAT3, in the absence of GRA‐II. These results suggest that glucagon has proinflammatory effects that may participate in the pathogenesis of hyperglycaemia and unfavourable cardiometabolic risk profile.

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