Metformin, a hypoglycemic drug used for treatment of type 2 diabetes, regulates inflammatory pathways. By using several models of intestinal inflammation, we examined whether metformin exerts anti-inflammatory effects and investigated the basic mechanism by which metformin blocks pathologic signals. Colitic mice given metformin exhibited less colonic inflammation and increased expression of active AMP-activated protein kinase, a mediator of the metabolic effects of metformin, in both epithelial and lamina propria compartments. Pharmacological inhibition of AMP-activated protein kinase reduced but did not prevent metformin-induced therapeutic effect as well as treatment of colitic mice with a pharmacological activator of AMP-activated protein kinase attenuated but did not resolve colitis. These data suggest that the anti-inflammatory effect of metformin relies on the control of additional pathways other than AMP-activated protein kinase. Indeed, metformin down-regulated p38 MAP kinase activation in colitic mice through an AMP-activated protein kinase-independent mechanism. Expression of active form of AMP-activated protein kinase was reduced in inflammatory bowel disease patients and treatment of mucosal cells of such patients with metformin enhanced AMP-activated protein kinase activation and reduced p38 MAP kinase activation, thereby inhibiting interleukin-6 expression. Our findings indicate that metformin is a good candidate for inhibiting pathological inflammation in the gut.
Metformin inhibits inflammatory signals in the gut by controlling AMPK and p38 MAP kinase activation
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Davide Di Fusco, Vincenzo Dinallo, Ivan Monteleone, Federica Laudisi, Irene Marafini, Eleonora Franzè, Antonio Di Grazia, Rami Dwairi, Alfredo Colantoni, Angela Ortenzi, Carmine Stolfi, Giovanni Monteleone; Metformin inhibits inflammatory signals in the gut by controlling AMPK and p38 MAP kinase activation. Clin Sci (Lond) 14 June 2018; 132 (11): 1155–1168. doi: https://doi.org/10.1042/CS20180167
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