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.

Di Fusco, D., Dinallo, V., Monteleone, I., Laudisi, F., Marafini, I., Franze, E., et al. (2018). Metformin inhibits inflammatory signals in the gut by controlling AMPK and p38 MAP kinase activation. CLINICAL SCIENCE, 132(11), 1155-1168 [10.1042/cs20180167].

Metformin inhibits inflammatory signals in the gut by controlling AMPK and p38 MAP kinase activation

Dinallo V.;Monteleone I.;Marafini I.;Colantoni A.;Ortenzi A.;Stolfi C.;Monteleone G.
2018-01-01

Abstract

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.
2018
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/12 - GASTROENTEROLOGIA
Settore BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA
English
Crohn’s disease
inflammatory bowel disease
ulcerative colitis
AMP-Activated Protein Kinases
Animals
Colitis, Ulcerative
Colon
Disease Models, Animal
Drug Evaluation, Preclinical
Enzyme Activation
Female
Hypoglycemic Agents
Inflammation Mediators
Interleukin-6
Intestinal Mucosa
Metformin
Mice, Inbred BALB C
Phosphorylation
Receptor, Insulin
p38 Mitogen-Activated Protein Kinases
Di Fusco, D., Dinallo, V., Monteleone, I., Laudisi, F., Marafini, I., Franze, E., et al. (2018). Metformin inhibits inflammatory signals in the gut by controlling AMPK and p38 MAP kinase activation. CLINICAL SCIENCE, 132(11), 1155-1168 [10.1042/cs20180167].
Di Fusco, D; Dinallo, V; Monteleone, I; Laudisi, F; Marafini, I; Franze, E; Di Grazia, A; Dwairi, R; Colantoni, A; Ortenzi, A; Stolfi, C; Monteleone, G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/253634
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