RESUMEN
Insulin resistance is a risk factor for obesity and diabetes and predisposes individuals to Staphylococcus aureus colonization; however, the contribution of S. aureus to insulin resistance remains unclear. Here, we show that S. aureus infection causes impaired glucose tolerance via secretion of an insulin-binding protein extracellular domain of LtaS, eLtaS, which blocks insulin-mediated glucose uptake. Notably, eLtaS transgenic mice (eLtaS trans ) exhibited a metabolic syndrome similar to that observed in patients, including increased food and water consumption, impaired glucose tolerance and decreased hepatic glycogen synthesis. Furthermore, transgenic mice showed significant metabolic differences compared to their wild-type counterparts, particularly for the early insulin resistance marker α-hydroxybutyrate. We subsequently developed a full human monoclonal antibody against eLtaS that blocked the interaction between eLtaS and insulin, which effectively restored glucose tolerance in eLtaS trans and S. aureus-challenged mice. Thus, our results reveal a mechanism for S. aureus-induced insulin resistance.
Asunto(s)
Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Resistencia a la Insulina , Insulina/metabolismo , Infecciones Estafilocócicas/complicaciones , Staphylococcus aureus/patogenicidad , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacología , Proteínas Bacterianas/metabolismo , Sitios de Unión , Línea Celular , Femenino , Células Hep G2 , Humanos , Hidroxibutiratos/metabolismo , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/genética , Síndrome Metabólico/metabolismo , Ratones , Ratones Transgénicos , Ratas , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/metabolismo , Staphylococcus aureus/metabolismoRESUMEN
A mixture of a pair of stereoisomeric new spirostanol saponins (1a and 1b) and a new cholestane saponin (2) were isolated from the rhizome of Paris pollyphylla Smith var. yunnanensis. Their structures were elucidated as (25R)-spirost-5-en-3beta, 7beta-diol-3-O-alpha-L-arabinofuranosyl-(1 --> 4)-[alpha-L-rhamnopyranosyl-(1 --> 2)]-beta-D-glucopyranoside (1a), (25R)-spirost-5-en-3beta, 7alpha-diol-3-O-alpha-L-arabinofuranosyl-(1 --> 4)-[alpha-L-rhamnopyranosyl-(1 --> 2)]-beta-D-glucopyranoside (1b) and 26-O-beta-D-glucopyranosyl-(25R)-Delta(5(6), 17(20))-dien-16, 22-dione-cholestan-3beta, 26-diol-3-O-alpha-L-arabinofuranosyl-(1 --> 4)-[alpha-L-rhamnopyranosyl-(1 --> 2)]-beta-D-glucopyranoside (2) by a combination of HR-ESI-MS, FAB-MS, 1D and 2D NMR techniques (including (1)H-NMR, (13)C-NMR, (1)H--(1)H COSY, HSQC, HMBC and NOESY).