Calenduloside E produced by Bifidobacterium animalis B960 increases glibenclamide efficacy and alleviates drug-induced adverse effects via the IRS1/PI3K/AKT signaling pathway in a type 2 diabetes model Calenduloside E produced by Bifidobacterium animalis B960 increases glibenclamide efficacy and alleviates drug-induced adverse effects via the IRS1/PI3K/AKT signaling pathway in cell, organ-on-a-chip, and mouse models of type 2 diabetes.

ABSTRACT:

Glibenclamide (GLIB), a type 2 diabetes therapy, has long-term safety concerns. Probiotic–drug coadministration, an emerging adjunctive approach for metabolic diseases, improves therapeutic outcomes and side effects. Here, Bifidobacterium animalis B960 was selected from 71 probiotic strains by HPLC and in vitro cell assays; it effectively maintained GLIB integrity and ameliorated insulin resistance. In vivo, combined B960+GLIB therapy significantly reduced blood glucose, prevented weight gain, improved intestinal homoeostasis and increased beneficial metabolite levels. Moreover, B960 significantly mitigated GLIB-induced side effects, particularly hepatotoxicity and inflammation. B960 activated a 9-enzyme cascade involving IolS and EpsJ, biotransforming oleanolic acid into calenduloside E, which synergized with GLIB by activating the IRS1/PI3K/AKT signaling pathway—upregulating insulin effectors (Irs1, Pik3r1, Akt1, Slc2a4) while suppressing gluconeogenic regulators (Gsk3b, Foxo1, Pck1) and increasing insulin sensitivity and glucose utilization. Proof-of-concept studies utilizing insulin-resistant models and a human-relevant gut–liver organ-on-a-chip platform demonstrated targeted insulin sensitization without compromising GLIB pharmacokinetics. This work offers an efficacy-enhanced and toxicity-reduced T2D therapeutic strategy

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS12697 | MetaboLights | 2025-07-08

REPOSITORIES: MetaboLights