Berberine Metabolites Stimulate GLP-1 Secretion by Alleviating Oxidative Stress and Mitochondrial Dysfunction

Area of Science:

• Pharmacology
• Endocrinology
• Metabolism

Background:

• Berberine (BBR) from Rhizoma coptidis shows potential for type 2 diabetes mellitus (T2DM) and obesity.
• BBR's therapeutic effects are linked to its metabolites, despite low plasma levels.
• The cytoprotective impact of BBR metabolites on intestinal L cells, which produce GLP-1, remains unexplored.

Purpose of the Study:

• To investigate the effects of BBR metabolites on GLP-1 secretion and underlying mechanisms.
• To identify specific BBR metabolites that enhance GLP-1 production and secretion.
• To explore the cytoprotective actions of these metabolites on L cells.

Main Methods:

• Screening of six BBR metabolites for effects on GLP-1 secretion in GLUTag cells.
• In vivo studies using standard and diet-induced obese mice to assess glucose tolerance and GLP-1 levels.
• Cell-based assays to evaluate the protective effects of metabolites against palmitic acid or TNF-α-induced cell damage, oxidative stress, and mitochondrial dysfunction.
• Analysis of the Akt signaling pathway.

Main Results:

• Berberrubine (BBB) and palmatine (PMT) significantly increased GLP-1 production and glucose-stimulated secretion in GLUTag cells.
• BBB and PMT enhanced GLP-1 and insulin secretion, improving glucose tolerance in mice.
• PMT administration improved glucose tolerance and increased plasma GLP-1 in diet-induced obese mice.
• BBB and PMT protected GLUTag cells from damage, oxidative stress, and mitochondrial dysfunction, while reversing inflammation-induced Akt pathway inhibition.

Conclusions:

• The therapeutic benefits of BBR in T2DM are largely mediated by its metabolites, BBB and PMT.
• BBB and PMT exert cytoprotective effects on intestinal L cells, enhancing GLP-1 secretion.
• These findings provide novel insights for developing strategies to stimulate GLP-1 secretion and treat T2DM.