Abstract

Metformin (MTF) is the primary treatment for type 2 diabetes, but its mechanisms for enhancing insulin sensitivity require thorough exploration. This study revealed that MTF improves insulin sensitivity by promoting the proliferation and translocation of immunoglobulin A (IgA)-antibody-secreting cells (ASCs) originating from the intestine. MTF enhances the growth of IgA-ASCs in Peyer’s patches, increasing their migration to insulin-sensitive tissues such as the liver and visceral adipose tissue. Within these tissues, these cells secrete the anti-inflammatory interleukin-10 (IL-10), promoting insulin signaling transduction. Crucially, the absence of B cells or IL-10 in IgA-ASCs abolishes MTF’s insulin sensitivity improvement, unlike the absence of IgA or the polymeric immunoglobulin receptor (PIGR), which is a protein mediating mucosal IgA secretion. The mechanism involves MTF stimulating the expansion of lipopolysaccharide (LPS)-producing bacteria, leading to increased LPS production and consequently enhancing intestinal IgA responses through TLR4.