Acylated Ghrelin Mediates the Link Between Akkermansia Abundance and Insulin Resistance in Type 2 Diabetes

Aims: This mediation analysis was aimed at examining whether ghrelin mediates the association between gut microbiota and glucose metabolic indices. Materials and Methods: Fifty-five patients with newly diagnosed Type 2 diabetes mellitus (T2DM) and 40 healthy controls (HCs) were included. Serum ghrelin levels were measured by ELISA. Fecal 16S rRNA gene sequencing was performed, and gut microbiota differences were assessed using linear discriminant analysis effect size (LEfSe). The relative abundance values of differential bacteria were extracted to correlate with ghrelin and glucose metabolic indices. Mediation analysis was conducted to evaluate ghrelin's effect on the relationship between bacterial abundance and glucose metabolic indices. Results: Acylated ghrelin (AG) levels were significantly elevated in the T2DM group and showed positive correlations with glycated hemoglobin (HbA1c), fasting blood glucose (FBG), C-peptide (CP), and homeostasis model assessment of insulin resistance (HOMA-IR). Microbial analysis revealed decreased abundances of Akkermansia, Lachnospira, and Phocaeicola, but increased abundances of Enterobacter, Escherichia, Megamonas, Segatella, Streptococcus, and Leyella in T2DM. AG levels were negatively correlated with Akkermansia abundance. HbA1c and FBG showed positive correlations with Enterobacter, Segatella, and Leyella abundances, but negative correlations with Akkermansia, Lachnospira, and Phocaeicola abundances. HOMA-IR was positively correlated with Segatella, Leyella, and Streptococcus abundances, but negatively correlated with Akkermansia and Lachnospira abundances. Mediation analysis demonstrated that serum AG partially mediated the association between Akkermansia abundance and both HOMA-IR (26.15%) and HbA1c (27.91%). Conclusions: AG mediated the relationship between Akkermansia abundance and HOMA-IR as well as HbA1c.