Acylated Ghrelin Mediates the Link Between <i>Akkermansia</i> Abundance and Insulin Resistance in Type 2 Diabetes

<b>Aims:</b> This mediation analysis was aimed at examining whether ghrelin mediates the association between gut microbiota and glucose metabolic indices. <b>Materials and Methods:</b> 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. <b>Results:</b> 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 <i>Akkermansia</i>, <i>Lachnospira</i>, and <i>Phocaeicola</i>, but increased abundances of <i>Enterobacter</i>, <i>Escherichia</i>, <i>Megamonas</i>, <i>Segatella</i>, <i>Streptococcus</i>, and <i>Leyella</i> in T2DM. AG levels were negatively correlated with <i>Akkermansia</i> abundance. HbA1c and FBG showed positive correlations with <i>Enterobacter</i>, <i>Segatella</i>, and <i>Leyella</i> abundances, but negative correlations with <i>Akkermansia</i>, <i>Lachnospira</i>, and <i>Phocaeicola</i> abundances. HOMA-IR was positively correlated with <i>Segatella</i>, <i>Leyella</i>, and <i>Streptococcus</i> abundances, but negatively correlated with <i>Akkermansia</i> and <i>Lachnospira</i> abundances. Mediation analysis demonstrated that serum AG partially mediated the association between <i>Akkermansia</i> abundance and both HOMA-IR (26.15%) and HbA1c (27.91%). <b>Conclusions:</b> AG mediated the relationship between <i>Akkermansia</i> abundance and HOMA-IR as well as HbA1c.