## 4 The Antidiabetic Effects of Dietary Phenolic Compounds: Preclinical and Clinical Evidence
In vitro studies with the human colonic Caco-2 epithelial cell line co-cultured with differentiated THP-1 cells reveal that, mechanistically, under inflammatory conditions, phenolic compounds provide protective effects on gut mucosa by restoring the expression of tight junction proteins and by reducing the intestinal epithelial cell apoptosis [140]. Furthermore, phenolic compounds such as the oligomeric proanthocyanidins polymers derived from blueberry polyphenic extract increase colonic mucin-secreting goblet cells required to create the protective mucus layer in diet-induced obese mice [133]. Moreover, phenolic compounds can modulate the abundance of intestinal immune cells. Indeed, the plant-derived phenolic compounds carnosol and curcumin inhibit the inflammatory-induced metabolic adaptation of human dendritic cells by activating the energy sensor AMPK [141], and apple condensed tannins increase the abundance of TCR \(\gamma\delta\) intraepithelial lymphocytes strengthening the intestinal tolerogenic properties [149]. On the other hand, strategies based on the gut hormone GLP-1 have been designed to treat T2D due to their benefits on postprandial glycemia by increasing insulin secretion and improving insulin sensitivity [150]. Studies in humans, mice, or GLP-1 secreting cells have also demonstrated that phenolic compounds such as delphinidin 3-utinoside, an anthocyanin derivative, curcumin, and resveratrol stimulate GLP-1 secretion, reducing postprandial glycemia [133; 137; 138; 139; 20]. The role of phenolic compounds as GLP-1 secretagogues is mediated by the G protein-coupled receptors (GPCRs) GPR40 and GPR120 and the bitter taste receptors Tas2 Rs [151] and is dependent on the GLP-1 receptor [19]. Furthermore, phenolic compounds' modulation of intestinal immune and GLP-1-mediated routes may be preceded by their effects on gut microbiota. Indeed, phenolic compounds reaching the colon can be metabolised by intestinal bacteria [152], generating metabolites that beneficially modulate the functionality of enterocytes and immune or enteroendocrine cells. Faecal microbiota transplant experiments conducted in diet-induced obese mice have demonstrated that the protective effects of phenolic compounds derived from the fruit _Myricaria dubia_ on metabolic syndrome are dependent on the gut microbiota [136]. Currently, identifying key intestinal bacterial species showing metabolic adaptations to dietary phenolic compounds is an early investigation stage nevertheless, some studies provide evidence in this regard. For instance, polyphenol-rich cranberry extract intervention in diet-induced obese mice increases the abundance of _Akkermansia muciniphila_[122; 123], which induces protective effects on the gut barrier, preventing systemic inflammation [153], enhancing GLP-1 secretion [154], and reducing postprandial glycemia. In addition, the microbial metabolite urolithin A derived from dietary phenolic compounds improves gut barrier function and limits intestinal inflammation in the colon by a mechanism mediated by the aryl hydrocarbon receptor (AhR) and the nuclear factor erythroid 2-related factor 2 (Nrf2) [155]. Further details of how these _in vivo_ and _in vitro_ approaches have been conducted are indicated in Table 4.