## 4 The Antidiabetic Effects of Dietary Phenolic Compounds: Preclinical and Clinical Evidence
Overall, the benefits of phenolic compounds in the aforementioned glucose-related metabolism routes are associated with the antioxidative and anti-inflammatory properties of these compounds that contribute to preserving functional pancreatic \(\beta\)-cells and improving insulin-dependent and independent pathways in muscle and liver. Experiments with rat insulinoma cells or RIN cells demonstrated that phenolic compounds such as genistein, quercetin, apigenin, luteolin, and sulfuretin prevent the cytokine-induced cytotoxicity and the impaired glucose-induced insulin secretion in \(\beta\)-cells by inhibiting the NF\(\kappa\)\(\beta\) cascade [144; 145; 146]. _In vivo_ experiments combined with in vitro approaches conducted in NOD mice have also demonstrated that resveratrol reduces insulitis by blocking the migration of IL17-producing T cells and CD11b+ F4/80 hi macrophages from spleen and pancreatic lymph nodes to the pancreas through a mechanism that involves the downregulation of the chemokine (C-C motif) receptor 6 (CCR6) [120]. Moreover, natural phenolic compounds such as curcumin or resveratrol prevent the fatty acid-induced proinflammatory cytokine and reactive oxygen species (ROS) production in skeletal muscle C2C12 cells by suppressing the phosphorylation of IKK\(\alpha\)-IKK\(\beta\), and JNK [137; 139]. In cultures of human hepatocytes (HepG2 cells), resveratrol attenuates the high glucose-induced ROS production by inducing the expression of oxidant genes through a mechanism that involves the downregulation of the methylation of the nuclear factor erythroid 2-related factor 2 (Nrf2) promoter [138]. Moreover, phenolic compounds limit the enhanced proinflammatory response in the hepatocytes associated with high adiposity. Indeed, the natural polyphenol gallic acid reduces the expression of the proinflammatoryatory cytokines TNF\(\alpha\) and IL1\(\beta\) in the co-cultures of macrophages and lipid-laden hepatocytes [70]. \begin{table}
\begin{tabular}{p{113.8 pt} p{113.8 pt} p{113.8 pt} p{113.8 pt} p{113.8 pt}} \hline \hline \multicolumn{2}{p{113.8 pt}}{_In Vitro Approaches_} & & & & \\ \hline
**Compound** & **Cell Line** & **Concentration and Time of Incubation** & **Molecular Mechanism** & **Refs** \\ \hline Quercetin, & RINm5F (RIN) cells & 25, 50 \(\upmu\)M (quercetin, & Prevention of & [144; 145; 146] \\ apigenin, luteolin & (rat insulinoma cells) & apigenin, luteolin) & cytokine-induced cytotoxicity in \(\beta\)-cells & \\ genistein, & & 5, 10, 20, 40 \(\upmu\)M (genistein) and sulfuretin & 40, 80, 100 \(\upmu\)M (sulfuretin) & \\  & & (3–48 h) & & \\ \hline Delphinidin & murine GLUTag & 10, 25, 50, 100 \(\upmu\)M (2 h) & GLP-1 secretion by activating GPR40/120 coupled with the Ca2\({}^{+}\)-CaMKII pathway & [147] \\ \hline Coffee & Human NCI-H716 cells & 0.05\%, 0.1\% (2 h) & GLP-1 secretion through a cAMP-dependent mechanism & [135] \\ \hline \hline \end{tabular}
\end{table} 
Table 4: _Cont._On the other hand, it is well established that the excessive intake of saturated fats and simple sugars increases intestinal permeability and proinflammatory pathways, leading to systemic inflammation and insulin resistance in tissues such as muscle and liver [148]. Thus, beyond the direct effects of dietary phenolic compounds on the pancreas, liver, and muscle, the glucoregulatory benefits of phenolic compounds may be derived from their capacity to modulate intestinal immunity. Although it has not been extensively explored, some studies demonstrated that polyphenol-dietary supplementation in diet-induced obese mice with impaired insulin sensitivity and glucose tolerance limits their enhanced intestinal oxidative stress, inflammation, and gut barrier permeability. These effects in turn could contribute to alleviating the proinflammatory response in the liver and improve glucose tolerance and insulin sensitivity [122; 123].