## 4 The Antidiabetic Effects of Dietary Phenolic Compounds: Preclinical and Clinical Evidence
\begin{table}
\begin{tabular}{l l l l l} \hline \multicolumn{2}{l}{_In Vitro Approaches_} & & & \\ \hline
**Compound** & **Cell Line** & **Concentration and** & **Molecular Mechanism** & **Refs** \\  & & **Time of Incubation** & & \\ \hline \multirow{4}{*}{Resveratrol} & Primary cultures of & Every other day & Reduced migration of & [120] \\  & splenocytes from & subcutaneous injection of & splenocytes from & \\  & resveratrol- & 25 mg/kg for 23 weeks & & resveratrol-treated NOD & \\  & treated-NOD mice & & mice into the compartment & \\  & & & containing CCL20, a CCR6 & \\  & & & ligand. This indicates & \\  & & & an inhibition of the & \\  & & & inflammatory cell trafficking & \\  & & & from peripheral lymphoid & \\  & & & organs to the pancreas & \\  & & & by suppressing & \\  & & CCR6 production & \\ \hline \multirow{4}{*}{Curcumin} & C2C12 myotubes & 20 uM & Enhanced glycogen depots & [137] \\  & (mouse myoblast & (12 h) & and reduced intracellular & \\  & cell line) & & triglyceride content & \\ \hline \multirow{4}{*}{Curcumin} & HepG2 cells & 20 uM & Downregulation of the & [138] \\  & (human hepatoma) & (48 h) & methylation of Nrf2 & \\  & & & promoter which attenuates & \\  & & & the glucose-induced & \\  & & & ROS production & \\ \hline \multirow{4}{*}{Curcumin} & C2C12 myotubes & 40 uM & Suppression of the & [139] \\  & (mouse myoblast & (16 h) & phosphorylation of & \\  & cell line) & & IKK\(\alpha\)-IKK\(\beta\), and JNK which & \\  & & & protects against fatty & \\  & & & acid-inflammation and & \\  & & & ROS production & \\ \hline \multirow{4}{*}{Curcumin} & C2C12 myotubes & 40 uM & Upregulation of & [140] \\  & (mouse myoblast & (16 h) & ZO-1 and claud-1 & \\  & (mouse myoblast & (16 h) & Attenuation of oxidative & \\  & & & stress markers and & \\  & & & endoplasmic reticulum & \\  & & & stress-induced & \\  & & & apoptosis-related molecules & \\ \hline \multirow{4}{*}{Curcumin and carnosol} & Primary human & 10 uM & Regulation of the dendritic & [141] \\  & dendritic cells & (6 h) & cell metabolism & \\  & & & through AMPK & \\ \hline \multirow{4}{*}{Aspalthin \
\begin{tabular}{} \end{tabular} } & L6 myoblast & 50–100 uM (4 h) & Increased glucose uptake by & [124; 127; 142] \\  & cell line (rat) & 10, 25, 50, 75 uM & enhancing GLUT4 & \\  & & Rat ex vivo culture of & (15 min–6 h) & translocation to & \\  & & isolated soleus muscle & ZF rats treated with & the cell surface & \\  & & & 200 mg/kg & \\ \hline \multirow{2}{*}{Epicatechin
\begin{tabular}{} \end{tabular} } & HepG2 cells & 1, 5, 10 uM & Activation of the & [143] \\  & (human hepatoma) & 1, 5, 10 ug/mL & AKT-mediated insulin & \\  & & (24 h) & signaling to inhibit & \\  & & & gluconeogenesis & \\ \hline \multirow{2}{*}{Gallic acid} & Co-culture of & 50, 100, 200 uM (24 h) & Prevention of secretion of & [70] \\  & lipid-laden Hepa & & proinflammatory cytokines & \\  & 1–6 hepatocytes and & & proinflammatory cytokines & \\  & RAW264 macrophages & & & \\ \hline \end{tabular}
\end{table} 
Table 4: _Cont._In muscle and liver, it has been described that phenolic compounds enhance glucose uptake and reduce endogenous glucose production [124; 125; 126]. For instance, the incubation of rat skeletal myoblast cell cultures with asphaltin or carnosol, a rosmary extract polyphenol, induces the translocation of the glucose transport GLUT4 to the cell surface, increasing glucose uptake by activating the AMPK signalling and independently of the insulin cascade [124; 124]. Nevertheless, through muscle ex vivo approaches, other investigations have identified insulin-mediated glucose uptake mechanisms induced by green tea phenolic compounds [127]. Moreover, phenolic compounds such as resveratrol enhance the glycogen depots in C2C12 myotubes pretreated with fatty acids [137]. Furthermore, in human hepatic cells, epicatechin (the main cocoa flavanol) and phenolic cocoa extract activate the AKT-mediated insulin cascade to inhibit gluco-neogenic enzyme expression, phosphoenolpyruvate carboxykinase (PEPCK), leading to reduce glucose production [143].