# Antidiabetic Potential of Monoterpenes: A Case of Small Molecules Punching above Their Weight
## 4 Antidiabetic Potential of Monoterpenes
### In Vitro Protective Effects
& [30] \\ \cline{1-1}  & C2C12 myotubes & 10 \(\mu\)M—Similar glucose uptake; promote GLUT4 translocation; increase insulin receptor IRS-1, AKT, and CGSK9 phosphorylation; increase ATP levels, close K(AIT) channels; increase intracellular calcium & [31] \\ \cline{1-1}  & Genipside & Rat INS-1 pancreatic \(\beta\) cells & Prevent cell damage induced by high (52 \(\mu\)M)glucose through the AMPK pathway & [32, 33] \\ \hline \multirow{3}{*}{Genipside} & Pancreatic \(\beta\)-cells—cultured primary cells of rats origin & 10 \(\mu\)M—Potentiate insulin secretion via activating the glucose-like receptor (GLP-1) as well as the adenylyl cyclase (AC)/cAMP signaling pathway; inhibitor voltage-dependent potassium channels; & [34] \\ \cline{1-1}  & & Achance PPAR phosphorylation; accelerate the release of phosphorylated Fox01 (forbach box O1) & \\ \cline{1-1}  & Primary cortical neurons; PC12 cells & from nuclear fraction to the cytosol; activate the activity of insulin-degrading enzyme promoter in & [35] \\ \cline{1-1}  & & PC2C12 cells & \\ \hline \multirow{3}{*}{Genipside} & INS-1 pancreatic \(\beta\) cells & 10 \(\mu\)M—Increase phosphorylation of POR1 and AKT73; inhibit the phosphorylation of downstream target GSK30; increase expression of GLUT2; effect abolished by inhibitor of PIKK (L2794002). & [36] \\ \cline{1-1}  & & US-1 pancreatic \(\beta\) cells & Up to 10 \(\mu\)M—Enhance glucose-stimulated insulin secretion in response to low or moderately high glucose concentrations; promote glucose uptake and intracellular ATP levels; modulate pyruvate carboxylase expression. & [37] \\ \hline \multirow{3}{*}{Genipside} & \multirow{3}{*}{Pancreatic INS-1 cells} & Attenuate palmitate-induced \(\beta\)-cell apoptosis and caspase-genesis; improve the impaired GLP-1R signaling by enhancing the phosphorylation of At and Food; increase the expression of POR-1; effect inhibited by cenpanding (9-39), antagonist for GLP-1 receptor. & [38] \\ \cline{1-1}  & & 10 \(\mu\)m!/L—Enhance acute insulin secretion in response to both the low (5.5 mm/L) and moderately high levels (11 mm/L) of glucose; Effect inhibited by GLP-1R antagonist sending (9-39) or knock-down of GLP-1R with shkNN4 in IN-1 cells. & [39] \\ \cline{1-1}  & & HepG2 fatty liver model-free fatty acid treatment & Suppress the intracellular pip accumulation; increase the intracellular expression of a fatty acid oxidation-related gene (PPARa). & [40] \\ \cline{1-1} \cline{1-1}  & Gentopicroside & HL1C hepatoma cells & 50 and 100 \(\mu\)M—Suppress P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P& P&& P& P&  
\begin{table}
\begin{tabular}{c c c c} \hline
**Compound** & **Model** & **Outcome** & **References** \\ \hline Paconiform & 3T3-L1 adipocytes and RAW & 12.5-100 ug/mL—Inhabit TNF-a and FFA production; inhibit TNF-a-stimulated adipocyte lipolysis; suppress phosphorylation of TNF-a-activated ERK1/2; attenuate (partially) palmitate-induced macrophage TNF-a production. & [43] \\ \hline Paconiform & & \\ derivatives (methoxy and glucoside & Human HepG2 cells and HUVECs & 10 u/mL—Increase glucose uptake; reverse glucose-induced inhibition of glycogen synthesis in HepG2; increase AMPK and GSK-3\(\beta\) phosphorylation; phosph  
The general antidiabetic effect of monoterepenes through specific biological targets are illustrated in Table 1. Even though essential oils are known for general antioxidant and enzyme inhibitory activities including \(\alpha\)-glucosidase, such effect may not be therapeutically relevant as it occur at relatively high concentrations. There is a great deal of diversity among the monoterepenes however as some such as thymol are phenolic in nature while the vast majority are highly non-polar compounds (Figure 2). As discussed above, direct reactive oxygen species and radical scavenging (ROS) is mainly a function of polyphenic compounds, which (with few exceptions such as thymol and carvacrol) are poorly represented in monoterepenes.