# Antidiabetic Potential of Monoterpenes: A Case of Small Molecules Punching above Their Weight
## 4 Antidiabetic Potential of Monoterpenes  
### In Vitro Protective Effects  
In vitro experiments (Table 1) on the antidiabetic effects of monoterenes include cell culture studies using pancreatic \(\beta\) cells, muscles, adipocytes and liver cells among others; as well as enzyme/protein-based assays [29; 40; 41; 42; 43; 44; 45; 46; 47; 48]. Of these, the study by [PERSON] et al. [45] included direct comparison of activity of a number of commercially available monoterenes: geraniol, nerol, citral, (\(R\))-(\(-\))-linalool, (\(R\))-(\(+\))-limonene, (\(S\))-(\(-\))-perillyl alcohol, (\(R\))-(\(+\))-\(\beta\)-citronellol, (\(S\))-(\(-\))-\(\beta\)-citronellol, \(\alpha\)-terpineol, L-menthol, \(\gamma\)-terpinene and terpinolene. Their study employed in vitro antioxidant; \(\alpha\)-amylase and \(\alpha\)-glucosidase enzyme inhibition; and glucose uptake and lipid metabolism in 3T3-L1 adipocytes. Even though these compounds have been shown to have some radical scavenging properties (DPPH and ABTS radicals) at higher concentrations such as 10 and 100 mM, the observed activity is not of therapeutic relevance. In fact, considering their structure (Figure 1), that lack a phenolic structural moiety (with few exceptions), they are not expected to display potent antioxidant effect and/or direct radical scavenging. Over the years, we have shown the potent direct radical scavenging effects of polyphenic compounds particularly those with catechol functional groups and those optimized with the flavonoids skeleton [11; 49; 60; 61; 62]. Hence, apart from compounds like carvacrol and thymol with phenolic skeleton, most monoterenes (Figure 2) do not seem to have direct radical scavenging mechanism that account for their antidiabetic effects. With respect to inhibition of key carbohydrate enzymes (\(\alpha\)-amylase and \(\alpha\)-glucosidase) inhibition, these compounds were reported to act at 10 mM range [45] and is once again of no therapeutic relevance. In this connection, we have shown that many promising natural products such as flavonoids and polyphenols are acting at micromolar range [9; 50; 52; 53; 62; 63; 64; 65]. On the other hand, the most prevalent effect of these monoterenol compounds were on glucose uptake and lipid metabolism in 3T3-L1 adipocytes cell culture [45]. (\(S\))-(\(-\))-\(\beta\)-citronellol, terpinolene and (\(R\))-(\(-\))-linalool did not affect the glucose uptake in 3T3-L1 adipocytes; while geraniol, citral, (\(R\))-(\(+\))-limonene, (\(R\))-(\(+\))-\(\beta\)-citronellol, nrerol, (\(S\))-(\(-\))-perillyl alcohol, \(\gamma\)-terpinene and \(\alpha\)-terpineol showed some degree of activity (up to 21% inhibition) when tested at 1 \(\upmu\)M. Readers should bear in mind that this concentration is so small and hence promising but a dose-dependent effect profile was not reported for these compounds. Similarly, the free glycerol released into the medium in the cell culture was measured, and at 1 \(\upmu\)M concentrations, the lipolysis effect of (\(R\))-(\(+\))-limonene, (\(S\))-(\(-\))-perilly alcohol, (\(R\))-(\(+\))-\(\beta\)-citronellol and geraniol were shown [45]. Once again, this is a screening result and does not show the concentration range and total profile of activity for these compounds. On the other hand, (\(R\))-(\(+\))-limonene treatment did not affect the mRNA expression of PPAR-\(\gamma\) in 3T3-L1 adipocytes; it increased the mRNA expression of GLUT1 by 1.2-fold whereas the mRNA expression of GLUT4 remained unchanged. These were all at a fixed concentration of one dose (1 \(\upmu\)M). \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Compound** & **Model** & **Outcome** & **References** \\ \hline \multirow{3}{*}{Carvacrol} & H\({}_{\text{G}}\)O\({}_{2}\)-induced cellular injury on isolated & & \\  & pancreas islets—Following 20, 40 and & & \\  & 80 mg/kg/day in vivo treatment & & \\ \hline \multirow{3}{*}{Cymene} & Advanced glycation end _paratus_ (AGES) & 100 \(\mu\)M—Inhibt ACE formation; inhibit glycation specific decline in BSA a-helix content and \(\beta\)-sheet.