# Antidiabetic Potential of Monoterpenes: A Case of Small Molecules Punching above Their Weight
## 6 General Summary and Discussion
The PIP3 in turn is linked to recruit protein kinase B (PKB), also known as Akt, that play a pivotal role in the insulin-dependent GLUT4 mobilization. Review articles on this cascade of insulin transduction pathways have been published [125; 126]. As discussed above, metformin that modulates the AMPK pathway affects the translocation of GLUT4 in insulin target cells [127]. Hence, agents that facilitate the expression or mobilize GLUT4 could have antidiabetic effect. In this regard, the various effect of monoterpenes in signaling pathways appear to be consistent with antidiabetic effect through upregulation of GLUT4 expression and/or translocation (Table 1). The modulation of the AMPK pathway by natural products that enhance glucose uptake while concomitantly inhibiting gluconeogenesis and stimulation of glycogen synthesis have previously been reported (e.g., [128; 129; 130; 131; 132]. Hence, possible multiple mechanisms involving insulin signaling and other pathways involving the AMPK, GLUT4 and PPARy are at play in the antidiabetic effect of monoterpenes. The liver plays a central role in glucose homeostasis by regulating glucose production and storage in the form of glycogen. In terms of drug therapy, agents that suppress the glycolysis pathways (glycogenolysis inhibitors) or hepatic glucose production (glucoseogenesis) have antidiabetic properties [133; 134; 135; 136]. These classical examples of antidiabetic (T2D) drugs therapy approaches target key enzymes involved in the cascades of reaction pathways in hepatic cells. The most important validated targets constitute the first important step of glycogenolysis that requires the enzymatic action of glycogen phosphorylase (GP) to convert glycogen to glucose-1-phosphate. On the other hand, glucose-6-phosphatase (G6 Page) at the final step of gluconeogenesis serves as an important drug target. In this regard, the effects of many monoterepenes as modulators of these pathways have been reported (Table 2). Hence, the antidiabetic mechanism of monoterepenes may include gluconeogenesis and glycolysis as potential targets. The role of inflammation as a link between diabetes and obesity has been documented in recent years [137]. The low grade persistent/chronic state of inflammation in obesity is generally considered to increase insulin resistance in target organs [138]. The closer link between inflammation under obesity condition and insulin resistance in diabetes has become clearer with the identification of proinflammatorycytokines such as tumour necrosis factor (TNF)-\(\alpha\) and interleukin-6 (IL-6) as major culprits [139; 140]. For example, the above-mentioned PI3K-AKT (or PKB) pathway of the insulin-signaling cascade can be inhibited by these cytokines via activation of the NF-kB. This crosstalk between the inflammation pathway and obesity/diabetes as mechanisms of action for natural products such as anthocyanins has also been described recently [122]. As various monoterepenes appear to suppress the inflammation associated with diabetes (Tables 1 and 2), their potential therapeutic effect could be in part attributed to such pharmacological effects. Hand in hand with all these multiple mechanism, the lipid lowering and/or antiobesity effect of monoterepenes appear to be demonstrated (Table 2). In this connection, the direct effect of monoterepenes on lipogenic expression via targeting key fatty acid synthesis enzymes (acetyl-CoA carboxylase and fatty acid synthase) have been demonstrated in vitro [42]. Besides the diverse possible mechanisms of actions that accounts to the pharmacological effects of monoterepenes, the reported specific effect through modulation of the GLP-1 receptor is very interesting. The best studied compound in this regard is the iridoid glycoside, geniposide [38]. By using the receptor antagonist, exenidin, the effect of geniposide through this mechanism has been confirmed [38; 39].