# Antidiabetic Potential of Monoterpenes: A Case of Small Molecules Punching above Their Weight
## 6 General Summary and Discussion  
The various in vitro and in vivo data now suggest that monoterenes, despite their structural simplicity, have a promise to be seriously considered as antidiabetic lead compounds either by their own or as part of structural moieties in complex structures. Hence, the diverse mechanism of action reported in these studies deserve further scrutiny. A growing body of evidence show that the PPARy play a vital role in the regulation of carbohydrate, lipid, and protein metabolism both in healthy and disease states (e.g., diabetes, obesity, metabolic syndrome, cardiovascular diseases, etc.). In the case of diabetes, the PPARy with its predominant expression in adipose tissues (but also in macrophages and intestine) has profound effects in the regulation of adipogenesis, insulin sensitivity, and inflammation [109; 110; 111]. The role of PPARy in key other insulin-target organs/ tissues such as the liver and muscles has also beenwell understood. Even though the thiazolidinedones (TZDs) groups of antidiabetic drugs have been reported to have numerous undesirable side effects [112; 113], targeting the PPARy by receptor agonists remains an attractive pharmacological target for the treatment and prevention of metabolic disorders including diabetes. In this regard, the role of natural products as a source of potential drugs that lack the undesirable effects of thiazolidinedones have been advocated [114; 115]. Hence, the modulatory effect of monoterpenes on the PPARy appear to be a well-defined mechanism of antidiabetic action. Furthermore, monoterpenes such as carvacrol, thymol and others that showed antidiabetic effects are common ingredients of foods and flavors and hence not expected to display the undesirable effects of thiazolidinedones. The role of the AMPK in regulating glucose metabolism and as a validated target for diabetes has gained lots of momentum in recent years. Drugs that activate the AMPK have been shown to enhance the phosphorylation of insulin receptor substrate 1 (IRS-1) Ser789 phosphorylation leading to the cascade of activation of phosphoinositide 3 kinase/protein kinase B (PI3K/PKB) signaling [116]. Such effects have been shown to be both insulin dependent (potentiation) and independent (in unstimulated state). The classical antidiabetic drug, metformin, also appear to act through activation of the AMPK pathway in various target organs [117]. Interestingly, the activation of AMPK in adipocytes has been shown to suppress lipogenesis while promoting energy dissipation suggesting potential antiobesity effect [118]. Even though some studies still show the paradoxical nature of the AMPK activation in glucose and lipid metabolism, mostly related to the level of stimulation (chronic verses acute) (e.g., [119; 120]), the role of AMPK activators in various disease condition have been well documented [121]. In a recent review [122], the antidiabetic potential of natural products such as anthocyanins through effect on the AMPK and insulin-signaling pathways have been highlighted. Interestingly, monoterpenes have been shown to share this crucial mechanism of antidiabetic effect (Table 1). The GLUT4 is an ATP-independent glucose transport system across cell membranes and predominantly expressed in adipose tissues and skeletal muscles. While under expression of the GLUT4 can predispose animals to diabetes and insulin resistance, its overexpression has been shown to overcome such physiological/pathological disorder [123; 124]. The reduced level of GLUT4 has also been noted in muscles of diabetic patients. The coupling between insulin receptor activation in target organs with the known insulin action in GLUT4-mediated glucose uptake has been the subject of intense research in recent years. The insulin receptor substrate proteins phosphorylation has been shown to lead to the activation of PI3K which intern leads to the generation of phosphatidylinositol 3,4,5-trisphosphate (PIP3).