# Antidiabetic Potential of Monoterpenes: A Case of Small Molecules Punching above Their Weight
## 4 Antidiabetic Potential of Monoterpenes
### In Vivo Antidiabetic Effects

Table 2: _Cont._enzymes of glucose metabolism such as glucose-6-phosphatase and fructose-1,6-bisphosphatase; decreased glucokinase and glucose-6-phosphate dehydrogenase activities, have been reported for carvacrol [69], carvone [73], citronellol [78], geniposide [84], myrtenal [91] and paeoniflorin [82; 93]. The common markers of hepatic function aspartate aminotransferase (ASP), alanine aminotransferase (ALA), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase have also been routinely measured in diabetes and their raised status in diabetes have been suppressed by carvacrol [69] and carvone [73]. Other organ functions primarily the kidney (cymene and logonin) and the brain (geniposide, thymol and d-limonene) have also been reported (Table 2). It is important to note the effect of the studied compounds on gross weight of the animals especially given administration of STZ-induced diabetes is associated with weight loss. For example, administration of borneol [67], carvacrol [68] and swertiamarin [94] have shown to reverse the body weight loss in diabetes. On the other hand, the body weight gain in HFD-obese model could be ameliorated by monoterenes. Even though, catalpol had no effect at the dose of 100 mg/kg (although it improved fasting glucose and insulin levels) [75], geniposide [83], paeoniflorin [82; 93] and thymol [97; 98] were among the monoterenes that showed good potential antiobesity effect. Geniposide also displayed antiobesity effect in spontaneously obese Type 2 diabetic Tsumura Suzuki Obese Diabetes (TSOD) mice model [40]. Given that STZ administration primarily targets pancreatic \(\beta\) cells leading to insulin depletion and hence diabetic condition, enhancing insulin secretion is one the well-defined mechanism of antidiabetic agents. While carvacrol did not have significant effect on the serum insulin level at the tested dose [72], carvone [73], citronellol [78], geniposide [82], geraniol [85], myrtenal [90] and swertiamarin [94] have all been shown to increase insulin level in the STZ-induced diabetes. As demonstrated for menthol [89] and myrtenal [91], improvement in the pancreatic and hepatic cellular and structures, as evidenced from histological studies, have been reported. On the other hand, in the HFD-obese model, hyperglycemia is associated with a rise in insulin level which appeared to be targeted/normalized by monoterenes. Good examples are geniposide [84] and thymol [98]. As discussed above, antidiabetic effect is often measured by assessing the level of glycation of proteins including hemoglobin which has been shown to be suppressed by monoterenes. Considering the link between glycation and oxidative stress, it is worth looking at the antioxidant effect of these compounds in vivo. Even though most monoterenes are not known for their potent direct ROS scavenging effect in vitro (Table 1), their in vivo antidiabetic effect is associated with an improved antioxidant status (Table 2). For example, borneol [67] has been shown to enhance antioxidant status in diabetic animals including augmented level/activity of superoxide dismutase (SOD), catalase, reduced glutathione (GSH) in the liver and kidney, while concomitantly suppressing the level of oxidation marker, malondialdehydedehyde (MDA). Similar results were obtained for aucubin [66], carvacrol [70; 71], genipin [79], d-limonene [87], logonin [88], and thymol [96]. The antihyperlipidemic and antiobesity effect of monoterenes appears to be well demonstrated in vivo. The diabetes-induced increase in the plasma or tissue levels of TC, TGs LDL-C, VLDL-C are often measured to assess the potential lipid lowering effect of drugs while raising the level of HDL is regarded as valuable parameter of lipid modulation. Borneol [67], carvacrol [72], genipin [79], geniposide [40], d-limonene [87], swertiamarin [94] and thymol [95; 96] are classical examples of monoterenes shown to display such effects (Table 2).