# Carbazoles: Role and Functions in Fighting Diabetes
## 2 Carbazole Derivatives in the Pathogenesis of Diabetes
### Carbazole Alkaloids  
_Murraya koenigii_ (L.) _Spreng_ is an endemic plant of India belonging to the _Rutaceae_ family, also known as \"meethi neem\" or \"curry patta\" [42]. The extracts of this plant have been extensively investigated for their antidiabetic activity. Recent studies have demonstrated that the main phytocompounds of this plant are alkaloids whose structures contain a carbazole nucleus [42,72,73]. In 2010, [PERSON] et al. [39] investigated the hypoglycemic effects of manhanine (**11**) (Figure 9), a carbazole-containing alkaloid, isolated from the leaves of the plant. The results of the experiments on mice with diet-induced diabetes showed a significant reduction in hyperglycemia and insulin resistance, most likely due to the ability of this phytocompound to modulate the expression of the IR gene and the activation of the NF-jB pathway [74].  
In a separate study, in addition to mahanine (**11**), [PERSON] et al. isolated from the fruit pulp extract another six carbazole-containing alkaloids: bisgerayafoline D (**12**), bismahanimbinol (**13**), bispyrayafoline (**14**), O-methyl mahanine (**15**), O-methyl mukonal (**16**) (Figure 9). All these compounds (**11-16**) were tested for antioxidant, anti-\(\alpha\)-glucosidase, DNA binding, protein interactions, and cytotoxic activities. Out of all the phytochemicals tested, manhanine (**11**) resulted to be the most promising as a radical scavenger and as  
Figure 9: Structures of: mahanine (**11**), bisgerayafoline D (**12**), bismahanimbinol (**13**), bispyrayafoline (**14**), O-methyl mahanine (**15**) and O-methyl mukonal (**16**).  
an \(\alpha\)-glucosidasealase inhibitor (IC\({}_{50}\) of 21.4 \(\pm\) 0.4 \(\upmu\)M). Furthermore, this compound showed cytotoxic activity due to its ability to act as a DNA-intercalating agent [40].  
The antidiabetic action of mahanine (**11**) was also confirmed in a study by [PERSON] et al. [41] in which the effects of the phytocompound on glucose uptake and translocation of glucose transporter 4 (GLUT4) in skeletal muscle and adipocyte cells were evaluated. In particular, the mahanine (**11**) treatment promoted a dose-dependent increase in glucose uptake in L6 myotubes and adipocyte cells through the stimulation of the Akt signaling pathway. These findings suggested that mahanine (**11**) acted similarly to insulin, promoting an enhancement of the Akt-mediated signaling pathway and leading to an increased translocation of GLUT4 on the cell membrane and, consequently, to a higher glucose uptake.  
Carbazole-containing alkaloids (**16** (Figure 9) and **17-20** (Figure 10)) found in _M. koenigii_ leaf extract promoted a substantial increase in glucose uptake, which was correlated to a higher translocation of GLUT4 into L6-GLUT4 myc myotubes. The activity of compounds **16-19** was also investigated in rats with streptozotocin-induced diabetes. Compound **18**, koenidine, was found to be the most effective in lowering blood glucose and was therefore selected for further in vivo assays in leptin-receptor-deficient db/db mice. As expected, a significant increase in insulin sensitivity and a progressive lowering of blood glucose level were recorded.  
Furthermore, Western blot studies confirmed that the stimulation of GLUT4 translocation observed in L6-GLUT4 myc myotubes is mediated by activation of the AKT-modulated signaling pathway. In vitro and in vivo pharmacokinetic studies revealed that compound **18** outperformed the other alkaloids due to its higher metabolic stability and systemic availability. The combination of properties of compound **18** makes it an ideal drug candidate for the treatment of diabetes and the treatment of insulin resistance [42].