# Carbazoles: Role and Functions in Fighting Diabetes
## 2 Carbazole Derivatives in the Pathogenesis of Diabetes
### Carvedilol
In a separate study, carvedidol (**1**) was found to be more effective than metoprolol, one of the most prescribed selective beta-1 adrenergic antagonists, in controlling glucose metabolism in diabetic hypertensive patients without affecting insulin resistance [51; 54]. This was most likely due to carvedidol's ability to also block beta-2 and alpha-1 receptors [56]. Unlike patients treated with metoprolol, who gained weight after 2 months of treatment, no significant change in body weight was observed in those treated with carvedidol (**1**). Long-term carvedidol treatment may have beneficial effects on endothelial dysfunction caused by oxidative stress in patients with type 2 DM. This could be due to the antioxidant properties of the compound, which acts as a radical scavenger, and to its capability to modulate endothelial NO production [28; 57]. [PERSON] et al., in 2012 [29], found that in hypertensive patients treated with metoprolol succinate, after six months, insulin levels increased by approximately 36%, whereas a decrease of about 10% was observed in those treated with carvedidol (**1**) (\(p=0.015\)). Many studies have discovered a relation between \(\beta\)2-AR polymorphisms and metabolic disorders, including hypertriglyceridemia, insulin resistance, and obesity [58; 59; 60]. In particular, two common \(\beta\)2-AR single-nucleotide polymorphisms, Arg16 Gly and Gln27 Glu, have been shown to be responsible for altered receptor function and, consequently, for an inadequate response to \(\beta\)-blocker treatment. [PERSON] et al., in 2019, demonstrated that low-dose carvedidol (**1**) can efficiently prevent hypoglycemic crises in rats treated with \(\beta\)-blockers. This study showed that rats with recurrent episodes of hypoglycemia treated with carvedidol required less exogenous glucose during the hypoglycemic clamp, thus supporting use of the drug to preserve hormonal responses to hypoglycemia. Furthermore, carvedidol treatment had no effect on plasma lactate levels, indicating that the drug can prevent some of the central adaptations that occur during recurrent hypoglycemic episodes [61]. In 2017, [PERSON] et al. [30] conducted a study aimed at evaluating the pharmacokinetic profile of the enantiomers of carvedidol and the corresponding metabolites, hydroxyphenyl-carvedidol (OHC) (**2**) and O-desmethylcarvedidol (DMC) (**3**) (Figure 4), in healthy volunteers and in patients with type 2 DM but with good glycemic control. For this purpose, thirteen healthy subjects were recruited and divided into two groups: the first group underwent treatment with carvedidol as a single agent, while the second one received a treatment of carvedidol (**1**) in combination with glibenclamide and metformin. In addition, patients with type 2 DM were enrolled and were treated with carvedidol as a single agent. The results of this study demonstrated that the pharmacokinetic profile of the carvedidol enantiomers did not differ between each other, even in the patients treated with glibenclamide and metformin. In a separate study, the same authors, using an integrated population pharmacokinetic modeling approach, confirmed that carvedidol does not induce insulin resistance or  
Figure 4: Structures of: hydroxyphenylcarvedidol (OHC) (**2**) and O-desmethylcarvedidol (DMC) (**3**). worsen glycemic control in diabetic hypertensive patients [31]. More recently, [PERSON] et al. conducted a study to evaluate the effects of carvedilol (**1**) treatment in subjects with obesity induced by a high-fat diet (HFD). The findings not only confirmed the improvement in glucose tolerance and insulin sensitivity, but also indicated that these effects are related to the suppression of hepatic glucose overproduction and to the enhancement of the muscle insulin signaling pathway. Hence, as a result of the drug's ability to block adrenergic hyperactivation, long-term treatment with carvedilol (**1**) may provide significant benefits in obese subjects [32; 60; 61]. The efficacy of carvedilol (**1**) is, however, limited due to its poor bioavailability.