Abstract
Diabetes mellitus (DM), a metabolic disorder is one of the most prevalent chronic diseases worldwide across developed as well as developing nations. Hyperglycemia is the core feature of the type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), following insulin deficiency and impaired insulin secretion or sensitivity leads insulin resistance (IR), respectively. Genetic and environmental factors attributed to the pathogenesis of DM and various therapeutic strategies are available for the prevention and treatment of T2DM. Among the numerous therapeutic approaches, the health effects of dietary/nutraceutical approach due to the presence of bioactive constituents, popularly termed phytochemicals are receiving special interest for pharmacological effects and therapeutic benefits. The phytochemicals classes, in particular sesquiterpenes received attention because of potent antioxidant, anti-inflammatory, and antihyperglycemic effects and health benefits mediating modulation of enzymes, receptors, and signaling pathways deranged in DM and its complications. One of the terpene compounds, β-caryophyllene (BCP), received enormous attention because of its abundant occurrence, non-psychoactive nature, and dietary availability through consumption of edible plants including spices. BCP exhibit selective full agonism on cannabinoid receptor type 2 (CB2R), an important component of endocannabinoid system, and plays a role in glucose and lipid metabolism and represents the newest drug target for chronic inflammatory diseases. BCP also showed agonist action on peroxisome proliferated activated receptor subtypes, PPAR-α and PPAR-γ, the main target of currently used fibrates and imidazolidinones for dyslipidemia and IR, respectively. Many studies demonstrated its antioxidant, anti-inflammatory, organoprotective, and antihyperglycemic properties. In the present review, the plausible therapeutic potential of BCP in diabetes and associated complications has been comprehensively elaborated based on experimental and a few clinical studies available. Further, the pharmacological and molecular mechanisms of BCP in diabetes and its complications have been represented using synoptic tables and schemes. Given the safe status, abundant natural occurrence, oral bioavailability, dietary use and pleiotropic properties modulating receptors and enzymes, BCP appears as a promising molecule for diabetes and its complications.
Highlights
Diabetes mellitus (DM) is the most prevalent metabolic disorder and continuing to affect a large number of people worldwide
Previous studies have demonstrated that small G-proteins e.g., ADP-ribosylation factor 6 (Arf6), cell division cycle 42 (Cdc42), and Ras-related C3 botulinum toxin substrate 1 (Rac1) play an important role in regulating signaling events involved in insulin trafficking [33]
All these effects are attributed to a direct effect of BCP, as cannabinoid receptors cannabinoid type 2 receptors (CB2R) agonist, other than of peroxisome proliferated activator receptors (PPARs)-γ receptors, involved in decreasing total cholesterol levels, low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL), in the restoring of nitric oxide concentration and nitric oxide synthase isoforms and in the inhibition of vascular inflammation and synthesis of adhesion molecules. It appears that BCP being PPAR-γ agonist leads to the reduction in fat mass and triglycerides and increases in high-density lipoprotein (HDL) [58]. These effects are mediated via the binding of BCP to CB2R, which activates PGC1-α and promotes the interaction between PPAR-γ and different transcriptional factors, such as PPAR-α leading to increase in the expression of enzymes involved in the oxidation of fatty acids in the liver
Summary
Diabetes mellitus (DM) is the most prevalent metabolic disorder and continuing to affect a large number of people worldwide. BCP has been suggested to be used as a nutraceutical, functional food, and dietary supplement because of its dietary bioavailability, ample natural occurrence, and multiple therapeutic benefits [23] Many formulations such as suspension, PEG formulations, liposomes, wound dressings, hydrogels, and nanoemulsions for topical use, inclusion complexes with cyclodextrins, as well as nanocomposites and nanoparticles have been developed [28]. In the past few years, the number of studies demonstrated that BCP possesses a wide range of pharmacological properties including anti-inflammatory and antioxidant and the potential to correct hyperglycemia and improve insulin secretion and sensitivity, appearing as a promising molecule for diabetes and its complications [29]. The pharmacological effects and mechanisms are summarized in synoptic tables and schemes
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