The Potential Role of Gossypetin in the Treatment of Diabetes Mellitus and Its Associated Complications: A Review

Abstract

Type 2 diabetes mellitus (T2DM) is a metabolic disorder caused by insulin resistance and dysfunctional beta (β)-cells in the pancreas. Hyperglycaemia is a characteristic of uncontrolled diabetes which eventually leads to fatal organ system damage. In T2DM, free radicals are continuously produced, causing extensive tissue damage and subsequent macro-and microvascular complications. The standard approach to managing T2DM is pharmacological treatment with anti-diabetic medications. However, patients' adherence to treatment is frequently decreased by the side effects and expense of medications, which has a detrimental impact on their health outcomes. Quercetin, a flavonoid, is a one of the most potent anti-oxidants which ameliorates T2DM. Thus, there is an increased demand to investigate quercetin and its derivatives, as it is hypothesised that similar structured compounds may exhibit similar biological activity. Gossypetin is a hexahydroxylated flavonoid found in the calyx of Hibiscus sabdariffa. Gossypetin has a similar chemical structure to quercetin with an extra hydroxyl group. Furthermore, previous literature has elucidated that gossypetin exhibits neuroprotective, hepatoprotective, reproprotective and nephroprotective properties. The mechanisms underlying gossypetin's therapeutic potential have been linked to its anti-oxidant, anti-inflammatory and immunomodulatory properties. Hence, this review highlights the potential role of gossypetin in the treatment of diabetes and its associated complications.

Keywords: diabetes mellitus; flavonoid; gossypetin.

Figure 1

Estimated age-adjusted comparative prevalence of diabetes in adults (20–79 years) in 2021 Adapted with permission from International Diabetes Federation, 2013 [3].

Figure 2

The complications associated with type 2 diabetes mellitus [5,6,27].

Figure 3

General structure of flavonoids. Adapted with permission from Ekalu and Habila,2020 [34].

Figure 4

The potential molecular mechanism of quercetin on the NF-kB inflammatory pathway [44,45]. The activation of toll-like receptor (TLR) pathways encourages the production of pro-inflammatory cytokines through the upregulation of transcription factors such as NF-κB [44,45]. Quercetin suppresses inflammatory cytokines production such as interleukin (IL)-6, tumour necrosis factor (TNF)-α and IL-1β via downregulating TLR4 [46,53]. Subsequently, repressed receptors yield targeted suppression of IκBα phosphorylation and mitogen-activated protein kinase (MAPK) expression and thereby inhibit nuclear transfer of the NF-κB [46,47]. Phosphorylation is represented as p in the above figure. In addition, quercetin may indirectly prevent inflammation by increasing peroxisome proliferator-activated receptor c (PPARγ) activity, thereby antagonising NF-κB [46,48]. In addition, TNF-α binds to TNF receptors, which causes the activation of extracellular signal-regulated kinase (ERK) [46]. Activated ERK inactivates PPARγ, therefore preventing nuclear translocation and the DNA binding of NF-κB [46,54]. This prevents the transcription of inflammatory mediators and triggers oxidative stress [46]. Quercetin activates nuclear factor erythroid 2-related factor 2 (Nrf2) and thereby contributes to increased heme oxygenase (HO)-1 levels, which are responsible for the downregulation of TNF-α [46]. Together, these block NF-kB-mediated induction of inflammatory cascades [46].

Figure 5

Structure of (A) gossypetin (GTIN) and (B) quercetin. Adapted with permission from Khan et al., 2013 and Zheng and Chow, 2009 [55,63].

Figure 6

The reported pharmacological importance of gossypetin [18,19,62,66,67].

Figure 7

The potential molecular mechanism of gossypetin on the NF-kB inflammatory pathway [55,73]. It is shown that gossypetin inhibits PDZ-binding kinase (PBK) phosphorylation, which is involved in the regulation of p38 MAPK and ERK1/2 kinases [73]. Consequently, MAPK and ERK are inhibited by gossypetin [55,73]. The downregulation of MAPK inhibits NF-kB activation and translocation into the nucleus [55,73]. As a result, there is a downregulation in the transcription of inflammatory mediators. In addition, the downregulation of ERK inhibits PPAR-y, thereby antagonising NF-kB [55,73]. Furthermore, gossypetin has been shown to stimulate Nrf2, thereby activating OH-1 and superoxide dismutase (SOD)-3 [73]. This promotes anti-oxidant and anti-inflammatory properties.