Flavonoids’ Dual Benefits in Gastrointestinal Cancer and Diabetes: A Potential Treatment on the Horizon?

Simple Summary The consumption of flavonoids positively influences the same (impaired) metabolic pathways in diabetes and gastrointestinal cancers, leading to the hypothesis that flavonoids could exert dual effects on these diseases, as some flavonoids can target the same pathways in both conditions, such as the apoptosis and AMPK pathways. Here, we identified flavonoids with such interactions and discussed their positive effects on both diseases. Nevertheless, more efforts are required to estimate the appropriate flavonoid dosage and flavonoid–flavonoid interactions, and to identify potential side effects. It is also necessary to assess the possibility of combining multiple flavonoids with the currently used treatment. Abstract Diabetes and gastrointestinal cancers (GI) are global health conditions with a massive burden on patients’ lives worldwide. The development of both conditions is influenced by several factors, such as diet, genetics, environment, and infection, which shows a potential link between them. Flavonoids are naturally occurring phenolic compounds present in fruits and vegetables. Once ingested, unabsorbed flavonoids reaching the colon undergo enzymatic modification by the gut microbiome to facilitate absorption and produce ring fission products. The metabolized flavonoids exert antidiabetic and anti-GI cancer properties, targeting major impaired pathways such as apoptosis and cellular proliferation in both conditions, suggesting the potentially dual effects of flavonoids on diabetes and GI cancers. This review summarizes the current knowledge on the impact of flavonoids on diabetes and GI cancers in four significant pathways. It also addresses the synergistic effects of selected flavonoids on both conditions. While this is an intriguing approach, more studies are required to better understand the mechanism of how flavonoids can influence the same impaired pathways with different outcomes depending on the disease.


Diabetes
Diabetes is a chronic and complex metabolic disorder with a high prevalence rate worldwide [1]. It is classified into type 1, type 2, and gestational diabetes. These types differ in their diagnostic criteria, genetics, and etiology [2]. Type 2 and gestational diabetes are attributed to unhealthy diet and lifestyle, aging, and urbanization [3]. Diabetes is categorized by hyperglycemia, a continued elevation of blood glucose levels caused either by a defect in insulin secretion or action [4] due to which multiple organs, such as the eyes, heart, and kidneys, become deleterious, leading to organ damage, dysfunction, and, ultimately, organ failure [5,6].
Additionally, complications of diabetes could have profound adverse effects on the social, psychological, and physical health of patients and their families [7]. Symptoms and Additionally, complications of diabetes could have profound adverse effects on the social, psychological, and physical health of patients and their families [7]. Symptoms and signs of diabetes include polyuria, polyphagia, polydipsia, blurred vision, and weight loss. Their severity depends on the type and duration of diabetes [8]. Currently, diabetes is treated by administering oral hypoglycemic drugs, antidiabetic drugs, and lifestyle management [9,10]. Further efforts are needed for the development of new therapeutic agents.

Gastrointestinal Cancer
Gastrointestinal cancer (GI) is one of the major causes of death and disability worldwide [11]. The term "GI cancer" describes cancers that affect the digestive system, including, but not limited to, colorectal cancer and gastric cancer [12]. It is a multifactorial disease and can be influenced by environmental and genetic factors such as obesity, diet, smoking, infection, and low socioeconomic status [13,14]. The symptoms of GI cancers depend on their etiology and may include weight loss, fatigue, anorexia, abdominal pain, and dysphagia [15]. GI cancer progression results from the impairment of major metabolic pathways, such as the intrinsic and extrinsic apoptotic pathways, cellular proliferation pathways, and metastatic pathways [16,17]. The field of cancer treatment is evolving continuously, and the applications of precision medicine and combination therapy provide an alternative approach and result in the long-term survival of patients with GI cancers [18]. Despite this, more efforts are required to estimate GI cancers' underlying mechanisms and develop new therapeutic approaches for prevention and treatment.

Flavonoids nfluence Diabetes and GI Cancer
Flavonoids are secondary metabolites derived mainly from plants, fruits, leaves, and vegetables [19]. They represent a large family of compounds consisting of benzopyran rings with polyphenolic groups at different positions. The structure of flavonoids consists of 15 carbons and two rings (A and B) linked by three carbon chains [20] (Figure 1). Flavonoids are classified into multiple types based on their chemical structure, unsaturated linking chain, and degree of oxidation [21]. Each of these groups possesses biological properties, and some are successfully used in therapeutic approaches for treating diabetes and GI cancer [22]. The administration of flavonoids to target diabetes modulated lipid and carbohydrate metabolisms, improved adipose tissue metabolism, attenuated hyperglycemia, and alleviated oxidative stress [23,24]. Moreover, for targeting GI cancer, flavonoids in berries and green tea reduced cellular proliferation and inflammation, inhibited metastasis, and increased apoptosis [25,26]. Additional efforts are necessary to address the mechanism of flavonoids in treating metabolic disorders such as diabetes and cancer.

Gut Microbiota: The Role in Diabetes and GI Cancer
The human digestive tract harbors several microbial species collectively called the gut microbiome [27]. The human gut microbiome influences health and disease status through its involvement in human nutrition, immunity, and physiology [28]. Recently, we

Gut Microbiota: The Role in Diabetes and GI Cancer
The human digestive tract harbors several microbial species collectively called the gut microbiome [27]. The human gut microbiome influences health and disease status through its involvement in human nutrition, immunity, and physiology [28]. Recently, we reported the effect of gut microbiome enzymatic modifications on flavonoid metabolism and how these modifications affect the observed biological properties of flavonoids [29].
Human gut microbiome diversity disruption is linked to pathological conditions such as inflammatory bowel disease (IBD), obesity, diabetes, and cancers [30,31]. In two population-based studies, the diversity and richness of the gut microbiome were associated directly with the development of type 2 diabetes and insulin resistance [32]. Furthermore, the gut microbiome's impact on cancer is not only limited to specific pathways such as apoptosis and cellular proliferation, but also enhances the efficacy and reduces the resistance of chemotherapeutic drugs [33]. Figures 2 and 3 summarize the overall interactions between the gut microbiome and specific pathways during diabetes and GI cancer.
reported the effect of gut microbiome enzymatic modifications on flavonoid metabolism and how these modifications affect the observed biological properties of flavonoids [29].
Human gut microbiome diversity disruption is linked to pathological conditions such as inflammatory bowel disease (IBD), obesity, diabetes, and cancers [30,31]. In two population-based studies, the diversity and richness of the gut microbiome were associated directly with the development of type 2 diabetes and insulin resistance [32]. Furthermore, the gut microbiome's impact on cancer is not only limited to specific pathways such as apoptosis and cellular proliferation, but also enhances the efficacy and reduces the resistance of chemotherapeutic drugs [33]. Figures 2 and 3 summarize the overall interactions between the gut microbiome and specific pathways during diabetes and GI cancer.  In our previous work, we identified the role of different flavonoids on diabetes and GI cancer separately [34,35]. In this review, we evaluate and analyze published studies to report and estimate the possible dual role of flavonoids in targeting diabetes and GI cancers. The literature supports a potential association between both conditions, as hyperglycemia level influences the development of diabetes and GI cancers. Furthermore, we assess the impact of this interaction on specific and common pathways in both metabolic conditions. Finally, we identify gaps in the current research. In our previous work, we identified the role of different flavonoids on diabetes and GI cancer separately [34,35]. In this review, we evaluate and analyze published studies to report and estimate the possible dual role of flavonoids in targeting diabetes and GI cancers. The literature supports a potential association between both conditions, as hyperglycemia level influences the development of diabetes and GI cancers. Furthermore, we assess the impact of this interaction on specific and common pathways in both metabolic conditions. Finally, we identify gaps in the current research.

Search Strategy and Selection Criteria
Medline, Scopus, and PubMed were searched for manuscripts published from 2000 to 2022 using the search terms "flavonoids", "microbiota", "flavonoids AND diabetes", "flavonoids AND cancer", "flavonoids AND GI cancer", "microbiome AND GI cancer", "gut microbiota enzymes", microbiome AND diabetes", and "flavonoids AND GI cancer AND diabetes". In this article, we selected 121 articles and analyzed them in detail. Eligible studies included in vivo, in vitro, and clinical trial papers addressing the influence of

Search Strategy and Selection Criteria
Medline, Scopus, and PubMed were searched for manuscripts published from 2000 to 2022 using the search terms "flavonoids", "microbiota", "flavonoids AND diabetes", "flavonoids AND cancer", "flavonoids AND GI cancer", "microbiome AND GI cancer", "gut microbiota enzymes", microbiome AND diabetes", and "flavonoids AND GI cancer AND diabetes". In this article, we selected 121 articles and analyzed them in detail. Eligible studies included in vivo, in vitro, and clinical trial papers addressing the influence of flavonoids on both conditions and the possible underlying dual effects. Duplicates and studies with other flavonoid metabolism mechanisms were excluded.

Role of Flavonoids on Diabetic and GI Cancer Pathways
As discussed in the previous section, flavonoids exhibit diverse biological properties that target diabetes and GI cancers. In the following paragraphs, we will discuss the influence of specific flavonoids on major impaired pathways in diabetes and GI cancers such as apoptosis, cellular proliferation, enzymatic modifications, and AMPK pathways. studies with other flavonoid metabolism mechanisms were excluded.

Role of Flavonoids on Diabetic and GI Cancer Pathways
As discussed in the previous section, flavonoids exhibit diverse biological properties that target diabetes and GI cancers. In the following paragraphs, we will discuss the influence of specific flavonoids on major impaired pathways in diabetes and GI cancers such as apoptosis, cellular proliferation, enzymatic modifications, and AMPK pathways.

Flavonoids and Apoptosis in Diabetes and GI Cancers
Cellular apoptosis is programmed cell death that involves numerous regulatory genes [36]. These regulatory checkpoints are critical to maintaining a homeostatic balance between the newly formed and damaged cells [37]. Loss of this balance may lead to the development of diseases such as diabetes and/or GI cancers [38]. Flavonoids restore the imbalance in these conditions [39].
In diabetes, long-term hyperglycemia in patients may contribute to the accumulation of reactive oxygen species (ROS), which results in endothelial cellular stress [40]. If unresolved, it may lead to apoptosis of microvascular endothelial cells, which, in turn, results in diabetic complications such as diabetic cardiomyopathy and diabetic nephrosis [41].

Flavonoids and Apoptosis in Diabetes and GI Cancers
Cellular apoptosis is programmed cell death that involves numerous regulatory genes [36]. These regulatory checkpoints are critical to maintaining a homeostatic balance between the newly formed and damaged cells [37]. Loss of this balance may lead to the development of diseases such as diabetes and/or GI cancers [38]. Flavonoids restore the imbalance in these conditions [39].
In diabetes, long-term hyperglycemia in patients may contribute to the accumulation of reactive oxygen species (ROS), which results in endothelial cellular stress [40]. If unresolved, it may lead to apoptosis of microvascular endothelial cells, which, in turn, results in diabetic complications such as diabetic cardiomyopathy and diabetic nephrosis [41]. However, baicalin, a flavone glycoside in tea, fruits, and vegetables, reduces apoptosis in a rat model of diabetes mellitus, thus supporting the neuroprotective efficacy of baicalein against diabetes-associated cognitive deficits [42]. Moreover, a study that stimulated diabetic mice cells with 60.0 M of glucose to induce oxidative stress showed that cells treated with baicalin had significantly alleviated oxidative stress and apoptosis through the regulation of PERK/Nrf2 pathway [43]. Additionally, hesperidin, a glycosidic flavonoid abundant in citrus fruit, also reduces oxidative stress [44]. Normal human hepatocytes stimulated with 33 mM of glucose for 24 h and then treated with hesperidin had improved oxidative stress levels and increased cell viability compared to the untreated cells. These findings demonstrated that hesperidin treatment might reduce apoptosis by regulating miR-149 expression, a critical apoptotic regulator [45]. Similarly, rutin also alleviated diabetic complications through apoptosis [46]. Myoplast cells stimulated with different glucose concentrations and then treated with rutin showed an improvement in cardiomyocyte injury through the direct inhibition of apoptosis and endoplasmic reticulum stress [47].
The reduction of apoptotic regulation allows cancerous cells to survive and progress [48]. Flavonoids such as apigenin, a plant flavone, induce cell cycle arrest, disruption, and apoptosis with low toxicity and mutagenicity rates [49]. Additionally, 200 umol/L of genistein for 48 h affected both Notch 1 and epithelial-mesenchymal transition (EMT) pathways and significantly induced apoptosis in colorectal cancer cells [50]. Moreover, the administration of 50 uM of Kaempferol also decreased the Bcl-2 level and increased the cleaved caspase 9 expression, thus inducing apoptosis in gastric cancer cells [51]. Interestingly, the same apoptotic pathway may be targeted by different flavonoid types such as chrysin, morin, and hesperidin. All three flavonoids induced apoptosis separately through the modulation of caspase 3, 9, and BAX expression in colorectal cancer or gastric cancer cells [52][53][54]. Moreover, cotreatment of apigenin and 5-flurouracil increased ROS and mitochondrial membrane potential in colorectal cancer cells, supporting flavonoids' potential role as a therapeutic agent [55]. Figure 5 summarizes the influence of specific flavonoids on the apoptotic pathways in diabetes and GI cancers.

Flavonoids and NF-κB Pathway in Diabetes and GI Cancers
Nuclear factor kappa B (NF-κB) transcription factors are critical regulators of flammatory and immune responses against infections and injuries [56]. NF-κB dysr

Flavonoids and NF-κB Pathway in Diabetes and GI Cancers
Nuclear factor kappa B (NF-κB) transcription factors are critical regulators of the inflammatory and immune responses against infections and injuries [56]. NF-κB dysregulation may lead to the development of cancers, chronic inflammation, and insulin resistance [57]. The activation of NF-κB by oxidative stress in diabetic patients due to the high glucose level plays a crucial role in the vascular complications of diabetes [58]. Additionally, persistent hyperglycemia in diabetes triggers the expression of chemokines, cytokines, and cell adhesion molecules by activating NF-κB expression [59]. Furthermore, activation of the NF-κB pathway correlates with GI cancers' tumor size, migration, and invasion through the modulation of inflammatory markers, just as in the pathogenesis of GI cancers [60]. Targeting the NF-κB pathway with flavonoids is reported to be a potential therapeutic target for diabetes and GI cancers [61,62].
Different flavonoids exert antidiabetic properties. Baicalin, a bioactive polyphenolic flavonoid, administered to diabetic mice significantly reduced glucose levels and inhibited insulin levels [63]. Additionally, the administered baicalin attenuated steatosis in diabetic mice's hepatic tissues through the suppression of inflammatory cytokines regulated by the NF-κB pathway. Treatment with 20 mg/kg of apigenin also reduced NF-κB and TNF-a expression and inhibited mouse inflammations [64]. Moreover, luteolin significantly reduced oxidative stress by inhibiting the NF-κB and activating the nuclear factor-erythroid 2related factor 2 signaling pathway [65]. Interestingly, as reported with quercetin, flavonoids inhibit NF-κB expression and target vascular complications in diabetes [66]. Daily administration of quercetin in rats for six weeks reduced NF-κB expression and protects against diabetic-induced exaggerated vasoconstriction.
Flavonoids also play a significant role in targeting the NF-κB pathway through different mechanisms in gastric cancer (GC). Chrysin, for example, significantly suppressed NF-κB and Egr-1 expression in gastric cancer cells by inhibiting endogenous recepteur d'órigine nantais (RON) expression and activity, a critical receptor for cancer cell invasion [67]. Additionally, treating colorectal cancer cells with morin suppressed the expression of NF-κB and the production of inflammatory cytokines such IL-8 and IL-6 [68]. Furthermore, genistein administration in gastric cells targeted and significantly reduced the expression of Cyclooxygenase-2 (COX-2), an isoenzyme critical in cancer progression, by targeting and inhibiting its regulator, NF-κB [69]. Quercetin also downregulated the NF-κB pathway, influencing the invasion, migration, and metastasis of gastric cancer cells [70]. Figure 6 highlights the influence of specific flavonoids on the NF-κB pathway and expression in diabetes and GI cancers.

Flavonoids and AMPK Pathway in Diabetes and GI Cancers
AMPK-activated protein kinase is a highly conserved protein kinase and a central regulator of cellular energy and homeostasis in eukaryotes [71]. It exists in the cell as an obligate heterodimer with a catalytic subunit and two regulatory subunits [72]. Several cellular stressors, such as hypoxia, can activate the AMPK pathway [73]. Impaired regulations of the AMPK pathway play an essential role in developing metabolic conditions such as diabetes, leading to insulin resistance and cancers and tumor progression [74,75]. However, flavonoids could positively influence and regulate AMPK pathways in diabetes and GI cancers.
Three main flavonoids regulate the AMPK pathway in diabetes: quercetin, daidzein, and Kaempferol. Skeletal muscle cells treated with quercetin induced glucose uptake in the cells, changed the mitochondrial membrane potential, and increased intracellular calcium concentration [76]. The observed antidiabetic effects were modulated mainly through the regulation of the AMPK pathway and GLUT4 expression and were similar to the mechanisms of the well-known antidiabetic drug metformin [76]. Additionally, diabetic mice and myotubes cells treated with daidzein showed that this flavonoid promoted glucose uptake through the phosphorylation of AMPK and the translocation of GLUT4 expression [77]. Moreover, the administration of Kaempferol to pancreatic cells upregulated the phosphorylation of the AMPK pathway. When an inhibitor was used, it reduced the pancreatic cells' survival rate suggesting a potential cytoprotective effect of Kaempferol on diabetes [78].
On the other hand, colorectal cancer cells treated with a soy-derived phytochemical, genistein, demonstrated activated AMPK expression [79]. Additionally, combination therapy of genistein and 5-flurouracil abolished cellular growth, induced cellular apoptosis, and activated AMPK phosphorylation, exerting a potential chemotherapeutic approach against colorectal cancers. Figure 7 illustrates the influence of specific flavonoids on the AMPK pathway and expression in diabetes and GI cancers.
cetin, flavonoids inhibit NF-κB expression and target vascular complications in diabetes [66]. Daily administration of quercetin in rats for six weeks reduced NF-κB expression and protects against diabetic-induced exaggerated vasoconstriction.
Flavonoids also play a significant role in targeting the NF-κB pathway through different mechanisms in gastric cancer (GC). Chrysin, for example, significantly suppressed NF-κB and Egr-1 expression in gastric cancer cells by inhibiting endogenous recepteur d'órigine nantais (RON) expression and activity, a critical receptor for cancer cell invasion [67]. Additionally, treating colorectal cancer cells with morin suppressed the expression of NF-κB and the production of inflammatory cytokines such IL-8 and IL-6 [68]. Furthermore, genistein administration in gastric cells targeted and significantly reduced the expression of Cyclooxygenase-2 (COX-2), an isoenzyme critical in cancer progression, by targeting and inhibiting its regulator, NF-κB [69]. Quercetin also downregulated the NF-κB pathway, influencing the invasion, migration, and metastasis of gastric cancer cells [70]. Figure 6 highlights the influence of specific flavonoids on the NF-κB pathway and expression in diabetes and GI cancers.

Flavonoids and Enzymatic Activities in Diabetes and GI Cancers
Enzymes are critical modulators in the body, aiding in regulating the metabolic process and chemical reactions [80]. Their influence on these reactions depends on the target tissue and regulatory mechanisms [81]. An imbalance in the regulation or the expression of specific enzymes, such as glucose 6 phosphatase or glutathione reductase, may lead to diabetes and cancers, respectively [82,83].
In diabetes, the level of hepatic enzymes such as glucose 6 phosphatase and phosphoenolpyruvate carboxykinase increases, while the level of hexokinase decreases. These enzymes are critical in maintaining blood glucose regulation in the body [84]. Flavonoids such as genistein, diosmin, morin, rutin, and baicalin improve the activities of these enzymes in diabetic models. The administration of genistein (0.02%) in mice reduced glucose 6 phosphatase and phosphoenolpyruvate carboxykinase activities in the liver compared to the control [85]. Additionally, oral administration of diosmin (100 mg/kg) significantly decreased glucose 6 phosphatase activities and increased hexokinase in diabetic-induced rats [86]. Moreover, rutin administration for 30 days to diabetic rats significantly ameliorated hyperglycemia, decreased glucose 6 phosphatase activities, and increased hexokinase activities [87]. Furthermore, glucose 6 phosphatase and hexokinase activities were

Flavonoids and Enzymatic Activities in Diabetes and GI Cancers
Enzymes are critical modulators in the body, aiding in regulating the metabolic process and chemical reactions [80]. Their influence on these reactions depends on the target tissue and regulatory mechanisms [81]. An imbalance in the regulation or the expression of specific enzymes, such as glucose 6 phosphatase or glutathione reductase, may lead to diabetes and cancers, respectively [82,83].
In diabetes, the level of hepatic enzymes such as glucose 6 phosphatase and phosphoenolpyruvate carboxykinase increases, while the level of hexokinase decreases. These enzymes are critical in maintaining blood glucose regulation in the body [84]. Flavonoids such as genistein, diosmin, morin, rutin, and baicalin improve the activities of these enzymes in diabetic models. The administration of genistein (0.02%) in mice reduced glucose 6 phosphatase and phosphoenolpyruvate carboxykinase activities in the liver compared to the control [85]. Additionally, oral administration of diosmin (100 mg/kg) significantly decreased glucose 6 phosphatase activities and increased hexokinase in diabetic-induced rats [86]. Moreover, rutin administration for 30 days to diabetic rats significantly ameliorated hyperglycemia, decreased glucose 6 phosphatase activities, and increased hexokinase activities [87]. Furthermore, glucose 6 phosphatase and hexokinase activities were restored after the oral administration of morin for 30 days in diabetic rats [88]. These data support the potential role of flavonoids in influencing the hepatic enzymatic activities in the liver, which may be applicable for diabetic management.
In contrast, in GI cancers, enzymes such as glutathione reductase and glutathione S transferase are critical in regulating glutathione utilization, a cellular regulator for the redox state [89]. An imbalance in the utilization of this intracellular antioxidant may impair biological pathways such as apoptosis and cellular proliferation [90]. Limited studies reporting the effect of flavonoids on glutathione utilization enzymes in GI cancers are available. Lycopene administration (2.5 mg/kg) suppressed gastric cancer by increasing glutathione reductase and glutathione S transferase activities [91]. More studies are required to confirm this observation and support the potential role of flavonoids in GI cancer pathogenesis. Figure 8 shows the influence of specific flavonoids on enzymatic activities and expression in diabetes and GI cancers. Tables 1 and 2 summarize the main findings from the reported studies. restored after the oral administration of morin for 30 days in diabetic rats [88]. These data support the potential role of flavonoids in influencing the hepatic enzymatic activities in the liver, which may be applicable for diabetic management.
In contrast, in GI cancers, enzymes such as glutathione reductase and glutathione S transferase are critical in regulating glutathione utilization, a cellular regulator for the redox state [89]. An imbalance in the utilization of this intracellular antioxidant may impair biological pathways such as apoptosis and cellular proliferation [90]. Limited studies reporting the effect of flavonoids on glutathione utilization enzymes in GI cancers are available. Lycopene administration (2.5 mg/kg) suppressed gastric cancer by increasing glutathione reductase and glutathione S transferase activities [91]. More studies are required to confirm this observation and support the potential role of flavonoids in GI cancer pathogenesis. Figure 8 shows the influence of specific flavonoids on enzymatic activities and expression in diabetes and GI cancers. Tables 1 and 2 summarize the main findings from the reported studies.

Possible Dual Effects of Flavonoids on Diabetes and GI Cancer
As illustrated in the tables above, we identified three main flavonoids targeting metabolic pathways that are impaired in diabetes and GI cancers. These flavonoids are hesperidin, Kaempferol, and quercetin, and they target apoptosis and the NF-κB pathways This could suggest possible dual effects of flavonoids on diabetes and GI cancer. In male diabetic rats, the administration of hesperidin (100 mg/kg) for four weeks significantly reduced blood glucose and increased insulin levels [104]. Additionally, and more importantly, hesperidin effectively regulated the expression of apoptotic proteins, as shown by the upregulation of the antiapoptotic Bcl-xl level and the downregulation of the pro-apoptotic Bax level [104].
Moreover, in three gastric cancer cell lines, the treatment of hesperidin also targeted apoptotic regulatory proteins but with a different biological effect. The administered hesperidin upregulated the pro-apoptotic Bax level and downregulated the antiapoptotic Bcl-2 levels [54]. Despite the differences observed in both studies (ranging from the targeted disease, the model used, the concentration of the hesperidin, the administration route, and the duration of the treatment), hesperidin affected apoptotic proteins and restored their physiological effects in both studies, but in an opposite manner, resulting in reduction in diabetes and induction in GI cancers. Moreover, Kaempferol also targeted the apoptotic pathway in both conditions. In diabetes, Kaempferol significantly improved the expression of antiapoptotic proteins such as Bcl-2, inhibited apoptosis, and reduced caspase 3 activities in INS-1E beta cells [105]. Kaempferol also targeted apoptosis in colorectal cancer cells by blocking ROS production [106]. Although these results may support the potential efficacy of hesperidin and Kaempferol to modulate apoptosis in different metabolic conditions, more efforts are required to test both conditions in alignment using a standardized technique.
As discussed in the previous section, quercetin can affect NF-κB pathways in diabetes and GI cancers. Diabetic mice treated with orally administered quercetin for two weeks showed a suppressed inflammatory response indicated by reduced NF-κB expression [96]. In gastric cancer cells, quercetin also inhibited the dose-dependent NF-κB pathway [107]. However, limited data are available in the literature to support the hypothesis that quercetin may have the same biological effect on the two conditions: diabetes and GI cancers.
Analyzing the available data on three flavonoids, the possible dual effect depends on the targeted pathway, the model used, and the flavonoid dosage, which needs standardization. Additionally, studies evaluating the impact of these flavonoids in combination with the currently used treatment are lacking in the literature; assessing the potential of dual effects of other flavonoids on diabetes and GI cancers is also highly required.

Targeting Multiple Pathways with Multiple Flavonoids That Act Synergistically?
As mentioned in the previous sections and the figures, the same flavonoid can trigger and improve diabetes and/or cancer-related pathways, as seen with baicalin and genistein, respectively. Baicalin, for example, exerts its antidiabetic effects by targeting three out of four discussed pathways: apoptosis, NF-κB, and enzymatic modification. Genistein, on the other hand, triggers apoptosis, NF-κB, and AMPK pathways in cancer. Therefore, can the positive effects of flavonoids on physiological pathways be further enhanced when different flavonoids are combined to complement and trigger additional pathways? For instance, with baicalin targeting three diabetic-impaired pathways, combining baicalin with one of the flavonoids that target the AMPK pathway in diabetes (Figure 7) might potentially initiate a positive effect in all four of the discussed pathways due to synergistic effects of both phytochemicals. This hypothesized approach may prevent the over-activation of the same pathway and reduce possible side effects while achieving the antidiabetic effects of these flavonoids. The same approach may also be used with genistein in GI cancer. So far, these thoughts are theoretical and only based on observation from the data cited above. In vitro or in vivo studies are still missing, and extensive studies are required to prove whether they are effective in an expected way. This hypothesis may be tested by first identifying the pathways targeted by the flavonoid in each metabolic condition, then identifying flavonoids that complement each other. Furthermore, estimating the appropriate concentration of each flavonoid is critical to ensure safety and prevent cytotoxicity. Recognizing the potential binding sites of each flavonoid and their bioavailability is essential to ensure their positive effects. Moreover, observing possible side effects from this combination with the currently used treatment is necessary, as the aim is not to replace the available therapeutic tools, but to complement them.

Gut Microbiome and Flavonoids' Effects
The relationship between the gut microbiome and flavonoids may be described as a bidirectional interaction. On the one hand, the consumed flavonoids act as a regulator of intestinal hemostasis by either enhancing or suppressing the growth of specific bacterial species. On the other hand, the gut microbiome contributes to the pharmacokinetics of ingested dietary flavonoids to produce aglycones and, subsequently, the ring fission products which facilitate absorption [108][109][110]. It is hypothesized that these enzymatically modified gut microbiome products are responsible for the positive physiological effects of flavonoids observed in diabetes and GI cancer (Figures 2 and 3). This may provide a potential therapeutic target for both metabolic conditions. Patients with type 2 diabetes exhibit gut microbiome dysbiosis characterized by a reduction in butyrate-producing bacterial species [111]. Additionally, the gut microbiome regulates the levels of short-chain fatty acids and lipopolysaccharides, which are critical for developing diabetes [112]. Furthermore, patients with type 2 diabetes exert a low-grade systemic inflammation mediated by the impaired gut barrier [113].
On the other hand, gut microbial species such as Streptococcus bovis, Fusobacterium nucleatum, and Enterococcus faecalis mediate inflammatory response and tumor progression in colorectal cancer [114,115]. The data above show that flavonoids and their metabolites could reduce or restore the observed pathological effects in diabetes and GI cancers. Despite this, more efforts are required to properly study the gut microbiome, including a suitable model and flavonoid interactions. More studies are required to evaluate whether the positive/dual effects observed are due to the flavonoids, their metabolites, or both. In addition, more efforts are needed to address the metabolites from the gut microbiome and the liver, and especially to discuss and understand the substances metabolized in the liver [116]. The development of more omics tools that help analyze data is necessary [117].

Challenges with Studying the Field
Although flavonoids reduce the pathogenesis of diabetes and GI cancers, further efforts are required to address the main challenges of their utilization in managing cancer and diabetes. First, the recommended dosage of flavonoids for each metabolic condition must be established. The literature shows variations in the estimated dosage for most flavonoids tested based on the population, ethnicity, gender, and geographical locations [118][119][120]. The observed variations may be due to the solubility and molecular weight of the flavonoids used [121]. Second, newly developed tools and techniques are required to overcome flavonoids' relatively low bioavailability rate.
Additionally, a better understanding of flavonoids' cellular permeability, excretion, and metabolic alternation is needed to enhance their bioavailability [122]. Third, the potential side effects of using multiple flavonoids to target various metabolic pathways or using flavonoids in combination with currently used drugs as a treatment method must be estimated. This will help to minimize the risk of negative flavonoid-drug interactions. Fourth, the field is in great need of standardization starting from the model used, flavonoid extraction and purification technique, administration route, and duration of the treatment. By overcoming these challenges, using flavonoids as a potential therapeutic target may be implemented with high effectiveness and safety levels.

GI Cancers and Diabetes: Their Relationship?
The prevalence of diabetes mellitus among patients with GI cancers varies depending on the tumor type. For example, the highest rate of diabetes mellitus was seen in patients with colon cancer (15.5%), rectal cancer (15.3%), and stomach cancer (14%) [123]. On the other hand, diabetes in patients can promote the progression, development, and metastasis of gastric cancers [124]. The observed association may be due to the shared risk factors between both conditions such as diet, smoking, infection, medication, obesity, and hyperglycemia [125]. More data are still needed to identify which condition comes first and whether we can predict the occurrence of one following the other. Despite this, the available data suggest a possible association between both conditions and how they may be targeted using flavonoids as a novel therapeutic agent, which might help improve the quality of the patients' lives and reduce the burden of both conditions.

Conclusions
Flavonoids are naturally occurring products found abundantly in fruits and vegetables. Upon ingestion, flavonoids are further metabolized by the gut microbiome into aglycones that exert antidiabetic and anti-GI cancer effects. Based on the current evidence, flavonoids target impaired pathways such as apoptosis and NF-κB in both conditions [126,127]. Despite this, the mechanisms by which flavonoids target the same pathway with different biological effects depending on the metabolic conditions need further research. Only limited evidence from the literature supports a potential dual effect of flavonoids.
Moreover, a combination of several flavonoids (affecting the pathology synergistically or additively) represents a promising strategy to be further evaluated to target impaired pathways. Still, more efforts are required for protocol standardization to ensure safety and effectiveness. Similarly, vitexin, an apigenin flavone glucoside, exerts beneficial effects in high glucose-induced endothelial cells via inhibition of apoptosis and oxidative stress, thus suggesting the potential effectiveness of vitexin in cardiovascular complications of diabetes. Specifically, vitexin decreased apoptosis via the disruption of Wnt/β-catenin and Nrf2, decreased ROS and malondialdehyde content, and increased superoxide dismutase activity in HG-mediated HUVECs [128]. In addition to isolated flavonoid compounds, extracts rich in flavonoids were also reported to influence metabolic pathways, such as Oldenlandia diffusa, which induced apoptosis via ROS accumulation, mitochondrial membrane potential loss, and activation of mitochondrial pathway in gastric cancer in vitro and in vivo [129]. In this regard, a lack of understanding of flavonoids' complex mechanisms of action, non-specific selectivity, and low bioavailability in organisms markedly impedes their pharmacological administration in clinical practice. Mentioned obstacles could be overcome using progressive methodological approaches in medicine, i.e., designing nano-engineering systems to achieve the delivery of flavonoids into targeted organs and tissues. Such techniques could improve flavonoids' efficacy and pharmacokinetic properties in diabetic cancer patients.
Our paper provides a theoretical base for advancing highly effective and low-toxicity flavonoid-based pharmaceutical molecules or their mixtures to target complex signaling pathways associated with diabetes and cancer concurrently. However, only precisely designed and well-controlled clinical evaluations of the context of the antidiabetic and anti-cancer effects of bioactive flavonoids could establish the role of these polyphenolic compounds as beneficial agents in diabetic and GI cancer patients.

Conflicts of Interest:
The authors declare no conflict of interest.