Spice-Derived Bioactive Ingredients: Potential Agents or Food Adjuvant in the Management of Diabetes Mellitus

Spices possess tremendous therapeutic potential including hypoglycemic action, attributed to their bioactive ingredients. However, there is no study that critically reviewed the hypoglycemic potency, safety and the bioavailability of the spice-derived bioactive ingredients (SDBI). Therefore, the aim of the study was to comprehensively review all published studies regarding the hypoglycemic action of SDBI with the purpose to assess whether the ingredients are potential hypoglycemic agents or adjuvant. Factors considered were concentration/dosages used, the extent of blood glucose reduction, the IC50 values, and the safety concern of the SDBI. From the results, cinnamaldehyde, curcumin, diosgenin, thymoquinone (TQ), and trigonelline were showed the most promising effects and hold future potential as hypoglycemic agents. Conclusively, future studies should focus on improving the tissue and cellular bioavailability of the promising SDBI to achieve greater potency. Additionally, clinical trials and toxicity studies are with these SDBI are warranted.


INTRODUCTION
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia resulting from the malfunction in insulin secretion and/or insulin action, both leading to impair metabolism of carbohydrates, lipids, and proteins (ADA, 2015). The prevalence of DM is increasing exponentially to over 425 million people globally, and this figure is likely to rise to 629 million by 2045 (IDF, 2017;Ogurtsova et al., 2017).
At present, the most prominent approach to control DM involves the use of oral synthetic hypogycemic drugs such as sulphonylureas, biguanide, α-glucosidase, and dipeptidyl peptidase-4 (DPP-4) inhibitors. However, these drugs have characteristic profiles of short-and/or long-term side effects, which include hypoglycemia, weight gain, gastrointestinal discomfort and nausea, liver and heart failure (Hung et al., 2012). Additionally, the drugs are costly in the developing countries especially in Asia and African regions. These limitations have prompted the search for potent plant-derived bioactive ingredients as possible alternative therapies for DM. The target is to identify newer compounds that could attenuate hyperglycemia, ameliorate the diabetes associatedcomplications with fewer adverse effects. These can be standardized and used as the drugs for the treatment of DM.
Spices add flavor, taste, and color in food preparation and most importantly, consumption of spices provide infinite health benefits to humans. Considerable evidence has shown that spices play a vital role in ameliorating DM complications and were documented in several reviews (Khan and Safdar, 2003;Kelble, 2005;Srinivasan, 2005;Mohamed, 2014;Kazeem and Davies, 2016;Bi et al., 2017). However, most of the available reviews focused on the extracts derived from the spices. Although some of the reviews highlighted the hypoglycemic roles of the bioactive ingredients derived from the spices (Upaganlawar et al., 2013;Zhang et al., 2013;Semwal et al., 2015), the critical assessment of their hypoglycemic potency based on the concentration/dose has not yet been well documented. The exaggerations of the data obtained from in vitro and in vivo studies are of concerns. In other words, whether these active ingredients are potential hypoglycemic agents or adjuvants, not clear at all. On the other hand, the lack of bioavailability is the major factor affecting the overall bioactivity of the spicederived bioactive ingredients (SDBI) Yao et al., 2015). Therefore, we intended to comprehensively review all the published studies on the hypoglycemic action of SDBI with critical assessment whether the ingredients are potential hypoglycemic agents or adjuvants. In addition, future prospects, safety and the progress made on the methods used to improve the bioavailability of the promising SDBI were included in this review as well.

METHODOLOGY
In the present study, we considered the SDBI as potential hypoglycemic agents based on multiple citations that showed >50% blood glucose reduction potential at non-toxic dosages. The potent hypoglycemic action using in vitro models (lower IC 50 values) and less toxicity associated with the target compounds were also considered in this study. The hypoglycemic roles of the SDBI were categorized and presented based on in vitro (  Table 2) studies. Additionally, proposed hypoglycemic mechanisms depicted by the promising SDBI are presented in Figure 1.

S-Allyl Cysteine and Its Derivatives
In vitro Studies Diallyl trisulfide (DATS) an organosulfur from garlic (Allium sativum L.) at various concentrations (1-5 µM) suppressed high glucose-induced cardiomyocyte apoptosis via inhibition of NADPH oxidase, reactive oxygen species (ROS) production and downregulated JNK/NF-κB signaling in H9c2 cells (Kuo et al., 2013). This shows the potential of DATS in the management of diabetes-associated inflammation.
Oral administration of alliin [S-allyl cysteine sulfoxide (SACS)] and S-methyl cysteine sulfoxide (SMCS) at 200 mg/kg bw for 30 days decreased FBG by 44.5 and 38%, respectively in alloxan-induced diabetic rats (Sheela et al., 1995). Furthermore, alliin, a sulfoxided from garlic, decreased serum glycosylated hemoglobin, the activities of phosphatases, lactate dehydrogenase and glucose-6-phosphatase enzymes and increased serum insulin level, liver and intestinal HMG-CoA reductase and hexokinase activities in alloxan-induced diabetic rats (Sheela and Augusti, 1992;Augusti and Sheela, 1996). Conversely, consumption of diallyl diasulfide (DADS) and DATS (40-80 mg/kg bw) for 16 or 3 weeks showed no effects on FBG in STZ-induced diabetic rats (Liu et al., 2005(Liu et al., , 2006. Interestingly, treatment of DATS (40 mg/kg bw) for 16 days reduced the expression of phosphorylated JNK and NF-κB, and active caspase 3 in cardiac myocytes of STZ-induced diabetic rats (Kuo et al., 2013). This supports the in vitro data published by Kuo et al. (2013) and further showed DATS ability to ameliorate diabetes-induced elevation of inflammatory mediators such as tumor necrosis factoralpha (TNFα) in the muscles. Additionally, oral administration of S-allyl-mercapto-captopril (alliin and Captopril conjugate) at 53.5 mg/kg bw for 55 days reduced FBG (42%) and blood pressure in Cohen-Rosenthal diabetic hypertensive rats (Younis et al., 2010). Allicin (derived from hydrolysis of alliin) at 250 mg/kg bw decreased blood glucose levels and improved glucose tolerance after 4 h post-administration period in alloxan-induced diabetic rabbits (Mathew and Augusti, 1973).

Toxicity
Based on the present literature search, studies on the detail toxicities associated with organosulfur compounds under study are scanty. However, Rao and Natarajan (1949) reported the subcutaneous and intraperitoneal LD 50 of allicin are 5 and 20 mg/kg bw, respectively.

Recommendation
According to the above-mentioned studies, the spice-derived sulfur containing ingredients showed their hypoglycemic effects not only by decreasing FBG, oxidative stress, inflammatory biomarkers but also by increasing insulin secretion and improving glucose tolerance and glucose metabolism-related enzyme activities. However, based on the levels of hypoglycemic potential of sulfur containing compounds and their derivatives, these compounds (SAC, SMCS, SACS, DADS, DATS, and allicin) cannot be considered as hypoglycemic agents but only as adjuvants.
Notably, administration of capsaicin (10 µg/kg bw) for 20 weeks prevented the onset of type 1 diabetes in a non-obese diabetic mouse model, attributed to the attenuation of antigenspecific T-cells in pancreatic lymph nodes (Nevius et al., 2012). Conversely, animals treated with other dosages (0.1, 1.0, 25.0, and 50.0 µg/kg bw) were hyperglycemic throughout the study period, which is a subject for further studies. More recently, dietary inclusion of capsaicin (0.014-0.1%) for 12 weeks decreased serum and tissue advanced glycation end products (AGEs) and activated the receptor for AGEs (RAGE) in STZ-induced diabetic rats (Hsia et al., 2016). However, the reduction of FBG in the capsaicin-treated groups was not significant compared to the diabetic untreated group (Hsia et al., 2016). This further supports the previous studies that capsaicin administration (0.015%) has no effect on the blood glucose level in the same animal model (Babu and Srinivasan, 1997a;Suresh Babu and Srinivasan, 1998). Furthermore, the dietary inclusion of capsiate (0.025%/7 weeks), a non-pungent capsaicin analog, improved glucose tolerance ability (28%) via improving insulin sensitivity in pancreatectomized diabetic rats .

Clinical Trials
In a randomized, double-blind, placebo-controlled trial, oral administration of capsaicin (5 mg/day) for 4 weeks attenuated insulin resistance and dyslipidemia with no significant effect on FBG in women with gestational diabetes . In addition, topical application of capsaicin (0.075%) for 8 weeks ameliorated painful diabetic neuropathy in diabetic patients (Scheffler et al., 1991;Tandan et al., 1992;Biesbroeck et al., 1994;Forst et al., 2002).

Toxicity
The oral LD 50 values of capsaicin were within the ranges 90-162 mg/kg bw for mice and rats (Saito and Yamamoto, 1996). However, the intraperitoneal, intravenous, and subcutaneous LD 50 values for mice were 7.65, 0.56, and 9 mg/kg bw in mice, indicating possible toxicity (Glinsukon et al., 1980). To further support this, some adverse consequences of capsaicin consumption reported include nausea, vomiting, abdominal pain, burning diarrhea, intense tearing and conjunctivitis (Goldfrank, 2002;Millqvist et al., 2005). Additionally, Marques et al. (2002) have reported that people consuming capsaicin (90-250 mg/day) are more susceptible gastrointestinal cancer compared to the subjects consumed lesser doses of capsaicin (0-29.9 mg/day).

Recommendation
From the above-mentioned studies, although capsaicin showed mild to moderate hypoglycemic activity by inhibiting glucose digesting enzymes activities, improving glucose uptake, decreasing insulin resistance, dyslipidemia, advanced glycation endproducts; the reduction of FBG and hyperglycemia was not promising. Therefore, it may not be a good candidate for DM therapy. Our argument is that none of the studies reported >50% reduction of blood glucose levels despite several weeks of administration. Additionally, capsaicin consumption showed weak antihyperglycemic effect in women with gestational diabetes . The toxicities associated with capsaicin consumptions are another great concern. Despite intraperitoneal administration conferred higher action compared to the oral administration, it was more susceptible to adverse consequences and hence should be discouraged. However, capsaicin topical application is encouraged to reduce some complications associated with diabetic neuropathy as this was validated in some clinical trials (Scheffler et al., 1991;Tandan et al., 1992;Biesbroeck et al., 1994;Forst et al., 2002). This justified the use of capsaicin as adjuvant in the management of DM, particularly diabetic neuropathy.

In vivo Studies
Oral administration of cinnamaldehyde (5-20 mg/kg bw) for 45 days reduced FBG (63.3%), lipid accumulation and showed insulinotropic action in STZ-induced diabetic rats (Subash Babu et al., 2007). Interestingly, the same authors have recently reported a more potent FBG reduction (71%) while used the same doses, study period and animal models (Subash Babu et al., 2014). The potent antihyperglycemic action of cinnamaldehyde was linked to the upregulation of GLUT4 protein expression that may facilitate the transport of glucose across the cells (Zhang et al., 2008;Anand et al., 2010;Jawale et al., 2016). Importantly, Zhang et al. (2008) showed a 62% reduction of FBG and improved insulin sensitivity in pancreatic β-cell upon cinnamaldehyde (40 mg/kg bw) consumption in a high-fat diet-fed STZ-induced diabetic rat model. This was supported even at a lower dosage of cinnamaldehyde (143.8 µmol/kg bw) for 4 weeks in high-fatdiet-induced insulin resistant rats (Farrokhfall et al., 2014), and thus, corroborates with the in vitro studies Li et al., 2015).
Ghrelin a hunger hormone, participate in the regulation of glucose and insulin metabolism. The plasma ghrelin levels are shown to correlate inversely with insulin levels and are associated with insulin resistance and could be a potential target to reduce the progression of type 2 diabetes (Pulkkinen et al., 2010;Tong et al., 2010). Conforming to this, dietary inclusion of cinnamaldehyde (0.2%) for 36 days retarded the endogenous ghrelin release and reduced FBG (10%) in C57BL6 diabetic mice (Camacho et al., 2015).

Toxicity
The low toxicity associated with cinnamaldehyde consumption in rodents via oral route has been well documented Sporn et al., 1965;Zaitsev and Rakhmanina, 1974;Subash Babu et al., 2007). Seemingly, Hooth et al. (2004) reported that the safety of cinnamaldehyde was approved by the Food and Drug Administration (FDA) and has been given Generally Recognized as Safe (GRAS) status in the United States. However, Weibel and Hansen (1989) have reported that cinnamaldehyde elicits some carcinogenic risk by acting as an alkylating agent that could react with cellular macromolecules.

Recommendation
According to the results of the above-mentioned studies, cinnamaldehyde is a potential hypoglycemic agent and adjuvant. Several studies have shown that cinnamaldehyde reduced FBG by >50% at 20 or 40 mg/kg bw in various animal models (Subash Babu et al., 2007Babu et al., , 2014Zhang et al., 2008;Kumar et al., 2012). Regarding the in vitro studies, this ingredient showed potent hypoglycemic potential at <10 µg/ml or µM and depicted IC 50 values of <10 µg/ml as well Kumar et al., 2012). These are of interest in the drug discovery as small amount of the compound stimulated beneficial action in various models. Additionally, the less toxicity associated with cinnamaldehyde intake is of significance in drug design and development. However, the lack of clinical trials with cinnamaldehyde is a major drawback in determining its exact hypoglycemic potential in human subjects. Hence, further studies, particularly clinical studies, are warranted to confirm the hypoglycemic effects of cinnamaldehyde in humans.

In vivo Studies
Several studies have reported the hypoglycemic effect of curcumin using various animal models. Babu and Srinivasan (1997b); Suresh Babu and Srinivasan (1998) have shown that dietary supplementation of curcumin (0.5%) for 8 weeks attenuated hyperlipidemia and renal dysfunction in STZ-induced diabetic rats. Conversely, the authors reported no reduction on the FBG levels in the treated diabetic rats which is consistent with some previous studies Palma et al., 2014). However, the above-mentioned studies have reported potent antioxidant action in the same model which is in line with some previous studies (Sajithlal et al., 1998;Rungseesantivanon et al., 2010;Gupta et al., 2011). These effects of curcumin are in line with the results of in vitro studiesas presented above (Zheng and Chen, 2004;Jain et al., 2006Jain et al., , 2009Masamune et al., 2006;Kanitkar et al., 2008;Lin et al., 2009;Lin and Chen, 2011).
Oral administration of curcumin (15 or 30 mg/kg bw) for 6 weeks reduced FBG (24.4%) and attenuated renal dysfunction at the maximum dosage administered in STZ-induced diabetic rats (Sharma et al., 2006). Similarly, consumption of curcumin (60 mg/kg bw) for 2 weeks to the same animal model improved brain stem function attributed to the regulations of cholinergic, insulin receptor and GLUT-3 in the brain stem (Peeyush et al., 2009;Kumar P. T. et al., 2013). Curcumin treatment for 10 weeks ameliorated hyperglycemia (44.3%), cognitive deficit, cholinergic dysfunction, oxidative stress and inflammation in the same animal model and dosage (Kuhad and Chopra, 2007). Furthermore, Awasthi et al. (2010) have reported that oral administration curcumin (10-50 mg/kg bw) for 3 weeks provented intracerebral STZ-induced impairment in memory and cerebral blood flow. Chiu et al. (2009) showed that curcumin treatment (150 mg/kg bw) for 4 weeks reduced FBG and downregulated the expression of p300 and nuclear factor-κB in STZ-induced diabetic rats. Oral administration of curcumin (200 mg/kg bw) for 2 weeks demonstrated anticholinesterase and antioxidant actions and attenuated diabetes-induced dementia in rats (Agrawal et al., 2010;Chanpoo et al., 2010;Mahfouz, 2011). This is in line with the previous data that curcumin protects pancreatic islets from cytokine-induced cell death via scavenging ROS and decreasing cytokine-induced NF-kB translocation (Kanitkar et al., 2008).
Administration of tetrahydrocurcumin (THC) a curcumin derivative (80 mg/kg bw) for 45 days reduced FBG (55%) and conferred potent antioxidant potential in STZ-induced diabetic rats (Karthikesan et al., 2010a,b). The effect was higher (67%) when co-administered with chlorogenic acid (5 mg/kg bw). This has indicated possible synergy with chlorogenic acid and warrant further study to understand the synergistic mode of interaction of THC and chlorogenic acid. Murugan and Pari have shown that administration of THC at the same dose and study period reduced FBG by 60% compared to 54.4% for curcumin (Pari and Murugan, 2005Pari, 2006a,b, 2007;Murugan et al., 2008). Additionally, a potent antihyperlipidemic, insulinotropic and antioxidant actions in diabetic rat models were also reported by the authors. This shows that the reduction of the FBG by the THC and curcumin is not significant and, Kanitkar et al. (2008) have reported a 69% reduction by the curcuim alone within short study period.

Clinical Trials
Chuengsamarn and colleague reported that daily administration of curcumin at 250 mg for 6 and 9 months improved insulin action and lowered atherogenic risks in type 2 diabetic patients (Chuengsamarn et al., 2012(Chuengsamarn et al., , 2014. Previously, Usharani et al. (2008) reported that intake of curcumin capsules (150 mg) twice daily for 8 weeks to type 2 diabetic patients showed improved antioxidative status comparable to that of atorvastatin. Neerati et al. (2014) have recently reported that ingestion of curcumin (475 mg) for 10 day attenuated hyperglycemia and hyperlipidemia in type 2 diabetic patients. These studies compliment the in vitro and in vivo data despite lack of detail hypoglycemic potential in human subjects and signify the greater potential of curcumin in diabetes management.

Toxicity
Considerable amount of data is available, demonstrating curcumin safety and tolerability at the high doses (12 g/day) in several animal models (Lao et al., 2006a,b) and human subjects (Shankar et al., 1980;Chainani-Wu, 2003;Hsu and Cheng, 2007). However, some studies have shown that curcumin and its derivatives may cause hepatotoxicity, skin irritation and stomach ulcers when taken in high doses or for a prolonged period (Babu and Srinivasan, 1997b;Kandarkar et al., 1998;Balaji and Chempakam, 2010). Therefore, it is suggested that curcumin consumption at lower doses has no potential side effects. To further support this daily consumption of curcumin (500 mg) for 2 months was reported not to cause any adverse consequences in humans, except mild nausea and diarrhea (Hsu and Cheng, 2007;Chandran and Goel, 2012).

Recommendation
From the above-mentioned studies, it is evident that curcumin is the most investigated SDBI. Interestingly, numerous studies have reported FBG reduction of >50% with potent amelioration of diabetes-induced damages in various animal models without noticeable toxicity (Mahesh et al., 2004(Mahesh et al., , 2005Pari, 2006a,b, 2007;Pari and Murugan, 2007b;Kanitkar et al., 2008;Murugan et al., 2008;Gutierres et al., 2012). To further support this, several in vitro studies have shown the potent curcumin hypoglycemic potential at concentrations even <10 µM (Best et al., 2007;Jain et al., 2006;Cheng et al., 2009;Wang et al., 2009;Kang and Kim, 2010). The less toxicity of curcumin intake in humans is encouraging and is of pharmacological interest as well.

In vitro Studies
Diosgenin is a steroidal saponin and dietary ingredient from popularly consumed spice fenugreek (Trigonella foenumgraecum L.). Based on the current literature search, the information regarding the hypoglycemic potential of diosgenin in vitro is scanty. Liu et al. (2012) have reported that diosgenin (0.1-10 µM) attenuated insulin resistance associated endothelial dysfunction via inhibition of IKKβ and IRS-1 pathways in human umbilical vein endothelial cells (HUVECs). However, Fang et al. (2016) have recently linked the inhibition of insulin resistance to increase expression of the phosphorylated estrogen receptor-α (Erα), sarcoma (Src), Akt/protein kinase B and glycogen synthase kinase-3β (GSK-3β). The above data have demonstrated the diosgenin potential in amelioration of diabetes-associated insulin resistance.

In vivo Studies
Dietary inclusion of diosgenin (10 g/kg bw) for 3 weeks reduced FBG (33.4%) and ameliorated dyslipidemia via modulation of Na + -K + -ATPase and increasing Ca 2+ ATPase activities in STZ-induced diabetic rats (McAnuff et al., 2002(McAnuff et al., , 2005. The increased action of the ATPases has direct effect on insulin, which plays major role in blood glucose regulation. Interestingly, oral administration of diosgenin (10-60 mg/kg bw) for 2 weeks decreased FBG (58%), elevated plasma insulin levels and tissue hexokinase activity with subsequent attenuation of oxidative stress in STZ-induced diabetic rats (Pari et al., 2012;Sangeetha et al., 2013;Saravanan et al., 2014). In another study, dietary inclusion of diosgenin (0.5 or 2%) for 4 weeks improved glucose tolerance ability as well as insulin sensitivity in high-fat diet-fed KK-Ay/Ta Jcl obese diabetic mice (Uemura et al., 2010).
In coherence with this finding, Naidu et al. (2015) have reported a 62.6% FBG reduction and amelioration of insulin resistance and hyperlipidemia after 30 day administration of diosgenin (60 mg/kg bw) in the same animal model. To further support this, diosgenin (10 mg/kg bw) treatment showed 70% reduction of FBG, improved antioxidant status and insulin levels in STZ-induced diabetic rats (Kalailingam et al., 2014). The higher hypoglycemic action of diosgenin was previously attributed to the reduction of serum levels of cytokines, and adipokines as well as increased PPARγ levels, implying the insulin-sensitizing potential of diosgenin in diabetic condition (Tharaheswari et al., 2014). In another study, oral treatment of diosgenin (40 mg/kg bw) for 7 weeks mitigated vascular dysfunction in STZ-induced diabetic rats (Roghani-Dehkordi et al., 2015). More recently, consumption of diosgenin (40 mg/kg bw) for 45 days decreased FBG (55%) and attenuated hyperlipidemia via inhibition of HMG-CoA reductase activity in STZ-induced diabetic rats (Hao et al., 2015).

Toxicity
Despite the fact that the detail toxicity studies of diosgenin has not been well documented, the oral LD 50 was reported to be >8,000 mg/kg bw in rats (Ryndina et al., 1977). Furthermore, available toxicity studies on some animal models have shown that diosgenin (3.5% w/w) was safe and did not cause any toxicity in the treated animals (Raju and Rao, 2011).

Recommendations
Based on the results of the above-mentioned studies, diosgenin could be regarded as a potential hypoglycemic agent although clinical studies are required to fully confirm its hypoglycemic potential. Regardless of the few data available, diosgenin was observed to reduce FBG by >50% in several diabetic animal models and ameliorated diabetes-associated complications at non-toxic dosages (Pari et al., 2012;Sangeetha et al., 2013;Kalailingam et al., 2014;Saravanan et al., 2014;Hao et al., 2015;Naidu et al., 2015). Additionally, the potent attenuation of insulin resistance and hyperlipidemia at a concentration <10 µM is quite promising (Uemura et al., 2010;Liu et al., 2012;Sangeetha et al., 2013). Furthermore, despite few data regarding the safety issues associated with diosgenin consumption, the less toxic effect reported (LD 50 : >8,000 mg/kg bw) associated with diosgenin is of a great interest.

In vivo Studies
Dietary supplementation of eugenol (200 mg/kg bw) for 2 weeks attenuated nerve and vascular dysfunction with no significant reduction of FBG in STZ-induced diabetic rats (Nangle et al., 2006). However, Mnafgui et al. (2013) have shown 62.5% reduction of FBG with potent antioxidant potential when eugenol (80 mg/kg bw) was administered orally for 30 days in alloxan-induced diabetic rats. Srinivasan et al. (2014) have reported that eugenol (2.5-10 mg/kg bw) treatment for the same study period demonstrated antihyperglycemic and antioxidant potential in STZ-induced diabetic rats. The highest reduction of FBG was about 70.6% with improved activities of key enzymes (hexokinase, pyruvate kinase, glucose-6phosphatedehydrogenase, glucose-6-phosphatase, fructose-1,6bisphosphatase) related to carbohydrate metabolism (Srinivasan et al., 2014).
In another study, oral administration of eugenol at 20 and 40 mg/kg bw for 15 weeks reduced FBG by 20 and 28.6%, respectively in high fat-fed C57BL/6J mice (Jeong et al., 2014). Furthermore, oral administration of eugenol (10 mg/kg bw) for 5 days or 6 weeks showed maximum reduction of FBG by 38% and improved the in vivo antioxidant status of STZinduced diabetic rats (Prasad et al., 2015;Singh et al., 2016). This variation could be linked to the different animal models used. On the other hand, Rauscher et al. (2001) have reported that intraperitoneal treatment of isoeugenol (10 mg/kg bw) for 2 weeks did not show any antihyperglycemic effect in STZ-induced diabetic rats. Additionally, a moderate antioxidant potential was reported in the treated animals, indicating weak hypoglycemic potential (Rauscher et al., 2001).

Recommendations
Based on the above studies the potential of eugenol as hypoglycemic agent is not consistent and thus, need further extensive studies to establish the potency of eugenol hypoglycemic action. However, some studies highlighted >60% FBG reduction at non-toxic dosages (<1,000 mg/kg bw) and attenuation of diabetes-induced complications which are quite encouraging (Mnafgui et al., 2013;Srinivasan et al., 2014;Prasad et al., 2015). Therefore, according to the current literature, the above-mentioned studies have shown the potential of eugenol as adjuvant in the diabetes management.

In vitro Studies
Galactomannan is a heterogeneous water-soluble polysaccharide from fenugreek with a structural similarity to standard hypoglycemic drug, acarbose. Galactomannan (0.1 and 0.5% w/w) was reported to reduce intestinal glucose uptake in isolated intestine of lean and obese rats and thus improve glycemia (Srichamroen et al., 2009). Furthermore, galactomannan enhanced glucose uptake (51.9%) in isolated hemidiaphragm of treated alloxanized rats (Anwar et al., 2009). Kashef et al. (2008) have shown that galactomannan (200 mg/ml) inhibited the α-amylase activity. This imply that galactomannan could be beneficial in amelioration of post-prandial hyperglycemia in diabetes.

In vivo Studies
Dietary inclusion of galactomannan (2.5 and 5% w/w) attenuated post-prandial hyperglycemia, hyperlipidemia and abdominal fat deposit in high sucrose-fed rats (Srichamroen et al., 2008). Oral administration of galactomannan to STZ-induced diabetic rats inhibited maltase, lactase and sucrase activities in the small intestine of treated rats (Hamden et al., 2010). These studies support the in vitro data and further confirm the amelioration of post-prandial hyperglycemia by the galactomannan. In another study, oral administration of galactomannan (250-500 mg/kg bw) for 3 weeks reduced FBG (59.4%) and improved serum insulin levels in alloxan induced diabetic rats (Al-Fartosy, 2015). However, a reduction of about 40% on FBG level and improved antioxidant potential were reported upon 2 h post-administration of galactomannan (500 mg/kg bw) in the same animal model . Kandhare et al. (2015) have reported that chronic consumption of galactomannan (60 and 100 mg/kg bw) for 12 weeks ameliorated hyperglycemia (50%) and insulin resistance in C57BL/6 mice.

Toxicity
Galactomannan was reported to be safe up to 8 g/kg with no deleterious effects after 3 days post-administration period (Anwar et al., 2009;Al-Fartosy, 2015). This was similarly reported even after repeated doses for 90 days (Deshpande et al., 2016a). To further support the galactomannan safety, oral administration during gestation induced no significant maternal and embryofetal toxicity up to 1,000 mg/kg bw in rats (Deshpande et al., 2016b).

Recommendations
Studies above have shown that little information are available regarding the hypoglycemic potential of galactomannan and thus strenuous to make logical conclusion. However, our observations showed that some studies used galactomannan at high dosages (500 mg/kg bw) or concentrations (200 mg/ml) in addition to being a high molecular weight molecule, signifying weak hypoglycemic action. Therefore, more detail studies are required to fully evaluate the hypoglycemic action of galactomannan both in humans and experimental animal models.
Li and co-authors have reported that gingerols (50-150 µM) enhanced glucose uptake in L6 myotubes and muscle C2C12 cells, attributed to an increased surface availability of GLUT4 protein and by activation of AMPK in the cells Li et al., 2013;Son et al., 2015). Available studies have shown that diabetes leads to an increase accumulation of βamyloid, a major component of senile plaques, leading to β-cell dysfunction and failure (Maher and Schubert, 2009;Takeda et al., 2011;Luo et al., 2016). Interestingly, [6]-gingerol (2.5-20 µM) attenuated β-amyloid-induced oxidative cell death in SH-SY5Y neuroblastoma cells .
Furthermore, in a number of previous studies, [6]-gingerol was shown to play a beneficial role in reducing lipid accumulation in 3T3 cells via downregulating PPARγ and decreasing Akt/GSK3β pathway (Isa et al., 2008;Tzeng and Liu, 2013;Tzeng et al., 2014;Choi et al., 2016;Suk et al., 2016). Reducing lipid accumulation may delay the onset and progression of insulin resistance in diabetes.

Toxicity
Fewer data are available regarding the potential toxicity associated with the intake of [6]-gingerol and its derivatives. Consumption of [6]-gingerol (20-80 µM) induced genotoxicity, lysosomal and mitochondrial damage in human hepatoma G2 (HepG2) cells (Yang et al., 2010). However, consumption of either [6]-gingerol or [6]-shogaol (2,000 mg) for 4 days was reported not to cause any potential toxicity in human subjects and are well tolerated (Zick et al., 2008). On the other hand, the LD 50 of zingerone was reported to be 1,000 mg/kg bw (Rao et al., 2009).

Recommendations
From the above-mentioned studies, it is obvious that information regarding the hypoglycemic potential and toxicity of [6]-gingerol and its derivatives are scanty and that makes the overall comment inconclusive. Moreover, according to the data, [6]gingerol showed higher hypoglycemic potential compared to its derivatives Namekata et al., 2013;Sampath et al., 2016;Mohammed et al., 2017). Therefore, more studies are required on [6]-gingerol and notwithstanding, these compounds could be regarded as hypoglycemic adjuvant as reported in the above-mentioned studies.

Toxicity
Oral LD 50 value of 4-OH-Ile was reported to be >5 g/kg bw indicating that consumption of 4-OH-Ile has no potential toxic effect (Shah et al., 2009).

Recommendations
Our candid opinion here is that 4-OH-Ile did not show a significant hypoglycemic action despite long administration period. However, based on the available data, 4-OH-Ile is insulinotropic and could be used in combination with other drugs to attenuate diabetes-induced oxidative damage, and hence regarded as an adjuvant. Most importantly, detail toxicological studies are required to evaluate the safety of 4-OH-Ile both in humans and experimental animals.

In vitro Studies
Piperine is the major alkaloid responsible for the pungency of black pepper (Piper nigrum L.).  have reported that piperine showed weak inhibition toward αlipase (IC 50 : 2,490 µg/ml), α-glucosidase (IC 50 : 2,550 µg/ml) and aldose reductase (IC 50 : 2,375 µg/ml) activities. Inhibition of the activities of these enzymes signify its potential in attenuating diabetes-associated complications. Kharbanda et al. (2016) have reported that piperine (36 mg/kg bw) isolated from black pepper demonstrated antihyperglycemia in STZ-induced diabetic rats by acting as PPAR-γ agonists. Interestingly, Atal et al. (2016) have shown that co-administration of piperine (10 mg/kg bw) with metformin for 4 weeks reduced FBG (40%) compared to metformin alone (19%) in STZ-induced diabetic mice, indicating synergistic effect between the two drugs. Furthermore, weak reduction on FBG was observed upon administration of piperine (10-50 mg/kg bw) for the same study period and model (Rauscher et al., 2000;Kharbanda et al., 2016). However, the levels of serum insulin, lipid profiles and antioxidant enzymes were significantly improved. Oral administration of piperine (20 or 40 mg/kg bw) for 11 weeks ameliorated hyperglycemia (40%) and oxidative damage in STZ-induced diabetic rats (Arcaro et al., 2014). On the other hand, several studies have reported the beneficial effect of piperine in reducing hyperglycemia and attenuating oxidative stress in high-fat diet rats (Vijayakumar et al., 2004;Shah et al., 2010;Bao et al., 2012;BrahmaNaidu et al., 2014).

Toxicity
The safety aspect of piperine has been controversial. Piyachaturawat et al. (1983) have reported that the LD 50 values of piperine via different route are in the order intravenous (15.1 mg/kg bw) < intraperitoneal (43 mg/kg bw) < subcutaneous (200 mg/kg bw) < intragastric (330 mg/kg bw) < intramuscular (400 mg/kg bw). The authors further showed that almost all the animals that received a lethal dose (>LD 50 ) died from respiratory complications in <20 min. However, during sub-chronic study, the death occurred within l−3 days after post-administration period. Some of the histopathologic alterations observed include severe hemorrhagic necrosis and edema in GIT, urinary bladder and adrenal glands (Piyachaturawat et al., 1983). Additionally, its toxic effect has been attributed to its structural similarity with some known carcinogens such as safrole, estragole, and methyleugenol (Ames, 1983). On the other hand, consumption of piperine orally (170 mg/kg bw) or intraperitoneally (85 mg/kg bw) did not cause any adverse consequences in rats, with 3% excreted as piperine in the feces (Bhat and Chandrasekhara, 1986).

Recommendations
The information derived from the above-mentioned studies revealed that piperine is a weak hypoglycemic agent despite longer administration period. None of the studies have shown up to 50% reduction on blood glucose levels. The higher IC 50 value depicted toward α-glucosidase and aldose reductase inhibitions indicated weak hypoglycemic action as well. Another major concern is the contradiction on the safety issues regarding pure piperine consumption. However, piperine could be regarded as food adjuvant in the management of diabetes based on the potent antioxidant action observed in the above-mentioned studies. Additionally, the use piperine as a naturally-based bio-enhancers to some drugs is receiving much attention and yielding fruitful results (Moorthi and Kathiresan, 2013;Arcaro et al., 2014).

Toxicity
Tremendous efforts were made to assess the toxicological properties of TQ using various in vitro and in vivo models (El-Dakhakhny, 1965;Badary et al., 1998;Mansour et al., 2001;Al-Ali et al., 2008;Khader et al., 2009;Qadri et al., 2009;Abukhader, 2012). The LD 50 of TQ in rats via oral and intraperitoneal administration were 794.3 and 57.5 mg/kg, when in mice the values were 870.9 and 104.7 mg/kg through oral and intraperitoneal route, respectively (Al-Ali et al., 2008). Previously, Badary et al. (1998) have shown that the acute LD 50 value in mice was 2.4 g/kg bw via oral ingestion of TQ. This indicates the relatively low toxicity of TQ since the LD 50 values were >10 and >100 times higher than the therapeutic dosages for TQ via intraperitoneal and oral routes, respectively. However, few signs of the toxicity such as hypoactivity and difficulty in respiration were observed after acute oral administration of TQ in rats (Badary et al., 1998).
Moreover, sub-chronic administration of TQ (35 and 50 mg/kg bw) induced disruption on embryonic development during the second trimester of rat pregnancy (Abukhader, 2012). Conversely, TQ (30-90 mg/kg bw/day) administration for 3 months caused no mortality or sign of toxicity in mice (Badary et al., 1998). Interestingly, Al-Amri and Bamosa (2009) have reported that oral ingestion of TQ for 3 weeks did not show any potential toxicity and was well tolerated up to dose of 2,600 mg/kg bw in human subjects. However, according to the authors TQ administration showed no therapeutic potential up to the maximum dosage used (Al-Amri and Bamosa, 2009).

Recommendations
Based on the above-mentioned studies, TQ possessed blood glucose lowering potential and could be used to attenuate diabetes-induced complications despite lack of relevant clinical trials. Our rationale is that TQ demonstrated hypoglycemic potential at 3-50 mg/kg bw in animal models (Hamdy and Taha, 2009;Pari and Sankaranarayanan, 2009;Roghani and Baluchnejadmojarad, 2012) and depicted IC 50 value <10 µM at the concentrations (10-50 µM) in addition to stimulating insulin release at 2.5 µM (Chandra et al., 2009). Moreover, most of the studies have reported more than 50% reduction on blood glucose levels and potent antioxidant actions (Fararh et al., 2005(Fararh et al., , 2010Hamdy and Taha, 2009;Pari and Sankaranarayanan, 2009;Roghani and Baluchnejadmojarad, 2012;Fouad and Alwadani, 2015;Sangi et al., 2015). However, lack of detail hypoglycemic and toxicity studies in human subjects are the major concerns.

Clinical Trials
Ingestion of trigonelline (500 mg) reduced blood glucose by about 7% and improved glucose tolerance after 15 min posttreatment period in overweight subjects (Van Dijk et al., 2009). The hypoglycemic action was found not to be dependent on the incretin hormones glucagon-like peptide 1 (GLP-1) or glucosedependent insulinotropic peptide (Olthof et al., 2011).
Toxicity Aswar et al. (2009) have shown that oral consumption of trigonelline was safe up to 5,000 mg/kg bw with no noticeable abnormal behavior in rats.

Recommendations
As per data from the above studies, trigonelline seems to be among the promising hypoglycemic agents despite few studies which showed weak or no significant hypoglycemic potential. Longer administration period such as 4 weeks at 10-100 mg/kg bw showed potent reduction (>50%) of FBG in diabetic rats (Shah et al., 2006;Monago and Nwodo, 2010;Al-Khateeb et al., 2012;Zhou et al., 2011;Hamden et al., 2013a;Subramanian and Prasath, 2014a,b;Folwarczna et al., 2016). Additionally, a potent amelioration of diabetes-induced complications was observed even in those studies that showed weak hypoglycemic potential. The weak blood glucose lowering potential in humans could be attributed to the shorter study period (Van Dijk et al., 2009). Although few data are available regarding trigonelline toxicity, its consumption did not show any potential toxic effect in rats (Aswar et al., 2009).

Bioavailability of Spice-Derived Ingredients
Conventionally, poor bioavailability is considered as a major factor linked to the lower therapeutic efficacy of the orally consumed SDBI. Therefore, improving bioavailability of the ingredients is a promising approach in enhancing their disease preventing efficacy in humans. The oral bioavailability of SDBI entails the portion of the ingested ingredient that get in to the blood circulation in its active form. Because, only bioavailable portion will be absorbed and distributed across the tissues and organs that eventually exert its therapeutic effects. Moreover, poor solubility in gastrointestinal fluids and slow absorption rate from the GIT are the crucial factors that thwart SDBI from reaching the systemic circulation in their active forms (Yao et al., 2015).
According to our critical observation, cinnamaldehyde, curcumin, diosgenin, TQ and trigonelline are the promising hypoglycemic SDBI despite their known poor bioavailability in the physiological system. Interestingly, there has been a renewed interest in developing methods that may improve the bioavailability of the SDBI to prevent or treat human diseases such as diabetes. In this regard, we have briefly presented some fact regarding the bioavailability of these promising ingredients and the methods being used to improved their bioavailability.

Bioavailability of Cinnamaldehyde
Cinnamaldehyde is absorbed rapidly from the gut, utilized and excreted via urine, regardless of the dosages, species and sex of the animals used. Oral consumption of cinnamaldehyde was shown to be metabolized into cinnamic acid partially in the stomach and small intestine and then completely metabolized into cinnamic acid in the liver before it enters the circulation . Previously, Yuan et al. (1993) and Peters and Caldwell (1994) have reported that the intravenous administration of the various dosages of cinnamaldehyde (5-25 mg/kw bw) to F344 rats decreased blood glucose 30 min after the dose administration. The disappearance of cinnamaldehyde is attributed to the rapid oxidation to cinnamic acid in blood (about 37-60%). This is because 1.7 h half-life has been considered for cinnamaldehyde release from the protein adducts (Yuan et al., 1992). Furthermore, the authors highlighted that the blood level of cinnamaldehyde after oral consumption was maintained 1 µg/ml for 24 h (Yuan et al., 1992). More recently, the elimination time of cinnamaldehyde (125-500 mg/kg bw) were 6.7 and 1.7 h for oral and intravenous administration, respectively and the oral bioavailability of about 20% in the blood (Hooth et al., 2004).

Improving Cinnamaldehyde Bioavailability
Based on the data available, improving cinnamaldehyde bioavailability focused on three major processes including use of cinnamaldehyde derivatives or metabolites, micelle, microencapsulation and nanoparticles approaches (Hooth et al., 2004;Raffai et al., 2014;Wani et al., 2014;Jo et al., 2015). However, with the exception of using cinnamaldehyde derivatives, none of the methods was so far employed regarding the hypoglycemic potential of cinnamaldehyde either in vitro, in vivo or in human subjects. These approaches could be used to explore the hypoglycemic potential of cinnamaldehyde and therefore, warrant for further study in this regard.

Bioavailability of Curcumin
It is well-established that curcumin is poorly bioavailable and thus its pharmacological effects are compromised. The low plasma and tissue levels of curcumin has been attributed not only to its poor absorption but rapid hepatic metabolism and systemic elimination (Anand et al., 2007;Cui et al., 2009;Bansal et al., 2011). For instance, about 51 ng/ml of curcumin was detected in the serum after 4 h oral consumption of curcumin (12 g) in healthy human subjects (Lao et al., 2006b). However, Marczylo et al. (2009) showed a relatively higher distribution of curcumin (340 mg/kg bw) in plasma (16.1 ng/ml), urine (2.0 ng/ml), intestinal mucosa (1.4 mg/g), liver (3,671.8 ng/g), kidney (206.8 ng/g), and heart (807.6 ng/g) after 2 h postoral treatment. Previously, oral ingestion of curcumin (400 mg) showed about <20 µg/tissue levels in the kidney or liver, when no curcumin or trace amount was found in the urine in rats after 24 h post-administration period (Ravindranath and Chandrasekhara, 1982).
Furthermore, about 60-67% of curcumin (10-400 mg/kg bw/ 12 days) was absorbed and maintained at relatively constant amount in the circulation independent of the dose administered (Ravindranath and Chandrasekhara, 1982). In another study, administration of curcumin (0.1 g/kg bw) intraperitoneally showed tissue distribution of 177.04, 26.06, 26.90, 7.51, and 0.41 µg/g in the intestines, spleen, liver, kidneys and brain, respectively after 1 h treatment in mice (Pan et al., 1999). Regarding the curcumin metabolism, curcumin undergoes bioreduction to dihydrocurcumin and tetrahydrocucurmin which are then converted to either glucuronide or sulfate conjugates in the body system (Garcea et al., 2004).

Improving Curcumin Bioavailability
In summary, the above-mentioned studies demonstrated the poor bioavailability of curcumin. Interestingly, tremendous efforts are introduced to alternatively increases the bioavailability, prolonged circulation, better permeability, and resistance to metabolic reactions of curcumin. These processes include the use of everted sacs of rat intestines, use of adjuvant that interferes with glucuronidation and the use of liposomal curcumin (Suresh and Srinivasan, 2007;Shaikh et al., 2009). Others are the use of nanoparticles, curcumin phospholipid complex and the structural analogs of curcumin (Suresh and Srinivasan, 2007). For instance, the oral bioavailability of curcumin was reported to improve by 9-fold using nanoparticles approach (Shaikh et al., 2009). Moreover, the bioavailability of THC has been recently shown to be higher compared to the curcumin (Aggarwal et al., 2014).
However, with regard to improving hypoglycemic potential of curcumin, available literatures have shown that the use of curcumin derivatives and nanoparticles approaches were employed in some diabetic models. The hypoglycemic potential of the former has been addressed in the earlier section of this review Murugan, 2005, 2007b,?;Murugan and Pari, 2006a,b;Murugan et al., 2008;Karthikesan et al., 2010a,b;Lekshmi et al., 2012a,b). For the later, Grama et al. (2013) have reported that oral administration of nano-curcumin (2 mg/kg bw) for 11 weeks reduced FBG (37%) and delayed cataract formation in STZ-induced diabetic rats. Recently, intranasal delivery of nano-micelle curcumin for 7 days was shown to significantly promote corneal epithelial/nerve healing in STZinduced diabetic mice (Guo et al., 2016). In a randomized clinical trial, ingestion of nano-curcumin (80 mg) for 3 months reduced FBG and glycated hemoglobin by about 32 and 19%, respectively in type-2 diabetic patients (Rahimi et al., 2016).
Based on the above few studies, it is obvious that nanoparticles approach may be another option to improve the antihyperglycemic as well as hypoglycemic efficacy of curcumin when compared to the use of curcumin metabolites or derivatives as pure compounds. However, the reduction of FBG was less with curcumin nanoparticles compared to that of curcumin alone or its derivatives. Hence, further studies are required to ascertain the efficacy of curcumin nanoparticles or come up with a more improved method.

Bioavailability of Diosgenin
The therapeutic applications of diosgenin are greatly tempered due to the poor pharmacokinetics. Cayen et al. (1979) have reported that 1 µg/ml of diosgenin was recovered from the serum of human subjects that received diosgenin (3 g/day) for 4 weeks, indicating poor absorption and bioavailability of diosgenin. Furthermore, oral bioavailability of diosgenin was highlighted to be 6% in rats and aqueous solubility was found to be 0.95 µg/ml (Okawara et al., 2010(Okawara et al., , 2013.

Improving Diosgenin Bioavailability
To improve the solubility and intestinal permeability of diosgenin, Kim et al. (2012) have shown that conjugating the hydrophilic unit, tetraethylene glycol to form diosgenintetraethylene glycol conjugate improved the hypoglycemic action of diosgenin. Although both the diosgenin and the conjugate treatment (10-20 mg/kg bw) for 9 weeks did not show any significant FBG reduction, the conjugate treated group showed better potential compared to the diosgenin alone (Kim et al., 2012;Okawara et al., 2013). Interestingly, some methods are available to improve the bioavailability of diosgenin, although not directly investigated in any diabetic model. The use of diosgenin and β-cyclodextrin inclusion complex, deglycosylation of diosgenin and diosgenin nanocrystals are receiving much attention in the recent years Okawara et al., 2013Okawara et al., , 2014Liu et al., 2016). For instance, the use of diosgenin and β-cyclodextrin inclusion complexes improved the bioavailability of diosgenin by 45% in rats (Okawara et al., 2013).

Bioavailability of Thymoquinone
Poor bioavailability in the systemic circulation has been highlighted as the major limitation for using TQ in clinic trials. Alkharfy et al. (2015) have attributed the poor bioavailability of TQ to the rapid elimination and relatively delay absorption following oral administration. Previously, Pathan et al. (2011) have detected TQ in the plasma (about 58%) for 12 h after oral administration of TQ (20 mg/kg bw) in rats. In another study, TQ was reported to accumulate greatly in the entire nuclei of kidney cells (Effenberger-Neidnicht et al., 2011).

Improving Thymoquinone Bioavailability
The consequences of TQ hydrophobicity leads to reduce amounts reaching the target which in turn increase toxicity to normal tissues. Taking into consideration many researchers have developed more aqueous-soluble TQ derivatives and encapsulate in a nanoformulations to overcome the poor bioavailability of TQ. The encapsulation increases the bioavailability, protects the TQ from prematured enzyme degradation and limits TQ diffusion to normal tissues (Schneider-Stock et al., 2014). Interestingly, this method has been widely used in various disease condition and improved actions with less toxicity were reported (Ravindran et al., 2010;Singh et al., 2013;Ong et al., 2016;Kalam et al., 2017). Unfortunately, no study is available that reported the potential of TQ-derived nanoparticle in diabetic models and hence further studies in this regard are warranted.

Bioavailability of Trigonelline
The solubility of trigonelline was reported to be higher compared to other SDBI and thus showed moderate rate of absorption and high elimination rate in the rabbit (Zhao et al., 2003). Similarly, most of the consumed trigonelline is usually absorbed at the small intestine and not degraded by the microflora in germ-free and specific pathogen-free rats (Yuyama, 1999). Consumption of coffee (another rich-source of trigonelline) showed peak plasma concentrations of 5.5-6.5 µM after 2-3 h in human subjects (Lang et al., 2010(Lang et al., , 2013. The authors further showed delay clearance and, hence, accumulation of trigonelline in the plasma with an average half-life of about 5 h. In addition, about 50% of the trigonelline consumed was detected in urine 0-8 h postingestion (Lang et al., 2010(Lang et al., , 2013. Moreover, about 20% of the ingested trigonelline was reported to be excreted in the urine as trigonelline when approximately 9% was excreted as N'-methyl-2-pyridone-5-carboxylic acid (Yuyama and Suzuki, 1991;Yuyama and Kawano, 1996). However, about 100% of trigonelline was recovered unchanged from the urine in the administered rats (Shibata and Taguchi, 1991). Hence, further studies are needed not only to confirm the true metabolism of trigonelline but also to clear the above-mentioned controversies.

Improving Trigonelline Bioavailability
According to the literature, no study is available that highlight the method that could improve the trigonelline bioavailability. This could be attributed to the higher solubility of trigonelline compared to the other SDBI.

CONCLUSION AND FUTURE PROSPECT
Data gathered in the present study have shown that SDBI hold promising hypoglycemic potential. Despite many of the ingredients showed weak hypoglycemic effects, cinnamaldehyde, curcumin, diosgenin, TQ and trigonelline have demonstrated promising hypoglycemic potential and need further scientific scrutiny to maximize their use as hypoglycemic therapies and adjuvants. Therefore, future studies on the most promising SDBI should be focused on bringing these ingredients to the forefront for the treatment of diabetes. These can be achieved via extensive clinical trials, improving the tissue bioavailability and distribution as well as detail toxicological studies. Furthermore, more detail studies are required on the combinatory effects of standard hypoglycemic drugs and the ingredients that showed adjuvant property. The idea is to evaluate whether the combined administration could attenuate advance consequences of the synthetic drugs as they showed strong amelioration of diabetesassociated complications.

AUTHOR CONTRIBUTIONS
AM gathered all the previously published articles and drafted the manuscript in its current form under the direct guidance of MI.

SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.