Ceratotheca sesamoides,Corchorus fascicularis,Corchorus olitorius,Abelmoschus esculentus,diabetes mellitus type 2,">
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Journal of Applied Sciences
Year: 2019 | Volume: 19 | Issue: 6 | Page No.: 585-592
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Research Article Dipeptidyl Peptidase IV and α-glucosidase Inhibitory Activity of Ceratotheca sesamoides, Corchorus fascicularis, Corchorus olitorius and Abelmoschus esculentus
Pamhidzai Dzomba
Department of Chemistry, Faculty of Science, Bindura University of Science Education, P. Bag 1020, Bindura, Zimbabwe
LiveDNA: 263.21435
Estele Mwanza
Department of Health Sciences, Faculty of Science, Bindura University of Science Education, P. Bag 1020, Bindura, Zimbabwe

ABSTRACT

Background and Objective: Ceratotheca sesamoides, Corchorus fascicularis, Corchorus olitorius and Abelmoschus esculentus are edible bush okras used to manage diabetes mellitus type 2 in traditional practices worldwide. In this study we investigate the alpha-glucosidase and dipeptidyl peptidase inhibitory activity of the four bush okras’ leaf, seeds and pods extracts. Materials and Methods: Liquid-liquid extraction was used for extracting the active phytochemicals. The extracts and standard inhibitors, sitagliptin and precose were then used in in vitro studies to determine percentage inhibition and IC50 values using UV-VIS spectrophotometry. Results: The C. sesamoides, C. fascicularis, C. olitorius and A. esculentus ethanolic extracts showed significant dipeptidyl peptidase inhibitory activity with IC50 values ranging from 1.53-92.32 μg mL–1 and α-glucosidase inhibitory activity with IC50 values ranging from 1.85-8.43 μg mL–1. Most of the extracts showed greater than 50% inhibition at concentration lower than 10 μg mL–1. Leaf and seed extracts showed the best results with IC50 values lower than those of standard inhibitors, 2.32 and 2.38 μg mL–1 for sitagliptin and precose, respectively. Among the okras A. esculentus showed the best results, IC50 values<2 μg mL–1. Conclusion: Results of the present studies show that administration of polar extracts i.e., aqueous infusions of C. sesamoides, C. fascicularis, C. olitorius and A. esculentus inhibits the enzymes, α-glucosidase and dipeptidyl peptidase. Thus the study supports the global use of the edible okra species in traditional medicine to manage diabetes mellitus type 2.
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Received: January 12, 2019;   Accepted: February 08, 2019;   Published: May 15, 2019
Copyright: © 2019. This is an open access article distributed under the terms of the creative commons attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

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INTRODUCTION

Diabetes mellitus type 2 (DM T2) is the fastest growing metabolic disease worldwide characterised by insulin resistance, progressive decline in the pancreatic beta cell activity and increasing hyperglycaemia1,2. DM T2 is now the world’s fifty leading cause of human morbidity and mortality. According to International Diabetes Federation, people suffering from DM T2 are expected to continue to rise from3,4 366 million in 2011-552 million 2030. Unmanaged DM T2 results in a multiple disorders including microvascular (renal and retinal) and macro-vascular (coronary, peripheral vascular and neuropathic) which are long term complications5. Thus better control of glycaemia lessens the development of angiopathic complications. Treatment to attain normoglycaemia is focused on increasing insulin secretion, responsive or both and decreasing the rate of metabolizing carbohydrates and fats.

Clinically accepted oral medicines for DM T2 include biguanides, sulphonylureas, meglitinides, thiazolidinediones, α-glucosidase inhibitors and dipeptidyl peptidase IV inhibitors6,7. Biguanides, the widely prescribed drugs act by blocking the production of glucose in the liver and sometimes stimulate uptake of glucose by tissue7. They increase the binding effect of insulin on receptors thus reduce insulin resistance however these do not stimulate the secretion of insulin by the pancreas8. Although biguanides can reduce glycated haemoglobin by 1-2, only 25% of patients may be controlled adequately by monotherapic administration9. Adverse effects including abdominal pain, blotting, nausea, diarrhoea and anorexia limits its use in controlling DM T2. It is no-longer prescribed to patients with renal insufficiency, liver challenges and metabolic acidosis9. Sulphonylureas and meglitinides are known as insulin secretagogues that is they cause the pancreas to secrete insulin. Although these drugs are effective in reducing glycated haemoglobin, many patients may experience loss of drug effect after years of successful treatment due to progressive failure of beta cells. In such a case combination therapy is recommended. Thus in future many patients will require multiple therapies10. Sulphonylureas and meglitinides also have a risk of weight gain. Thiazolidinediones function by regulating carbohydrate and lipid metabolism. They enhance insulin action but have no effect on its secretion8. Major draw backs of thiazolidinediones include fluid retention, unpredicted weight gain, development of peripheral oedema and mild anaemia 9. Alpha-glucosidase and dipeptidyl peptidase inhibitors function by inhibiting enzymes. These are well tolerated and have fewer adverse effects thus current studies are now focusing on searching for food based alternative remedies which have similar mode of action. Synthetic and botanical inhibitors of alpha-glucosidase and dipeptidyl peptidase have been reported in previous studies however clinical application has been hampered by lack of potency in vivo due to lack of oral bio-availability, poor permeability in membranes and weak selectivity11. It is crucial due to the above arguments that the search for new anti-DM T2 remedies continues.

Bush okras including, Abelmoschus esculentus, Ceratotheca sesamoides, Corchorus olitorius and Corchorus fascicularis, Fig. 1 are widely consumed in Africa, Asia and some parts of Europe as vegetables12. A. esculentus, C. sesamoides, C. olitorius and C. fascicularis are used to manage DM T2 in traditional practices however scientific studies to support this use is still limited. Thus the present study was designed to investigate dipeptidyl peptidase IV and alpha glucosidase inhibitory activity of four bush okra species, A. esculentus, C. sesamoides, C. olitorius and C. fascicularis.

The C. olitorius and C. fascicularis consist of several types of phytocompounds including phytosterols, triterpenoids and polyphenolic compounds which have portrayed anti-inflammatory, anti-cancer, anti-histaminic, anti-oestrogenic and antipyretic activity13,14.

MATERIALS AND METHODS

Plant material collection: Plant material were collected during the rainy season (January-April) from Mashonaland East in Mudzi district and Mashonaland Central in Bindura district with the help of elderly persons and separated into pods, seeds and leaves. Samples were kept in a freezer until required for analysis. The plants were further authenticated by taxonomists at the Harare National Herbarium and voucher specimens 2017/1, 2, 3, 4 were kept in the Bindura University of Science Education natural product herbal library for future reference.

Sample preparation: Fresh plant material, 60 g each was crushed into a paste using a wooden mortar and pestle and extracted three times with 100 mL of absolute ethanol. The filtrate were then combined and the solvent evaporated on a Buchi rotary evaporator to dryness. The contents were weighed and dissolved in 9:1 water-ethanol solution to a final volume of 10 mL. The resultant stock solutions were then kept in a refrigerator waiting further analysis.

Image for - Dipeptidyl Peptidase IV and α-glucosidase Inhibitory Activity of Ceratotheca sesamoides, Corchorus fascicularis, Corchorus olitorius and Abelmoschus esculentus
Fig. 1:Pictorial view of Ceratotheca sesamoides, Corchorus fascicularis, Corchorus olitorius and Abelmoschus esculentus

Dipeptidyl peptidase IV inhibition assay: Pods, Leaves and seeds extracts DPPIV inhibitory activity was screened following a method reported by Bharti et al.15 with minor modifications using a total well volume of 100 Ml. Crude extracts or sitagliptin (standard inhibitor of DPPIV) were diluted to various concentration in the range 0-100 μg mL–1 using 50 mM TrisHCl buffer at pH7.5 to a final volume of 35 μL. Absorbance of the solutions were recorded at 405 nm followed by adding 15 μL of 0.05 U mL–1 of DPPIV enzyme. One unit of enzyme was taken as the amount of an enzyme required to catalyze the production of 1 μM of paranitroanilidine per minute. The mixture was pre-incubated for 10 min at 37°C to allow maximum contact of enzyme with inhibitor followed by addition of 50 μL of 0.2 mM Glypro-p-nitroanilidine diluted in TrisHCl buffer. The resultant mixture was incubated at 37°C for 30 min. The reaction was terminated by adding 25 μL of 25% glacial acetic acid. The absorbance results were compared with results of a control experiment (without inhibitor). The percentage inhibition was computed using the equation:

Image for - Dipeptidyl Peptidase IV and α-glucosidase Inhibitory Activity of Ceratotheca sesamoides, Corchorus fascicularis, Corchorus olitorius and Abelmoschus esculentus

where, I (%) is percentage inhibition, AC: Absorbance of control experiment (without inhibitor) and AS: Is absorbance of experiment with standard inhibitor or with extracts.

The IC50 value was defined as the concentration of extract that inhibited 50% of DPPIV activity under the assay conditions dose-activity curve.

Alpha-glucosidase inhibition assay: The assay was conducted following a method reported by Sabitha et al.16.

Statistical analysis: The results are expressed as means±standard error of three replicate analysis. Differences between the group means was analyzed using the IBM SPSS version 20 software by applying a one way ANOVA with the Turkey-karner post hoc test to identify significance among groups. A p<0.05 was considered to be statistically significant.

RESULTS

Dipeptidyl peptidase IV inhibition activity: Results in Fig. 2 show that C. sesamoides, C. olitorius, C. fascicularis and A. esculentus extracts are natural inhibitors of DPPIV with leaves and seeds showing an inhibition activity that was not significantly different from that of the standard inhibitor sitagliptin for concentrations lower than 10 μg mL–1, (p>0.05).

Image for - Dipeptidyl Peptidase IV and α-glucosidase Inhibitory Activity of Ceratotheca sesamoides, Corchorus fascicularis, Corchorus olitorius and Abelmoschus esculentus
Fig. 2(a-d): Dipeptidyl peptidase IV inhibition activity of (a) C. sesamoides, (b) C. fascicularis, (c) C. olitorius and (d) A. esculentus in comparison to standard inhibitor sitagliptin

Seeds and pods extracts from C. sesamoides and C. olitorius showed a lower inhibition activity while for C. fascicularis and A. esculentus the inhibition pattern was similar for all the extracts. As the concentration was increased from 10 μg mL–1, the percentage inhibition activity increased slightly however the extracts from C. fascicularis and A. esculentus became better inhibitors than sitagliptin (Fig. 2b and d). For C. sesamoides the percentage inhibition trend was leaves, 97.1±0.06>pods, 88.4±0.03> sitagliptin, 76.4±0.01> seeds, 48.9±0.05% (Fig. 2a), while for C. olitorius the trend was leaves, 97.6±0.09>seeds, 88.9±0.00> sitagliptin, 76.4±0.00>pods 66.2±0.03%, (Fig. 2b). For C. olitorius (Fig. 2c), the percentage inhibition trend was leaves, 88.9±0.05>pods, 81.6±0.07>sitagliptin, 76.4±0.02 = seeds, 76.4±0.03%, (Fig. 2c) and lastly that for A. esculentus, (Fig. 2d) was leaves, 98.9±0.00>pods, 96.2±0.09>seeds, 91.6±0.03> sitagliptin, 76.4±0.03. Thus all the extracts from A. esculentus showed higher inhibition than sitagliptin a tight binder inhibitor for DPPIV.

Table 1 shows IC50 values for the inhibition of DPPIV. The IC50 values ranged from 1.53-92.32 μg mL–1. The A. esculentus extracts showed the greatest inhibition activity with IC50 values, 1.53, 1.55 and 1.58 μg mL–1 and all are significantly lower than for sitagliptin, 2 .32 μg mL–1 (p<0.05). Also C. fascicularis leaf and seeds extract showed greater inhibition activity than sitagliptin p<0.05. The C. sesamoides (leaf extract) and C. olitorius (seeds and leaf extract) showed inhibition activity that was significantly similar to that of sitagliptin, (p>0.05).

Image for - Dipeptidyl Peptidase IV and α-glucosidase Inhibitory Activity of Ceratotheca sesamoides, Corchorus fascicularis, Corchorus olitorius and Abelmoschus esculentus
Fig. 3(a-d): A-glucosidase inhibition activity of (a) C. sesamoides, (b) C. fascicularis (c) C. olitorius and (d) A. esculentus in comparison to standard inhibitor precose

Table 1:
Half maximal inhibitory concentration (IC50) of C. sesamoides, C. fascicularis, C. olitorius, A. esculentus and standard inhibitor sitagliptin
Image for - Dipeptidyl Peptidase IV and α-glucosidase Inhibitory Activity of Ceratotheca sesamoides, Corchorus fascicularis, Corchorus olitorius and Abelmoschus esculentus

Alpha-glucosidase inhibition assay: Figure 3 shows that C. sesamoides, C. fascicularis, C. olitorius and A. esculentus extracts inhibit α-glucosidase in a similar pattern as the commercial drug precose. A sharp increase in percentage inhibition activity was observed within the 0-10 μg mL–1 concentration range. Later on the inhibition activity increased steadily. The percentage inhibition activity of the extracts and the standard inhibitor precose did not differ significantly for all the bush okra species within the 0-10 μg mL–1 concentration range, (p>0.05).

Table 2:
Half maximal inhibitory concentration (IC50) of C. sesamoides, C. fascicularis, C. olitorius, A. esculentusand standard inhibitor precose on α-glucosidase
Image for - Dipeptidyl Peptidase IV and α-glucosidase Inhibitory Activity of Ceratotheca sesamoides, Corchorus fascicularis, Corchorus olitorius and Abelmoschus esculentus

Above 10 μg mL–1, extracts from C. sesamoides and C. fascicularis pods showed inferior inhibition activity than precose, seed and leaf extracts (Fig. 3a and b). The C. fascicularis seeds and leaf extracts showed significantly greater inhibition activity than precose p<0.05 (Fig. 3b). The case was also similar for C. olitorius and A. esculentus leaf and seeds extracts (Fig. 3c and d). When the concentration was increased to 100 μg mL–1 the inhibition activity of the extracts and precose did not differ significantly p>0.05 showing that concentration of the inhibitor ceased to affect the rate of catalysis.

Table 2 shows that all the extracts from A. esculentus, IC50 values, 1.85, 2.05 and 2.10 μg mL–1 for seeds, leaves and pods, respectively are better α-glucosidase inhibitors than precose with an IC50 value of 2.38 μg mL–1. Also leaf and seed extracts of C. sesamoides, C. fascicularis and C. olitorius are better α-glucosidase inhibitors than precose IC50 values<2.38 μg mL–1. The results clearly showed that A. esculentus seed extracts are the best inhibitors of α-glucosidase. Precose is a better inhibitor than extracts from C. sesamoides, C. fascicularis and C. olitorius pods, IC50 values>2.38 μg mL–1.

DISCUSSION

The four bush okras, C. sesamoides, C. olitorius, C. fascicularis and A. esculentus extracts portrayed potent inhibitory activity against DPPIV that was comparable to that of the standard inhibitor sitagliptin. Previous studies have shown that inhibition of DPPIV provides a novel approach for treatment of DM T217,18. The DPPIV is responsible for the inactivation of glucagon like peptide that has the role of stimulating insulin secretion and the increase in the population of beta cells15,19.

Sitagliptin is sold under the name januvia in the market. It is an oral medicine that can be used in combination with metformin9. Thus the four bush okras can be potent DM T2 alternative medicine to sitagliptin which has revealed side effects in some patients. The side effects in some patients include pancreatitis, frequent urination and weight gain9. Among the four okras, A. esculentus is the best substitute with IC50 values for both seed, leaf and pods extract lower than that for sitagliptin. Comparing the extracts from seed, leaf and pods the seed extract is a superior alternative inhibitor. The A. esculentusis consumed as a vegetable worldwide20. It can be used in salads, soups and stews. It is more a diet than staple food. The A. esculentus seeds consist of oligomeric catechin, flavonols derivatives, hydroxycinnamic derivatives and quercetin20. Previously these phytochemicals have been reported to consist of DPPIV inhibitory activity21,22.

The C. sesamoides, C. fascicularis, C. olitorius seed and leaf extracts are also better potent DPPIV inhibitors than sitagliptin, IC50 values< that of sitagliptin. According to Khan et al.13, C. fascicularis and C. olitorius consisted of tetraterpenes (ursolic acid, corosolic acid and betulinic acid), flavonoids (quercetin, kaempferol and flavonoids) and phenolic acids (scopolin and chlorogenic acid). In a related study23 anti-diabetic activity of the tetraterpene, betulinic acid was demonstrated using protein tyrosine phosphatase 1b inhibition. Quang et al.24 also demonstrated the anti-diabetic activity of flavonoids and prenylated xanthones using the same assay. Lacroix and Li-Chan25 demonstrated whey protein isolate can be potential sources for sources of DPP-IV and α-glucosidase inhibitors with an IC50 value of 0.036 mg mL–1.

The percentage inhibition activity and IC50 values showed that C. sesamoides, C. olitorius, C. fascicularis and A. esculentus extracts are good inhibitors of α-glucosidase with an activity that was better or comparable to that of the standard drug precose. Precose chemically known as o-4, 6-dideoxy-4-[(1S,4R, 5S,6S)-4, 5, 6-tryhydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]amino] α-D-glucopyranosyl-(1, 2, 3, 4)-o-α-D-glucopyranosyl-(1, 2, 3, 4)-D-glucose is an oligosaccharide prescribed as an oral α-glucosidase competitive inhibitor for use as a drug for DM1 T2. The biggest challenge with precose is that there is no fixed dosage thus it has to be individualized according to effectiveness and tolerance8. Common side effects of precose among some patients include, constipation, rectal bleeding, stomach pain, diarrhea and pneumatosis cystoides1. Thus the present results are interesting. They showed that C. sesamoides, C. olitorius, C. fascicularis and A. esculentus can also be used as alternative remedies to precose especially to patients showing serious side effects when prescribed precose. Among the okras once again A. esculentus proved to be the best alternative followed by C. fascicularis then C. sesamoides and lastly C. olitorius see (Table 2). While all extracts from A. esculentus showed better activity than precose only leaf and seeds extracts of C. sesamoides, C. olitorius, C. fascicularis portrayed superior activity than precose. The IC50 values obtained in the present study are comparable to values reported by Li et al.26 for Punica granatum flower extract and Zhang et al.27 for Castanea mollissima extracts. IC50 values around 1.8 and 0.33 μg mL–1, respectively. However the values are lower than values reported by Sabitha et al.16. The lower IC50 values show that the extracts bind to the enzyme with higher affinity than the substrate and the standard inhibitor precose. This may be due to the fact that the extracts consist of a mixture of compounds that may bind either at the active site or the allosteric site or to metals responsible for the maintenance of the quaternary structure of the enzyme.

CONCLUSION

The experimental evidence of the present study support the use of C. sesamoides, C. olitorius, C. fascicularis and A. esculentus in management of DM T2 in traditional medicine. The ethanolic extracts show significantly better or similar inhibition activity for both DPPIV and α-glucosidase as compared to standard inhibitors sitagliptin and precose respectively. Among the extracts the seed and leaf extracts showed the best results as compared to pods extracts. For A. esculentus, all the extracts showed better results than the standards showing that A. esculentus is the best candidate than the other okra species. Since the anti-diabetic drugs sitagliptin and precose have side effects on some patients, C. sesamoides, C. olitorius, C. fascicularis and A. esculentus can be alternative remedies. The okra species can also be future candidates for developing food derived DPPIV and α-glucosidase inhibitors as potential approach for glycaemia regulation.

SIGNIFICANCE STATEMENT

This study discovered that Ceratotheca sesamoides, Corchorus fascicularis, Corchorus olitorius and Abelmoschus esculentus extracts inhibits α-glucosidase and dipeptidyl peptidase 1V thus providing a scientific explanation for the use of the four bush okra species in the management of diabetes in traditional medicine. The results shows that the four okra species are good candidates for developing food based remedies for diabetes type 2.

ACKNOWLEDGMENT

The authors would like to appreciate the post graduate and research center of Bindura University of science education for block grant allocation 2017 to purchase standards and other laboratory reagents for this study. Acknowledgments are also given to diabetic patients who provided useful information on the use of the okra species in management of DM T2. The information you gave us provided the impetus for this study.

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