Antidiabetic and Hypoglycaemic Activities of Commonly Used African Traditional Vegetables

Introduction : Diabetes mellitus is a common and complex metabolic disorder associated with high blood glucose levels leading to complications. Adopting a sedentary lifestyle characterized by low physical activity and consumption of high-energy diets contributes to the development of diabetes mellitus. Lifestyle changes and the use of pharmacological agents that target particular biochemical pathways involved in nutrient metabolism are currently used as management guidelines for managing risk factors associated with diabetes mellitus. The use of prescription medications for an extended period is linked to several negative side effects. Alternative management strategies of risk factors linked to diabetes mellitus involve the use of African leafy vegetables. African leafy vegetables contain a variety of biologically active compounds that provide health benefits. These crops have the potential to be a valuable source of new oral hypoglycemic agents for diabetes management. This review analyses the antidiabetic activities of nine African leafy vegetables whilst also defining the gap areas for future research. Methods : Data was acquired via electronic search engines of which only peer-reviewed papers published in journals were considered. Results : African traditional vegetables showed diverse in vitro and in vivo antidiabetic activities. Conclusions : There is an urgent need to document and use the knowledge of African leafy vegetables that have potential in the treatment and management of diabetes mellitus.


INTRODUCTION
Diabetes mellitus (DM) is a metabolic disorder characterised by abnormal glucose, protein and lipid metabolism, resulting in an elevated plasma glucose level. 1 Diabetes is also associated with polyurea, weight loss, muscle weakness, polydipsia, polyphagia, and hyperlipidaemia and hyperglycaemia. Insulin suppresses the function of lipase-stimulating hormones in adipose tissue. 2 When insulin is not functioning optimally, the rate of lipolysis rises releasing free fatty acids into the bloodstream; this also increases β-oxidation of fatty acids and cholesterol. Insulin also mediates cholesterol elimination; thus, its absence results in hyperlipidaemia and hypercholesterolemia in diabetes. 2 According to the World Health Organisation (WHO) data, 400 million people worldwide have diabetes, with approximately 1.5 million deaths, and this rate is expected to double by 2035 due to people's affluent lifestyles. 3,4 If blood sugar levels are not controlled, it can have a major influence on multiple organs, leading to ailments such as hypertension, kidney disease and blindness. Diabetes treatment is costly, and it also has negative side effects such as weight gain and gastro-intestinal issues. Furthermore, people find it difficult to adjust to lifestyle changes such as consuming sugar-free foods. As a result, it is critical to seek out alternate methods of controlling blood sugar. 5 Food plants with promising therapeutic potential and few adverse effects are gaining attention and acknowledgment for diabetes control. Unlike pharmaceutical antidiabetic medicines, which are laden with notable side effects, wild plants do not have these side effects and do not require a strict regimen because they can be consumed as food. 5 The various mechanisms by which plant drugs demonstrated anti-diabetic activity include glycosidase (glucosidase) inhibition, α-amylase inhibition, and inhibition of hepatic glucose metabolizing enzyme. 6 Furthermore, plant foods can be effective by stimulating insulin production or acting as an insulin mimic, stimulating glycogenesis, reducing the release of glucagon and other hormones that counteract insulin action, antioxidant mechanism, preventing glycosylation of haemoglobin and regulating glucose absorption from the gut. 5 This review article enumerates some commonly consumed wild plants in South Africa possessing antidiabetic activity. The nine vegetables are Chinese cabbage (Brassica rapa), pigweed (Amaranthus species), Jew's mallow (Corchorus olitorius), spider flower (Cleome gynandra), pumpkin (Cucurbita pepo), purslane (Portulaca oleracea), tsamma melon (Citrullus lanatus), blackjack (Bidens pilosa) and white goosefoot (Chenopodium album). The vegetables were chosen on the basis of popularity. 7,8 much lower concentrations than the extracts. It would therefore seem as if the extract is not as effective as the known anti-diabetic drugs as the majority of the plants were more effective at higher concentrations than the positive controls. The most studies (n = 29) were performed on P. oleraceae followed by C. lanatus (n = 19) and C. olitorius (n = 12) with positive results reported for all of them. There was significant variance in the duration of treatment among in vivo studies, ranging from 2 hours to 18 weeks. Noteworthy, significant acute blood glucose level control was reported in all the plants (Table 2).

CONCLUSION
An extensive literature survey was performed on commonly consumed wild foods in South Africa, namely Portulaca oleracea, Citrullus lanatus, Bidens pilosa, Amaranthus spp., Brassica rapa, Chenopodium album, Cucurbita pepo and Cleome gynandra. Alloxan-and streptozotocininduced diabetic rats and mice were commonly used as the model to assess the antidiabetic activity for preclinical in vivo studies ( Table 2). In vitro antidiabetic activity was mostly conducted using α-amylase and α-glucosidase inhibition assays. Some of the mechanisms of action for reported plants include improvement in insulin sensitivity and pancreatic β-cell function (Table 1).
Even though all the plants have been extensively studied for their antidiabetic activity, better results were rarely reported than the drugs acarbose and glibenclamide used as positive controls. Noteworthy is that much more in vivo studies (n=96) have been reported than in vitro studies (n=34), which is unexpected as in vitro studies are normally used as an indicator potential to be tested further for in vivo activity.
Surprisingly, only three plants, P. oleracea, B. pilosa and A. cruentus, have been subjected to clinical trials, given the large number of in vivo studies conducted. The majority of the methodology used for clinical trials was not appropriately designed and hence led to inconclusive findings. This therefore creates an opportunity and need for exploring wild foods in clinical trials. In addition to antidiabetic activities, the reported wild foods extracts showed an improvement of lipid profile parameters. As a result, it was demonstrated that these plant extracts might be used to treat diabetes mellitus complications and risk factors. However, more research is warranted to investigate and underline in-depth mechanisms of action towards the management of diabetes mellites, associated complications and to isolate antidiabetic active constituents. All the plants reported in this study describe the potential of these plants to aid in the treatment of diabetes as part of the diet by consumption of indigenous vegetables. The review present strong support for well-designed clinical trials and the development of novel antidiabetic drugs from the indigenous leafy vegetables discussed in this review. This section is not mandatory but can be added to the manuscript if the discussion is unusually long or complex. pilosa', 'Corchorus olitorius', 'Brassica rapa', 'Citrullus lanatus' and 'Chenopodium olitorius' were used separately and in combination with 'diabetes mellitus', 'antidiabetic', 'hypoglycaemic', 'antihyperglycemic' and 'type-2 diabetes'. The search was limited to only peer reviewed papers published in English, and therefore theses and dissertations were excluded. In addition, references of the articles were also searched. To be included in this study, the plant materials should be eaten as part of the diet. All articles that addressed indigenous medicinal plants and trees as well as indigenous fruits not consumed as vegetables, were also excluded. A total of 2 021 articles were retrieved of which only 192 matched the inclusion criteria for the review.

Extraction of wild foods
The in vivo antidiabetic activities of the crude extracts and solvent fractions of different wild vegetable parts using different chemicals were investigated as displayed in figure 1. Among solvents, aqueous was the most commonly used solvent for the extraction of plants, followed by ethanol and methanol solvents. Some studies tested for antidiabetic effects using dried plant parts, juice prepared from the leaves, and other methods.

In vitro studies
In vitro studies that were undertaken to assess commonly consumed wild foods in South Africa involve the use of cell culture and the use of carbohydrate-hydrolysing enzymes, α-amylase and α-glucosidase. Glucose uptake in the skeletal muscles and adipose tissue is critical for the reduction of postprandial blood glucose concentrations in people with type-2 diabetes mellitus. 9 A total of 34 in vitro studies were reported with α-amylase and α-glucosidase (n = 15) being the most commonly used enzymes, followed by studies that investigated only one of the enzymes with α-amylase (n = 10) being the most common, and closely followed by α-glucosidase (n = 4). Significant differences in concentrations were reported from 1.70 and 1.60 μg/ml up to as high as 0.19 mg/mL and 0.32 mg/mL for α-amylase and α-glucosidase respectively. Similar to the in vivo studies, most studies (n = 7) were performed on P. oleraceae followed by C. lanatus (n = 5), C. olitorius and C. pepo (both n = 4), although the group of Amaranthus spp. in combination showed the most reports (n = 8).
(E)-5-hydroxy-7-methoxy-3-(2'-hydroxybenzyl)-4-chromanone (HMchromanone) isolated from P. oleracea showed a significant increase in glucose uptake in 3T3-L1 adipocytes by stimulating translocation of GLUT4 to the plasma membrane. 10 HM-chromanone also promoted glucose uptake into L6 skeletal muscle cells in a dose-dependent manner. Notably, Portulaca oleracea exhibited more α-glucosidase and α-amylase activities when compared with the reference drug (acarbose). 11 In addition, Chenopodium album inhibited α-amylase enzyme more effectively than conventional acarbose. 12 The in vitro antidiabetic activities of commonly consumed wild foods, which have been investigated in South Africa, are summarized in table 1.

In vivo studies
A total of 96 studies were reported, which is a very high number of in vivo studies that have already been conducted with most using mice and rats as experimental animals. Of the 96 studies that were conducted, the STZ-induced rat model was the most common (n = 50) followed by the Alloxan-induced rat model (n = 37). Most studies found positive results at activity of 50 to 800 mg/kg bw, although concentrations as low as 1.25 mg/kg bw and as high as 2 000 mg/kg bw have been reported with positive results. It is however interesting that in the majority of studies the control (mostly glibenclamide and metformin) showed activity at Protection of the pancreatic β-cell from high glucoseinduced oxidative stress and apoptosis. [10] Ethanol extract INS-1 Pancreatic β Cells 0.1, 0.2, 0.5, 1.0, or 2.0 mg/mL Significantly increased insulin secretion dosedependently. [13] (E)-5-hydroxy-7-methoxy-3-(2'hydroxybenzyl)-4chromanone (HMchromanone). α-Amylase and α-glucosidase α-glucosidase IC 50 α-amylase IC 50 Significantly reduced α-glucosidase enzyme than acarbose. Significantly inhibited α-amylase enzyme.

weeks
There were no significant differences in plasma glucose and serum insulin observed between C. olitorius fed OLETF and LETO rats. There were no significant differences in serum triglyceride, total serum cholesterol, total liver cholesterol, and total liver fat among the groups.