Hypoglycemic Activity of Plant-Derived Traditional Preparations Associated with Surinamese from African, Hindustani, Javanese, and Chinese Origin: Potential Efficacy in the Management of Diabetes Mellitus

2.1 Worldwide epidemiology

Diabetes is generally considered a major public health threat with a growing burden in many parts of the world. According to the International Diabetes Federation [3], approximately 537 million adults of the 7.9 billion people who populated our globe in 2021, were living with diabetes. This corresponded to about 6.8% of the world population in that year, and this number is anticipated to rise to 643 million by 2030 and 783 million by 2045, i.e., roughly 7.5% and 8.3%, respectively, of the projected sizes of the world population in these years [3]. Furthermore, 541 million adults were at increased risk of developing type 2 diabetes, almost 240 million adults were living with undiagnosed diabetes, more than 1.2 million children and adolescents (0–19 years) with type 1 disease, and 21 million live births (i.e., 1 of 6 live births) were affected by diabetes during pregnancy [3].

Apart from the complications that may accompany diabetes such as nephropathy, retinopathy, neuropathy, and associated foot problems, this disease dramatically increases the risk of cardiovascular problems including coronary artery disease with angina pectoris, heart attack, stroke, and atherosclerosis [4]. Not surprisingly, the costs associated with this disease are astronomical, globally amounting to at least USD 966 billion dollars last year, i.e., 9% of the total worldwide spending on health expenditure in adults [3].

Diabetes was responsible for 6.7 million deaths in 2021 [3]. Notably, this disease occupied in 2019 the 9th position on the list of the top ten causes of death globally, which represented an increase of 70% when compared to 2000 [5]. Diabetes was also responsible for the largest rise in male deaths among the top ten causes, with an 80% increase the mortality rate increasing since 2000 [5]. In that year, it was in 10th place of the leading causes of death in high-income countries and in 9th and 6th place of those in low- and middle-income, and upper-middle-income countries, respectively [5]. It has been estimated that 3 of 4 adults suffering from diabetes are living in low- and middle-income countries [3]. This has largely been attributed to these countries rapidly adopting a Western lifestyle including Western dietary patterns (particularly during adolescence), reduced physical activity, and increased stress [6, 7]. The Caribbean, for instance, has the highest age-adjusted prevalence of diabetes in the world at 10.8% [6], with some countries in that region reporting prevalence rates of 18% [7]. This is considerably higher than both the worldwide prevalence and the prevalence in South and Central America, which is about 7.5% [6]. Indeed, diabetes particularly represents a major public health threat for developing countries.

2.2 Diagnosis and subtypes

The most recent diagnostic criteria for diabetes are those from the American Diabetes Association, involving glycosylated hemoglobin (HbA1c) blood levels ≥6.5%, fasting plasma glucose levels ≥126 mg/dL or 7.0 mmol/L, 2-h plasma glucose levels ≥200 mg/dL or 11.1 mmol/L during an oral glucose tolerance test, and/or classic symptoms of hyperglycemia or hyperglycemic crisis with random plasma glucose ≥200 mg/dL or 11.1 mmol/L [8]. Depending on the severity and the etiologic background, diabetes is distinguished in the clinical categories prediabetes, type 1 diabetes, type 2 diabetes, gestational diabetes, and other subtypes such as those caused by genetic defects in cell function, genetic defects in insulin, disorders of the pancreas, and the use of certain drugs [9].

Individuals with prediabetes have elevated blood sugar levels which are, however, not sufficiently high to qualify for the diagnosis of “diabetes” [10]. Many such individuals are not aware of their condition, but prediabetes is an important predisposing factor for 2 diabetes as well as heart disease [10]. Type 1 diabetes (also referred to as insulin-dependent diabetes and previously called juvenile-onset diabetes) is most common in childhood and early adulthood [11]. It is an autoimmune condition involving own antibodies attacking and destroying the pancreatic β-cells, eventually resulting in absolute insulin deficiency [11]. Type 1 diabetes can cause a multitude of health problems which are mostly related to retinopathy, neuropathy, and nephropathy as well as a high risk of heart disease and stroke [11].

Type 2 diabetes is also known as non-insulin-dependent, insulin-resistant, and adult-onset diabetes, but has become more common in children and teens over the past 20 years, largely because more young people are overweight or obese [12]. Currently, about 90% of individuals with diabetes have type 2 [12]. In patients with type 2 diabetes, the pancreas either produces insufficient amounts of insulin, or the target tissues in the body (particularly fat, liver, and muscle) do not properly respond or do not respond at all to insulin [12]. Although type 2 diabetes is often milder than type 1, it can cause major health complications including retinopathy, neuropathy, and nephropathy, as well as an increased risk of heart disease and stroke [12].

Gestational diabetes occurs in 1–14% of all pregnancies depending on the population and the method of assessment [13]. This condition is a form of insulin resistance that usually manifests in middle or late pregnancy as a result of progressive changes in the metabolism of the pregnant woman including hormonal levels such as those of cortisol and estrogen [13]. Gestational diabetes usually ceases after birth, but up to 10% of women suffering from this condition are at risk to develop type 2 diabetes in a later stage of their life and carry the risk of unusual weight gain of the baby before birth necessitating cesarean section, respiratory problems of the newborn at birth, as well as a higher risk of obesity and type 2 diabetes of the child at an older age [13].

An estimated 1–5% of cases of diabetes are caused by conditions other than those mentioned above, including those with a genetic background and those that are non-genetically related. Types of diabetes with a genetic background are neonatal diabetes [14] and maturity-onset diabetes in the young [15], Wolfram syndrome-related (type 1) diabetes [16], and cystic fibrosis-related (type 1) diabetes [17]. Types of diabetes with a non-genetic background are, among others, chronic pancreatitis-associated diabetes, which is usually caused by extensive damage to the exocrine tissue of the pancreas [18], brittle diabetes, which primarily affects patients with type 1 diabetes and manifests as frequent and severe fluctuations in blood glucose levels [19], and Cushing’s syndrome-related diabetes [20].

2.3 Treatment

Since the early days of diabetes treatment involving insulin replacement therapy [21], this treatment modality has taken considerable strides in terms of devices for administration and formulations with variability in onset, peak, and duration of action. Some examples of injectable devices are single-use syringes, insulin pens, insulin jet injectors, and external insulin pumps [22]. As well, the biochemical and pharmacological properties of endogenous insulin have been modified in order to produce insulins that give a constant low basal level of insulin or lower insulin spikes in response to meals so as to attain less hypoglycemia and improvement of postprandial glucose control. This has resulted in rapid-acting, short-acting, intermediate-acting, long-acting, and ultra-long-acting insulin preparations, as well as certain mixtures and concentrated formulations [23]. The next steps in insulin therapy will likely involve “smart” insulins which will be delivered according to an endogenous glucose-sensing feedback mechanism, novel needle-free insulin delivery devices for subcutaneous administrations, and alternative routes of insulin delivery such as pulmonary, nasal, buccal, oral, and transdermal routes [24].

Furthermore, a host of antidiabetic remedies other than insulin have become available [25, 26]. These drugs can be classified according to their mechanism of action as insulinotropic or non-insulinotropic, and they are given as a monotherapy or in certain combinations without or with insulin, usually for type 2 diabetes [25, 26]. The insulinotropic agents depend on their actions on residual β-cell function and stimulate the secretion of insulin from the pancreatic β-cells. They include the sulfonylureas (such as tolbutamide and glibenclamide), the meglitinide analogs (such as repaglinide), the glucose-dependent glucagon-like peptide-1 receptor agonists (GLP-1 agonists) or incretin mimetics (such as exenatide), and the dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitors) or gliptins (such as sitagliptin). The non-insulinotropic agents are effective in patients with non-functional pancreatic β-cells. They include the biguanides (such as metformin), the sodium-glucose co-transporter-2 inhibitors (SGLT-2 inhibitors) or gliflozins (such as dapagliflozin), the thiazolidinediones or glitazones (such as rosiglitazone), the α-glucosidase inhibitors (such as acarbose), and the amylin agonist analogs (such as pramlintide). Almost all these antidiabetic drugs are taken orally, except for the GLP-1 agonists and the amylin agonist analogs which are injectable. Of note, several new drug combinations such as metformin in combination with an SGLT2 inhibitor and a DPP4 inhibitor are now undergoing clinical evaluation [26].

3.1 Geography, demographics, and economy

The Republic of Suriname is located on the northeastern Atlantic coast of South America, adjacent to French Guiana, Brazil, and Guyana (Figure 1). The country has a land area of about 165,000 km² that can be distinguished into a northern narrow low-land coastal plain that harbors the capital city Paramaribo as well as other urbanized areas, a broad but sparsely inhabited savannah belt, and a southern forested hinterland that comprises about three-quarters of its surface and largely consists of dense, pristine, and highly biodiverse tropical rain forest (Figure 1). Roughly 80% of the population of about 600,000 lives in the urbanized northern coastal zone while the remaining 20% populates the rural and interior savannas and hinterlands [27].

Suriname is renowned for its ethnic, religious, and cultural diversity, harboring various Amerindian tribes, the original inhabitants of the country; Afro-Surinamese, comprising the descendants of enslaved Africans brought in between the sixteenth and the 19th century who fled the plantations and settled in the country’s hinterland (called Maroons) as well as those from mixed Black and White origin (called Creoles); the descendants from contract workers from India (called Hindustanis); Java, Indonesia (called Javanese); and China, all of whom arrived between the second half of the 19th century and the first half of the 20th century; the descendants from a number of European countries; and more recently, immigrants from various Latin American and Caribbean countries including Brazil, Guyana, French Guiana, Haiti, etc. [27]. The largest ethnic groups in the country are the Afro-Surinamese (Creoles and Maroons), Hindustanis, Javanese, and Chinese, accounting for 37.4, 27.4, 15.7, and 7.3%, respectively, of the total population [27]. All ethnic groups have largely preserved their own specific identity, making Suriname one of the culturally most diverse countries in the world [28].

Suriname is situated on the Guiana Shield, a Precambrian geological formation estimated to be 1.7 billion years old and one of the regions with the largest expanse of undisturbed tropical rain forest in the world with a very high animal and plant biodiversity [29]. The high mineral density contributes to its ranking as the 17th richest country in the world in terms of natural resources and development potential [30]. Suriname’s most important economic means of support are crude oil drilling, gold mining, agriculture, fisheries, forestry, as well as ecotourism [30]. These activities have substantially contributed to the gross domestic income in 2020 of about USD 3 billion and the average per capita income in that year of USD 4920 [30, 31]. This positions Suriname on the World Bank’s list of upper-middle-income economies [31].

3.2 Epidemiology of diabetes in Suriname

As observed in many low- and middle-income countries [32], increasingly more Surinamese are adapting to a Western lifestyle. Indeed, only about half of the country’s overall population meets the levels for physical activity recommended by the World Health Organization [33]; almost three-quarters of school children aged 13–15 years have less than 1 h of physical activity per day and 81% have too high calorie intake [34]; about 1 of 5 adults is overweight and approximately 1 of 15 is obese [35]; the average tobacco and alcohol consumption per capita in individuals of 15 years and older is unacceptably high [34]; the overall estimated prevalence of the metabolic syndrome is 39.2% [36]; and more than 25% of adults has a raised blood pressure [36]. Notably, with almost 200 deaths per year, diabetes is the 4th principal cause of mortality in Suriname, after cardiovascular diseases, external causes, and cancer [37].

Accordingly, the Suriname Health Study—the first nationwide study on non-communicable disease risk factors in Suriname [38]—reported an overall prevalence of prediabetes in the country of about 7.4% and diabetes of 13.0% [39]. The latter value is well in agreement with that of 12.7% recently estimated for Suriname by the International Diabetic Federation [3]. This figure represents a substantial increase with respect to that of 8.9% in 2011 and is likely to rise to 14.0% by 2030 and 14.6% in 2045 [3]. Accordingly, the health expenditures for diabetes in Suriname—estimated at about USD 63.5 million in 2021—are anticipated to reach USD 70.1 million in 2030 and USD 80.1 million in 2045 [3].

5.1 Acanthaceae: Ruellia tuberosa L.

The minnieroot R. tuberosa L. (Acanthaceae) (Figure 2) is probably native to Central America, the West Indies, and northern South America including Suriname, but has become naturalized in many other tropical countries throughout the world. It is popularly known as “cracker plant” in English-speaking regions and as “watra kanu” (“water canon”) in Surinamese-Creole because of the loud crack emitted when the ripe fruits in a pod with the black seeds burst open on contact with water, hurdling the seeds away. The whole plant as well as leaf, seed, and root are used in various traditional medical systems including those from the Afro-Surinamese, for preparing medicines for treating, among others, stomach ache, indigestion, constipation; problems of the urinary tract; eczema and skin eruptions; headache, fever, influenza, bronchitis, asthma, pneumonia, and whooping cough; hypertension and heart ailments; malaria; joint pain; venereal diseases; vaginal discharge; and reduced sexual performance or pleasure [56, 57]. Some of these uses are supported by the results from pharmacological studies reporting, among others, gastroprotective, antiurolithiatic, antimicrobial, anti-inflammatory, larvicidal, and antifertility activities of the plant [56, 57]. These activities have been associated with the presence in the plant of certain alkaloids, triterpenoids, saponins, sterols, and flavonoids [58].

In Suriname and various other Caribbean countries, an infusion or decoction of R. tuberosa root is also used against diabetes [52, 54, 55]. So far, however, no clinical studies have been carried out to corroborate this use. Still, there is ample preclinical evidence for the antidiabetic activity of this plant. Firstly, extracts and fractions of several of its parts elicited clear hypoglycemic effects in normal and alloxan- or streptozotocin-induced rodent models of diabetes [59, 60, 61, 62, 63]. The decline in blood glucose was accompanied by a decrease in HbA1c levels and an amelioration of abnormal hepatic detoxification function [62] as well as a decrease in insulin resistance [63]. Furthermore, the R. tuberosa preparations led to substantial improvements in the histopathology of kidney, pancreas, and liver of the diabetic animals [64, 65]. The extract also caused a notable improvement in glucose uptake in insulin-resistant mouse C2C12 myoblasts [63], supporting that it may overcome insulin resistance in skeletal muscle cells. The hypoglycemic activity (of root preparations) was comparable to that found for tolbutamide [59] and glibenclamide [60].

The hypoglycemic activity of R. tuberosa may be associated with the antioxidant properties of some of its constituents, as shown by the notable 2,2-diphenyl-1-picrylhydrazyl (DPPH)-scavenging activity of preparations from the plant [59]. Furthermore, the administration of a root extract led to an increase in catalase and superoxide dismutase activities as well as a decrease in malondialdehyde levels (a measure of lipid peroxidation) in induced hypercholesterolemic rats and streptozotocin-induced rats [62, 64, 65, 66]. R. tuberosa preparations also displayed a relatively high content of total phenolic compounds and flavonoids [59, 60, 67], some of which have been shown to protect against the oxidative stress that is considered an important contributing factor to the initiation and development of many diseases including diabetes [68, 69]. The hypoglycemic effects were accompanied by a decrease in blood concentrations of cholesterol, triglycerides, LDL-c, and VLDL, and an increase in HDL-c in various animal models [60, 66, 70]. These observations compared favorably with glibenclamide [60, 70].

The results from animal and in vitro studies suggest that the hypoglycemic actions of R. tuberosa could also be associated with the inhibition of α-amylase activity [61] and/or α-glucosidase activity [71]. Thus, preparations from this plant may be useful for controlling postprandial hyperglycemia by preventing the digestion of carbohydrates and delaying the increase in blood glucose [72]. Compounds in R. tuberosa that may be responsible for its α-amylase and α-glucosidase inhibitory activity are the pentacyclic triterpenoid betulin [61] and certain phenolic compounds including several flavonoids [67, 71, 73], respectively. This is consistent with the identification in the plant of triterpenoids and flavonoids [67], the hypoglycemic effects of these substances [59], and the implication of antioxidant activities in their blood glucose-lowering capacity [68, 69].

5.2 Amaranthaceae: Gomphrena globosa L.

The globe amaranth Gomphrena globosa L. (Amaranthaceae) (Figure 3) is an annual herb that grows to a height of 1 meter and that presumably originates from Asia but is now cultivated as an ornamental in many tropical and subtropical parts of the world including Suriname. G. globosa produces small and inconspicuous flowers but vividly colored round-shaped flower inflorescences that range from pink to red and purple in some cultivars. The flower inflorescences do not readily wither and retain their shape and color after drying and are therefore used in long-lasting garlands. This characteristic is reflected by the Surinamese-Creole vernacular names “stanvaste” and “stanfasti” for the plant, meaning “lasting” or “steadfast.” For this reason, the more fanatical supporters of the mostly Creole social-democratic political party “National Party of Suriname” have claimed G. globosa as their (unofficial) symbol.

The flowers of G. globosa also serve as a source of betacyanins for use as a (red-violet) colorant in the food, cosmetic, and pharmaceutical industry [74]. Betacyanins are a subclass of betalain pigments, aromatic indole derivatives that are synthesized from tyrosine to produce glycosides consisting of a sugar and a colored portion [75]. One of the most notable betalains is betanin or beetroot red in the beet Beta vulgaris L. (Amaranthaceae) [75]. Betalains are chemically distinct from anthocyanins or flavonoids but replace anthocyanin pigments in plants of the order Caryophyllales (that includes G. globosa) and in certain fungi [75]. In plants, they probably attract pollinators and seed dispersers and act as antioxidants, providing protection against harmful reactive oxygen species [75].

Parts of Gomphrena species are used in various countries for preparing traditional remedies. A few indications are oliguria and other urinary conditions; reproductive problems; microbial and parasitic infections; skin diseases and wounds; fever and respiratory disorders such as bronchitis and whooping cough; gastrointestinal disorders such as jaundice; high cholesterol; as well as hypertension [76, 77]. The potential therapeutic usefulness against these conditions is supported by, among others, the antioxidant, anti-inflammatory, analgesic, antimicrobial, and cytotoxic activities of preparations from the plant [76, 77]. These pharmacological activities have mainly been associated with the betalains but also with certain saponins, tannins, flavonoids, and alkaloids in the plant [76, 77, 78].

G. globosa is also a popular traditional remedy against diabetes in various parts of the world [76, 77]. In Suriname, an infusion of its leaf and flower is used to lower excessively high blood glucose levels [52]. There are no studies with diabetics to back this custom, but there is some preclinical support for hypoglycemic activity of this plant. For instance, a crude methanol extract from the whole plant as well as an n-hexane fraction therefrom showed meaningful hypoglycemic activity in Swiss-albino mice subjected to a glucose tolerance test [79]. The hypoglycemic activity was comparable to that of glibenclamide [79]. As well, repeated administration of a leaf ethanolic extract lowered blood glucose in alloxan-induced hyperglycemic Wistar rats [80].

Rather than to the betalains, the hypoglycemic activity of G. globosa has been attributed to one or more flavonoids in the plant [76, 77, 78, 80]. These compounds have been suggested to lower blood sugar in laboratory animals by stimulating the secretion of insulin by the pancreatic β-cells, the utilization of glucose by the body tissues, and/or the decrease of hepatic gluconeogenesis [80]. In a series of in vitro studies, an ethanolic leaf extract of G. globosa exhibited meaningful α-amylase inhibitory activity [81], suggesting that eliminating postprandial blood glucose spikes was also involved in its antidiabetic effects. The leaf extract also displayed notable in vitro antiglycation and antioxidant activity [81, 82], suggesting that antioxidant mechanisms may also contribute to the antidiabetic activity of the plant [68, 69].

6.1 Myrtaceae: Syzygium cumini (L.) Skeels

The jambolan Syzygium cumini (L.) Skeels (Myrtaceae) (Figure 4), called “jamún” by Surinamese-Hindustani, is native to the Indian subcontinent but is now grown in various tropical and subtropical regions worldwide. It has presumably brought to Suriname by Hindustani indentured laborers at the end of the 19th and the beginning of the 20th century. This is reflected in the Surinamese vernacular “kulidroifi,” meaning “the grape from the coolies,” in reference to the then European pejorative for Hindustani indentured laborers. S. cumini produces ovoid, edible fruits that are green when unripe and become pink, then crimson red, and finally purplish-black as they mature. The sweet and mildly sour-tasting and astringent fruits are eaten raw, and can also be made into juices, wines, jellies, sorbets, syrups, jams, sauces, or fruit salads.

All parts of S. cumini, but particularly its bark, leaf, seed, and fruit, have since long been used in Indian Ayurveda and Unani as well as various other traditional medical systems for treating, among others, coughing, asthma, and bronchitis; stomachache, dyspepsia, colic, diarrhea, dysentery, liver problems, and hemorrhoids; ringworm, piles, pimples, skin blemishes, and acne; various types of inflammation; fatigue and strain; blisters in the mouth and weak teeth and gums; cancer; and diabetes [83, 84]. In Suriname, a tea or coffee-like beverage prepared from macerated S. cumini seeds is also used against the symptoms of diabetes, a custom that probably originates from the Hindustanis [53, 55].

Some of the traditional uses of S. cumini may be accounted for by alkaloids such as jambosine, glycosides such as glycoside jambolin, as well as phenolic compounds including gallic acid, caffeic acid, and ellagic acid; flavonoids such as quercetin, myricetin, and kaempferol; anthocyanins such as delphinidin-3,5-O-diglucoside, petunidin-3,5-O-diglucoside, and malvidin-3,5-O-diglucoside; and tannins such as ellagitannins [83, 84]. These compounds as well as crude S. cumini preparations displayed, among others, antioxidant, antimicrobial, antimalarial, anti-inflammatory, analgesic, and anticancer activities [85, 86].

There is also substantial pharmacological evidence to support the broad traditional use of S. cumini—particularly with its seed—for treating diabetes. Thus, administration of the seed powder or various types of extracts from the seed or the seed kernel, led to a decrease in blood glucose levels in alloxan- or streptozotocin-induced rodents [87, 88, 89, 90], an increase in glucose tolerance [91], a reduction in insulin resistance [92], positive effects on pancreatic islet cell regeneration [93, 94], and an improvement in blood lipid profiles [87, 90, 91, 95]. Comparable, although less pronounced results were obtained with S. cumini root, stem bark, leaf, and fruit preparations [92, 96, 97].

The blood-glucose-lowering activity of S. cumini may involve the mitigation of the oxidative stress associated with the development of diabetes [68, 69]. This can be inferred from preclinical studies showing an increase in antioxidant defenses and a decrease in lipid peroxidation in animal models of diabetes treated with a seed preparation [98, 99, 100]. Candidates in the seed with such antioxidant properties are phenolic compounds such as ferulic acid [101, 102, 103] and flavonoids such as kaempferol and myrecetin [98, 99]. The hypoglycemic activity of S. cumini may also be attributable to its capacity to activate and increase the expression of the genes encoding for peroxisome proliferators activated receptors gamma and alpha (PPARγ and PPARα) in the liver, increasing insulin sensitivity of the target tissues [95]. In addition, various in vitro and animal studies with S. cumini seed and leaf preparations showed an inhibitory effect on α-amylase and α-glucosidase activity, suggesting that these substances lowered postprandial blood glucose [104, 105, 106]. This effect may be ascribed to the alkaloid jambosine and the glycoside jambolin in the seed [83].

So far, only a relative handful clinical studies have been conducted on the antidiabetic efficacy of S. cumini in diabetics [107]. Unfortunately, the results from these studies were inconclusive, some suggesting that the preparations helped control blood sugar levels whereas others did not show any improvement [107]. For instance, the administration of seed preparations to patients with (severe) type 2 diabetes reportedly led to promising reductions in fasting and postprandial blood glucose levels [108, 109, 110, 111, 112, 113, 114] as well as less polyphagia, polyuria, polydipsia, and fatigue [109, 113]. However, a dried and powdered leaf decoction did not elicit an effect on blood glucose levels in either non-diabetic young volunteers submitted to a glucose blood tolerance test [115] or type 2 diabetic patients [116].

6.2 Rutaceae: Aegle marmelos (L.) Corrêa

Aegle marmelos (L.) Corrêa (Rutaceae) (Figure 5), commonly known as bael or golden apple, is the only member of the genus Aegle. It is probably native to India and has spread to nearby countries such as Bangladesh, Sri Lanka, and Nepal as well as more distant tropical and subtropical countries including Suriname. In the latter country, it has presumably been introduced by Hindustani indentured laborers around the turn of the 20th century. A. marmelos is also called “bhel” or “bill patr,” meaning “the flavorful fruit with the hard shell” [53], in reference to its globose or slightly pear-shaped fruit of 5–12 cm in diameter with a hard-wooden, yellow to gray-greenish shell and an aromatic, pale-orange, sticky, sweet and resinous pulp. A. marmelos has presumably been cultivated for its fruit since 800 BC that can be consumed fresh, prepared as lemonade, or processed into candy, toffee, pulp powder, or nectar after being dried. The leaves and small shoots are eaten as salad greens. The alkaloid aegeline in leaf and fruit has been marketed as the dietary supplement OxyELITE Pro^® for weight loss and muscle building [117]. However, it has been withdrawn from the market due to its association with potentially fatal liver damage [117].

All parts of A. marmelos—but particularly its fruit and leaf—have a long medical use in Indian Ayurveda and other traditional medical systems [118, 119]. Some indications are chronic diarrhea, dysentery, dyspepsia, peptic ulcers, constipation, and malabsorption; wheezing cough and bronchial spasms; microbial, viral, and parasitic infections; fever and rheumatism; neurological diseases; and cancer [118, 119]. Scientific studies have validated many of the ethnomedical uses of A. marmelos, showing antidiarrheal, gastroprotective, bronchospasmolytic, anti-inflammatory, analgesic, antimicrobial, antiviral, as well as anticancer and chemopreventive effects [120, 121]. These pharmacological activities could partially be attributed to alkaloids in the plant other than aegeline, as well as phenolic compounds, flavonoids, tannins, monoterpenes, and sesquiterpenes, coumarins, saponins, and phytosterols [120, 121].

A. marmelos is also used for the traditional treatment of diabetes in many parts of the world [122, 123] including Suriname [53]. There is ample pharmacological support for this use. Aqueous, methanolic, and ethanolic extracts from fruit, leaf, or an in vitro callus culture from a leaf explant produced marked antidiabetic effects in several animal models of diabetes, including normalization of fasting blood glucose level, tolerance to a glucose load, increased serum insulin levels, decreased insulin resistance, improved glucose homeostatic enzymes, and improved blood lipid profile [124, 125, 126, 127]. The hypoglycemic activities have been associated with marked antioxidant effects including a decrease in oxidative stress that manifested as a decrease in lipid peroxidation, an increase in the activity of cellular antioxidant mechanisms [128, 129, 130], and the regeneration of pancreatic β-cells [126]. These observations are in accordance with the notable antioxidant activity of A. marmelos leaf extracts in a DPPH free radical-scavenging assay and a ferric reducing antioxidant power assay [131, 132] as well as in HepG2 cells cultured under glucose-rich conditions [132].

The phytochemicals in the plant that may be involved in its antioxidant activities are the phenolic compound eugenol [133], the furanocoumarin marmesinin [134, 135], the 7-hydroxycoumarin analog umbelliferone β-D-galactopyranoside [136], and the cyclic monoterpene limonene [137]. In addition, A. marmelos’ antidiabetic activity may be related to the stimulation of insulin release from the pancreas, stimulation of glucose uptake by the skeletal muscles, and lowering of postprandial blood glucose levels. These suggestions are based on the stimulatory effects of A. marmelos preparations on insulin release by cultured pancreatic islet cells [128] and on glucose uptake by isolated mouse psoas muscle tissue [127], and their substantial inhibitory effects in in vitro α-amylase and α-glycosidase assays [138]. At least the α-glycosidase inhibitory activity has been associated with the presence in the leaf of a series of phenylethyl cinnamides, particularly anhydroaegeline [138].

At this moment, only a few clinical studies have been conducted to explore the therapeutic efficacy of A. marmelos against diabetes. Leaf preparations given orally to type 2 diabetic patients reportedly lowered levels of fasting blood glucose [139, 140, 141], postprandial blood glucose [138, 139, 140, 141, 142], and HbA1C [141], along with total blood cholesterol and triglycerides while increasing HDL levels [140, 141]. However, a crossover clinical study evaluating the unripe fruit pulp for 0–21 and 28–49 days with a 7-day wash-out period, did not find an effect on fasting blood glucose [143].

7.1 Acanthaceae: Strobilanthes crispa (L.) Blume

The black face general Strobilanthes crispa (L.) Blume (Acanthaceae) (Figure 6) is probably native to the Sunda Islands, a group of islands in the Malay Archipelago that includes the Indonesian island of Java. The plant has spread to many south-eastern Asian countries and has presumably been brought to Suriname by Javanese indentured laborers at the end of the 19th century and the beginning of the 20th century [51]. It is a woody spreading shrub that carries yellow-colored flowers, attains a height of 50 cm to 1 m, and can be found on riverbanks and abandoned fields. S. crispa is known as “ketji beling” in Surinamese-Javanese, “etji” meaning “very bad” or “vile” and “beling” meaning “broken glass” or “shards” which probably refers to the very rough texture of both surfaces of the leaves. Nevertheless, this part of the plant is eaten as a vegetable.

In addition, S. crispa is used in Indonesian and Malaysian traditional medicine as a diuretic, antilithic, laxative, and anticancer agent [144, 145]. Some of these folk medicinal uses are supported by data from pharmacological studies with leaf preparations showing antimicrobial, antioxidant, antiulcerogenic, anticancer, antiangiogenic, acetylcholinesterase-inhibitory, and wound healing activity [146, 147, 148]. Phytochemical investigations have revealed that S. crispa leaf contains polyphenols, flavonoids, catechins, alkaloids, caffeine, and tannins, all of which are known to elicit some of these as well as other pharmacological activities [146, 147, 148].

S. crispa has also been used for a long time in particularly Indonesian and Malaysian folk medicine as an ingredient of popular jamus for lowering elevated blood sugar levels [149]. As a result, some products prepared from the leaf of the plant have recently entered the health-food market as antidiabetic nutraceuticals in the form of sachets containing the raw crude powder (fermented and unfermented) for preparing a tea, as an additive in coffee, or as capsules for oral intake [150]. So far, no clinical data are available on the safety and side effects of the long-term use of these products, but several pharmacological studies reported that they do not exert acute toxicity [151, 152].

Like Indonesians and other peoples from south-eastern Asian countries, Surinamese-Javanese use tea from S. crispa leaves (alone or together with those from certain other plants) to lower elevated blood sugar levels [51]. This traditional use is supported by the blood-glucose-lowering effects of hot water extracts of fermented and/or unfermented leaf in both normal and streptozotocin-induced diabetic rats [150]. Both preparations also improved lipid profile (total cholesterol, triglyceride, LDL-cholesterol, and HDL-cholesterol) in the animals [150]. S. crispa leaf juice given together with a basic diet to streptozotocin-induced diabetic and normal rats produced comparable results, along with significantly increased glutathione peroxidase and superoxide dismutase activities in both groups of animals [153]. Fresh S. crispa leaf juice also stimulated the healing of incision wounds on the back of normal and streptozotocin-induced hyperglycemic rats [154]. These observations are in accordance with the stimulatory effects of a topically applied ethanol extract of S. crispa leaf on excision wounds in the posterior neck area of normal rats [155] and suggest that this plant may also be useful for treating poorly healing wounds occurring in diabetics.

As mentioned before, plant antioxidants seem to elicit beneficial effects on various aspects of diabetes since oxidative stress probably represents an important contributing factor to the initiation and development of the disease [68, 69]. This is in accordance with the notable antioxidant effects of S. crispa preparations in several in vitro models of diabetes [148, 156] and their positive effects on endogenous antioxidant mechanisms in diabetic animals such as glutathione peroxidase and superoxide dismutase activities [153]. These effects might be attributed to the abundance of phenolic compounds with antioxidant properties in the plant such as p-hydroxybenzoic acid, p-coumaric acid, caffeic acid, vanillic acid, gentinic acid, ferulic acid, syryngic acid, as well as quercetin, rutin, catechin, myricetin, apigenin, and luteolin [147, 148, 156, 157].

7.2 Clusiaceae: Garcinia mangostana L.

The mangosteen Garcinia mangostana L. (Clusiaceae) is a tropical evergreen tree that is believed to be native to south-eastern Asia where it is called “manggis” or “manggustan.” The exact origin of G. mangostana is uncertain but it has been cultivated since ancient times in southern USA, Central America, and north-western South America. It has probably introduced in Suriname by Javanese indentured laborers around the beginning of the 20th century [51]. G. mangostana produces round, slightly sweet and sour, flavorful, juicy fruits consisting of fluid-filled vesicles with an inedible, deep reddish-purple colored exocarp when ripe (Figure 7). The ripe fruit is eaten raw, incorporated into desserts, added to salads, or made into jams. It is rich in carbohydrates, minerals, vitamins, and various other nutrients [158], and mangosteen-based products are also offered in many parts of the world as “liquid botanical supplements” [159], although the claims of their invigorating properties are being disputed [160]. Interestingly, extracts of the peel have been used for centuries in Indonesia as a natural dye for the brown, dark brown, purple, and red colorings of the characteristic batik textiles [161].

Preparations from G. mangostana parts are since ancient times extensively used in traditional south-eastern Asian medicine. A few indications are skin infections, infected wounds, and suppurating sores; dysentery; cystitis; gonorrhea; chronic ulcer, abdominal pain, diarrhea, and dysentery; obesity; as well as cancer [161, 162]. Pharmacological studies have provided support for some of these uses, showing that G. mangostana preparations elicit, among others, anti-inflammatory, antibacterial, antiviral, antiprotozoal, antioxidant, anti-obesity, anticancer, and chemopreventive activities [163, 164]. Phytochemical studies have suggested that these activities may particularly be attributed to the high content of polyphenolic compounds in the plant (particularly in pericarp, whole fruit, heartwood, and leaf) such as xanthones, prenylated benzophenone derivatives, flavonoids, anthocyanins, and condensed tannins [163, 164, 165]. Xanthones—tricyclic polyphenols consisting of two benzene rings attached through a carbonyl group and oxygen—are the major bioactive constituents in G. mangostana and include, among others, α-, β-, and γ-mangostins [166, 167].

G. mangostana preparations are also used against diabetes in various traditional systems [161, 162, 163] including Surinamese Jamu [51]. Support for this use is provided by the reduction in blood glucose levels and/or insulin resistance as well as the increase in insulin levels noted in high-fat diet and streptozotocin-induced type II diabetic and nephropathic rodents treated with pericarp extracts enriched with xanthones [168, 169, 170]. The G. mangostana preparations also improved, among others, oral glucose tolerance and the histology of the β-cells [168, 169, 170] as well as blood lipid profiles in the animal models [171, 172]. These effects have been ascribed to α-mangostin and γ-mangostin, which elicited comparable antidiabetic activities as the crude G. mangostana extracts in vivo [173], stimulated insulin secretion in cultured INS-1 rat insulinoma cells, and protected the cells from apoptotic damage [174], and decreased insulin resistance in primary cultures of newly differentiated human adipocytes [175].

The antidiabetic activities of G. mangostana have been associated with the antioxidant properties of the xanthones in the plant, which elicited potent DPPH free radical-scavenging activity, superoxide dismutase and catalase stimulatory activities, and notable malondialdehyde inhibitory activity [168, 169, 170]. Furthermore, the G. mangostana preparations inhibited α-amylase and α-glycosidase activities in vitro [176, 177], which was consistent with the lowering of postprandial blood glucose levels by an ethanol extract of the pericarp in streptozotocin-induced diabetic rats [177]. Candidates for the anti-enzymatic effects are the xanthone garcimangostin A which displayed acarbose-like α-amylase inhibitory activity in molecular docking studies [178], and oligomeric proanthocyanidins as well as α-mangostin and γ-mangostin that inhibited α-amylase and α-glucosidase in vitro [170, 176, 177].

Until today, there is only some indirect evidence on the clinical efficacy of G. mangostana. Thus, a fruit juice herbal blend, either alone or in combination with parts from other plants, and a fruit extract in a capsule formulation led to a reduction in body weight, body mass index, and waist circumference of non-diabetic obese patients [179, 180, 181]. Since these positive changes were accompanied by an improvement in insulin sensitivity [181], the data from these studies have merit.

8.1 Araliaceae: Panax notoginseng (Burkill) F.H.Chen

The Chinese ginseng Panax notoginseng (Burkill) F.H.Chen (Araliaceae) (Figure 8) is probably native to south-eastern China and Vietnam but has spread to forests from China to the Himalayas and Myanmar. P. notoginseng must not be confused with other Panax species such as the Asian ginseng P. ginseng C.A. Meyer and the American ginseng P. quinquefolius L., which it superficially resembles. However, an important distinguishing characteristic of P. notoginseng is the presence of three petioles with seven leaflets each. This is the reason this plant is referred to in China as “sān-qī,” meaning “the three-seven herb.” P. notoginseng is either cultivated or gathered from the wild, and the interest in this plant is particularly for its root and rhizome which are used to prepare foods, health products, beauty products, dietary supplements, and medicines [182].

P. notoginseng dried root and rhizome are very common ingredients of traditional Chinese medicines including those used by Surinamese-Chinese [183]. A few indications are arteriosclerosis, high blood pressure, coronary heart disease, and angina pectoris; internal and external bleedings ranging from nosebleeds to intracerebral hemorrhages; inflammatory conditions such as osteoarthritis and rheumatoid arthritis; pains and swellings; liver disease; poor cognitive ability or mood; and substandard athletic performance and muscle soreness following exercise [184, 185]. Pharmacological studies supported some of these uses, showing, among others, beneficial effects on the cardiovascular system and cerebrovascular diseases; hemostatic, wound healing, and angiogenesis-modulating effects; anti-inflammatory, antioxidant, antimicrobial, and antiviral activities; estrogen-like properties; cognitive enhancing, antidepressant, and anxiolytic activities; as well as performance-enhancing activities [185, 186, 187].

The main active constituents believed to be responsible for these activities are the unique triterpene saponins in the plant called dammarane saponines, which consist of a dammarane skeleton (17 carbons in a four-ring structure) with various sugar moieties attached to the C-3 and C-20 positions [185, 186, 187]. The biologically most important dammarane saponines in P. notoginseng are believed to be the notoginsenosides [185, 186, 187]. This was the rationale for developing and patenting a saponin-enriched P. notoginseng product as a traditional treatment for cardiovascular disorders in China [188]. Other phytochemicals in P. notoginseng with pharmacological activity are polysaccharides such as starch-like glucans and pectin; amino acids and proteins; volatile oils comprising, among others, sesquiterpenoids; polyacetylenes, phytosterols, and flavonoids, as well as the triacylglycerol trilinolein [186].

P. notoginseng root and rhizome extracts as well as purified notoginsenosides or notoginsenoside-containing formulations have also been used for thousands of years in traditional Chinese medicine for treating the symptoms of diabetes [182]. The results from many pharmacological studies—both in vivo and in vitro—have supported this use [189, 190]. For instance, the administration of P. notoginseng saponins led to a decrease in blood glucose in alloxan-induced diabetic mice [191], hyperglycemic and obese KK-Ay mice [192, 193], and high-fat diet-induced diabetic KKAy mice [194]. These effects were accompanied by an increased synthesis of liver glycogen in normal mice [191] and improved serum insulin levels, glucose tolerance, insulin resistance, glomerular lesions [192], and body weight in diabetic animals [192, 193, 194, 195]. The latter observation was consistent with the in vitro and in vivo anti-obesity effects of notoginsenosides [195].

These findings were in accordance with the increased (insulin-stimulated) glucose uptake by a rat liver homogenate [191], 3 T3-L1 murine adipocyte-like cells [196], and cultured C2C12 skeletal myoblast [197] following exposure to P. notogensing saponins, as well as the concomitant increase in the expression of several elements of signaling pathways considered important in the pathogenesis of diabetes including the glucose transporter type 4 GLUT4, p-PI3K, and p-Akt [194, 196]. P. notoginseng saponins treatment also increased intracellular superoxide dismutase and catalase levels and decreased reactive oxygen species and malondialdehyde content in rat retinal capillary endothelial cells exposed to high glucose [198]. All these data taken together suggest that P. notoginseng and its notoginsenosides affect multiple metabolic pathways involved in glucose homeostasis, including, among others, glucose absorption, glucose transport, and/or glucose disposal, as well as insulin secretion and binding.

A few clinical studies support the antidiabetic efficacy of P. notoginseng in diabetic patients. For instance, the daily intake of 3 g of P. notoginseng for 3 days lowered postprandial glycemia in untrained non-diabetic adults of 20–45 years when compared to one cycling exercise of 30 min on day 3 prior to the glucose intake by these men [199]. Furthermore, the saponins delayed the progress of diabetic nephropathy [200] and elicited beneficial effects in type 2 diabetic angiopathy [201]. And a meta-analysis suggested that some commercial products containing P. notoginseng saponins may well be beneficial as adjuvant therapy for diabetic kidney disease [200].

8.2. Lauraceae: Cinnamomum cassia (L.) J.Presl

Cinnamomum cassia (L.) J.Presl (Lauraceae) (Figure 9), also called Chinese cassia, Chinese cinnamon, or “guān guì” in Mandarin (referring to something precious or valuable), is an evergreen tree that originates from southern China and has spread to various neighboring countries in southern and south-eastern Asia. C. cassia is, along with several other Cinnamomum species including the Ceylon cinnamon C. verum, the Saigon cinnamon C. loureiroi, the Indonesian cinnamon C. burmannii, and the Malabar cinnamon C. citriodorum (from the Malabar region in India), widely cultivated for its aromatic, reddish inner bark that gives the spice cinnamon after drying. Cinnamon is used as a flavoring agent for confectionery, desserts, pastries, and meat dishes including many savory curry recipes. One of the several flavoring substances is coumarin, a benzopyrone that has, however, anticoagulant properties and can cause liver damage in sensitive individuals if consumed in larger amounts [202].

C. cassia has a long traditional use for treating a wide variety of diseases, particularly in China [203, 204, 205] but also in the Chinese community in Suriname. Preparations from mainly the bark of this plant are used against, among others, microbial and parasitic infections; the common cold; inflammation; joint pain and hernia; loss of appetite stomach, spasms, nausea and vomiting, flatulence, and diarrhea; chest pain; kidney disorders; bed-wetting; erectile dysfunction; menopausal symptoms, menstrual problems, and to cause abortions; as well as hypertension, cancer, and diabetes [203, 204, 205]. Some of these traditional uses are supported by the many pharmacological studies carried out with C. cassia preparations, cinnamon spice, and isolated compounds from the plant showing antimicrobial, antiviral, antioxidant, anti-inflammatory, gastroprotective, nematicidal, acaricidal, repellent, anti-obesity, anti-angiogenic, and anticancer activities [203, 204, 205]. Phytochemical analyses have shown the presence in the plant of bioactive phenylpropanoids including cinnamaldehyde that is considered its main pharmacologically active ingredient (and that also contributes to its flavor and aroma), as well as terpenoids, glycosides, lignans, and lactones in addition to coumarin [203, 204, 205].

There is also ample preclinical evidence for hypoglycemic activity of C. cassia. For instance, aqueous extracts of the bark decreased blood glucose concentration in streptozotocin-induced diabetic mice [206, 207], type II diabetic C57BIKsj db/db mice [208, 209], and rats challenged by a glucose load [210]. The C. cassia preparations were also able to stimulate the release of insulin from the insulin-secreting rat cell line INS-1 in vitro [210] and to increase plasma insulin levels in the animal models [208, 210]. In addition, serum insulin levels and HDL-cholesterol levels were increased while those of triglycerides, total cholesterol, and LDL were decreased [208, 209].

The hypoglycemic effects of C. cassia were accompanied by a reduction in malondialdehye levels [206] and a rise in glutathione levels and glutathione peroxidase activity [211], suggesting the involvement of antioxidant activity in its mechanism of action. This is supported by the abundance of polyphenolic compounds with considerable antioxidant activity in the plant [204, 205, 212] and by the decrease of plasma malondialdehyde levels in overweight and obese adults with prediabetes who had consumed the C. cassia bark-based supplement Cinnulin PF^® [213]. In addition, both in vitro and in vivo studies reported that cinnamon led to a decrease in α-amylase and α-glycosidase activities [208, 214, 215, 216]; an increase in hepatic glycogenesis [217], and an increase in the consumption of extracellular glucose in both insulin-resistant HepG2 and normal HepG2 cells [207]. Thus, C. cassia may alleviate diabetes through its antioxidant activity, by delaying carbohydrate digestion and lowering postprandial glucose levels, by storing excess glucose in the liver, and by improving insulin resistance and sensitivity.

In some clinical studies, the consumption of cinnamon spice or a phenolic-enriched extract of C. cassia bark indeed led to a reduction in fasting [218, 219] and postprandial blood glucose levels [220, 221, 222, 223] as well as an improvement in insulin sensitivity in healthy [220, 222, 223, 224], obese [223, 224], and type 2 diabetic patients [219]. Cinnamon and powdered aqueous C. cassia bark extract also caused a delay in gastric emptying [220], and enhanced insulin sensitivity [224], as well as improvements in fasting plasma glucose and HbA1c along with lipid profiles in type 2 diabetic patients [218]. However, other studies reported no effect of cinnamon spice or encapsulated C. cassia bark on blood sugar levels, insulin sensitivity, oral glucose tolerance, blood lipid profile, and/or liver enzymes in either normal-weight non-diabetic individuals or obese diabetic subjects [225, 226, 227].