Introduction to Hypoglycemia

### **Chapter 1**

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

*Dennis R.A. Mans*

#### **Abstract**

Diabetes represents one of the most frequent causes of morbidity and mortality in the world. Despite the availability of a wide range of efficacious forms of treatment, many patients use traditional (plant-derived) preparations for treating their disease. The Republic of Suriname (South America) has a relatively high prevalence of diabetes. Due to its colonial history, the Surinamese population comprises descendants of all continents, the largest groups being those from enslaved Africans and from indentured laborers from India (called Hindustanis), Indonesia (called Javanese), as well as China. All these groups have preserved their cultural customs including their ethnopharmacological traditions, and are inclined to treat their diseases with plantbased preparations, either alone or together with allopathic medications. This chapter opens with some generalities about diabetes; subsequently provides some information about the history, worldwide epidemiology, diagnosis, types, and treatment of this disorder; then focuses on Suriname, giving some information about its geography, demographics, and economy, as well as the epidemiology of diabetes in the country; then extensively evaluates eight blood-glucose-lowering plants that are mainly associated with the four largest ethnic groups in Suriname by reviewing phytochemical, mechanistic, preclinical, and clinical literature data; and concludes with a consideration of the potential clinical usefulness of the plants against diabetes.

**Keywords:** diabetes mellitus, medicinal plants, Suriname, preclinical studies, clinical studies, phytochemical composition, pharmacological activity, mechanism of action

#### **1. Introduction**

Diabetes mellitus (in short, diabetes) is a metabolic disorder of multiple etiology characterized by sustained hyperglycemia with disturbances of carbohydrate, fat, and protein homeostasis resulting from defects in insulin secretion, insulin action, or both [1]. The defects in insulin secretion are the result of inappropriate functioning of the β cells of the pancreas, while those in insulin action are generally associated with resistance of the peripheral tissues to insulin. In all cases, the end result is a defective availability of insulin [1].

Diabetes usually presents with characteristic symptoms including thirst, polyuria, blurring of vision, as well as weight loss, and when not properly treated, ketoacidosis or a non-ketotic hyperosmotic state that may lead to stupor, coma, and eventually death. However, in many cases, these symptoms are not severe or may even be absent. As a result, potentially critical hyperglycemia may be present long before the diagnosis is made [2]. In the long-term, the effects of diabetes include retinopathy and potential blindness, nephropathy that may lead to renal failure, and/or neuropathy with the risk of foot ulcers, amputation, and features of autonomic dysfunction including sexual debility [2].

This paper first briefly addresses the worldwide epidemiology, diagnosis, and subtypes, as well as the forms of treatment of diabetes; subsequently presents the geography, demographics, and economy, as well as the epidemiology of the disease in the Republic of Suriname; then focuses on the traditional forms of treatment of diabetes in that country, and extensively discusses eight plant species with hypoglycemic properties, two of which are traditionally used against diabetes by each of the four largest ethnic groups in Suriname, namely, the Afro-Surinamese, Hindustani, Javanese, and Chinese; and concludes with the prevision of these plants in the treatment of diabetes.

#### **2. Background**

#### **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].

#### *Hypoglycemic Activity of Plant-Derived Traditional Preparations Associated with Surinamese… DOI: http://dx.doi.org/10.5772/intechopen.105106*

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 lowand 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 syndromerelated (type 1) diabetes [16], and cystic fibrosis-related (type 1) diabetes [17]. Types of diabetes with a non-genetic background are, among others, chronic pancreatitisassociated 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, intermediateacting, 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. The Republic of Suriname**

#### **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 km<sup>2</sup> 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

#### **Figure 1.**

*Map of the Republic of Suriname, showing the southern interior or hinterland (yellow-brown); the savanna belt (dark green); and the northern coastal plain (light green) (from: https://images.app.goo.gl/ Gr8fsdAaoqp3LpVn7). Insert: the position of Suriname (red) in South America (from: https://images.app.goo.gl/ i4KL8WisoWW8TFmS9).*

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

*Hypoglycemic Activity of Plant-Derived Traditional Preparations Associated with Surinamese… DOI: http://dx.doi.org/10.5772/intechopen.105106*

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 noncommunicable 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].

#### **4. Traditional forms of treatment of diabetes in Suriname**

As mentioned above, the different ethnic groups in Suriname have largely preserved their cultural heritage including their specific (plant-based) traditional customs [28]. This has resulted in the many forms of traditional medicine practiced in the country including those based on traditional Indigenous medicine, traditional African medicine, Indian Ayurveda and Unani, Javanese Jamu, traditional Chinese medicine, and several other forms of complementary and alternative medicine [28]. The botanical knowledge and the plant materials for establishing and maintaining these systems probably came from several sources, including previous acquaintance with useful plants, new information about the local flora from the Indigenous peoples, and/or the selection of potentially valuable plants by trial and error [28, 40].

That the enslaved Africans and Asian indentured laborers were familiar with certain plants they encountered in Suriname, is presumably for an important part attributable to the Columbian Exchange in the fifteenth and sixteenth centuries, when many plants—as well as animals, people, commodities, and diseases—had been transferred from the Old World (Europe, Asia, and Africa) to the New World (the Americas) and vice versa [41, 42]. As a result, when the newcomers arrived in Suriname in the second half of the seventeenth century on, they immediately recognized many New World food crops and medicinal plants which were indigenous to their homeland [43, 44] or which had been introduced into their homeland more than 100 years before [42, 45]. A few examples are several yam species in the genus *Dioscorea* (Dioscoreaceae), and a number of ginger species in the plant family Zingiberaceae [43, 44], as well as okra (*Abelmoschus esculentus* (L.) Moench; Malvaceae), bitter melon (*Momordica charantia* L.; Cucurbitaceae), and eggplant (*Solanum melongena* L.; Solanaceae) [42, 45]. In addition, the enslaved Africans had carried medicinal plants such as the tamarind *Tamarindus indica* L. 1753 (Fabaceae) with them in order to fight diseases such as fever, diarrhea, and worm infections on the slave ships [46, 47].

Furthermore, the Maroons—but perhaps also individuals who arrived in Suriname after them—acquired new knowledge about useful plants through contact with the indigenous peoples and by trial and error. For instance, the application of the paste from the ground orange-red seeds from the annatto *Bixa orellana* L. (Bixaceae) as an insect repellent [48], and that of preparation from the leaves from the ink plant *Renealmia alpinia* (Rottb.) Maas (1975) (Zingiberaceae) as a remedy for snakebites


#### **Table 1.**

*Plants with hypoglycemic activity addressed in this chapter, parts mostly used, and mode of preparation.*

[49] stems from Indigenous knowledge. And the selection of potentially useful plants by trial and error has not only led to fatalities by poisonous plants but also to the use of such plants (like the jackass breadnut *Clibadium surinamense* L. (Asteraceae)) as arrow and fish poisons [50].

The next sections address in detail eight plant species with hypoglycemic properties, two of which are traditionally used against diabetes by each of the four largest ethnic groups in Suriname (the Afro-Surinamese, Hindustani, Javanese, and Chinese). The plants and herbal products associated with the three former groups have been selected on the basis of the number of times they have been mentioned in comprehensive publications on Surinamese medicinal plants [51–55]. Such documents are not available for plants and herbal products related to the Surinamese-Chinese. Therefore, information about anti-diabetic substances associated with this group has been obtained from a Surinamese-Chinese pharmacist, and from the imports of herbal products from the People's Republic of China by Surinamese-Chinese importers and distributors. Relevant information about the plants is given in **Table 1**. Preclinical and clinical indications for their hypoglycemic effect, as well as their presumed bioactive constituent(s) and mechanism(s) of action, are in detail addressed hereunder and have been summarized in **Table 2**.

#### **5. Plants with hypoglycemic properties associated with Surinamese from African origin**

#### **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


*Hypoglycemic Activity of Plant-Derived Traditional Preparations Associated with Surinamese… DOI: http://dx.doi.org/10.5772/intechopen.105106*

#### **Table 2.**

*Preclinical and clinical evidence for antidiabetic activity of eight commonly used plants in Suriname for the traditional treatment of diabetes mellitus, the presumed key active constituent(s) in the plants, and their presumed mechanism of action.*

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

#### **Figure 2.**

*Flowers of the minnieroot or watrakanu* Ruellia tuberosa *L. (Acanthaceae) (from: https://images.app.goo.gl/ JjLuHr66h8rca2c67).*

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 [59–63]. 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, 64–66]. *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

*Hypoglycemic Activity of Plant-Derived Traditional Preparations Associated with Surinamese… DOI: http://dx.doi.org/10.5772/intechopen.105106*

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 glucoselowering 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.

#### **Figure 3.**

*Flower inflorescences of the globe amaranth or stanvaste* Gomphrena globosa *L. (Amaranthaceae) (from: https://images.app.goo.gl/fxEMirfxTQZPZhENA).*

The flowers of *G. globosa* also serve as a source of betacyanins for use as a (redviolet) 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 [76–78].

*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 [76–78, 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. Plants with hypoglycemic properties associated with Surinamese from Hindustani origin**

#### **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

*Hypoglycemic Activity of Plant-Derived Traditional Preparations Associated with Surinamese… DOI: http://dx.doi.org/10.5772/intechopen.105106*

#### **Figure 4.**

*Fruits of the jambolan or jamún* Syzygium cumini *(L.) Skeels (Myrtaceae) (from: https://images.app.goo.gl/ AXjEW9A1nFFgi1nDA).*

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 purplishblack 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 [87–90], 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 [98–100]. Candidates in the seed with such antioxidant properties are phenolic compounds such as ferulic acid [101–103] 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 [104–106]. 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 [108–114] 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].

*Hypoglycemic Activity of Plant-Derived Traditional Preparations Associated with Surinamese… DOI: http://dx.doi.org/10.5772/intechopen.105106*

#### **Figure 5.**

*Fruits of the bael tree or bhel* Aegle marmelos *(L.) Corrêa (Rutaceae) (from: https://images.app.goo.gl/ SqaKhRAEja9Se8Rx8.*

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 [124–127]. 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 [128–130], 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 radicalscavenging 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 [139–141], postprandial blood glucose [138–142], 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. Plants with hypoglycemic properties associated with Surinamese from Javanese origin**

#### **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"

#### **Figure 6.**

*Leaves and flowers of the black face general or ketji beling* Strobilanthes crispa *(L.) Blume (Acanthaceae) (from: https://images.app.goo.gl/AMKPw44x1JPFUqnn9).*

*Hypoglycemic Activity of Plant-Derived Traditional Preparations Associated with Surinamese… DOI: http://dx.doi.org/10.5772/intechopen.105106*

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 [146–148]. 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 [146–148].

*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 [163–165]. 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 [161–163] including Surinamese Jamu [51]. Support for this use is provided by

**Figure 7.**

*Fruits of the mangosteen* Garcinia mangostana *L. (Clusiaceae) (from: https://images.app.goo.gl/6tU39NW2AB ubRr7t7).*

#### *Hypoglycemic Activity of Plant-Derived Traditional Preparations Associated with Surinamese… DOI: http://dx.doi.org/10.5772/intechopen.105106*

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 [168–170]. The *G. mangostana* preparations also improved, among others, oral glucose tolerance and the histology of the β-cells [168–170] 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 [168–170]. 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 [179–181]. Since these positive changes were accompanied by an improvement in insulin sensitivity [181], the data from these studies have merit.

#### **8. Plants with hypoglycemic properties associated with Surinamese from Chinese origin**

#### **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

#### **Figure 8.**

*Rhizmes of the Chinese ginseng or sān-qī Panax notoginseng (Burkill) F.H.Chen (Araliaceae) (from: https:// images.app.goo.gl/NB2rRHGPbEQrg1id9). In de insert de flower of the plant (from: https://images.app.goo.gl/ HbVFx8SkBDNy2zp37).*

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 performanceenhancing activities [185–187].

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 [185–187]. The biologically most important dammarane saponines in *P. notoginseng* are believed to be the notoginsenosides [185–187]. This was the rationale for developing and patenting a saponinenriched *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

#### *Hypoglycemic Activity of Plant-Derived Traditional Preparations Associated with Surinamese… DOI: http://dx.doi.org/10.5772/intechopen.105106*

in normal mice [191] and improved serum insulin levels, glucose tolerance, insulin resistance, glomerular lesions [192], and body weight in diabetic animals [192–195]. 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. ver*um, 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 [203–205] 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 [203–205]. 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,

**Figure 9.**

*Leaves, flowers, and fruits of the Chinese cassia or guān guì* Cinnamomum cassia *(L.) J.Presl (Lauraceae) (from: https://images.app.goo.gl/HGEBbvErrXoR43UL9).*

anti-inflammatory, gastroprotective, nematicidal, acaricidal, repellent, anti-obesity, anti-angiogenic, and anticancer activities [203–205]. 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 [203–205].

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, 214–216]; an increase in hepatic glycogenesis [217], and an increase in the consumption of extracellular glucose in both insulin-resistant

#### *Hypoglycemic Activity of Plant-Derived Traditional Preparations Associated with Surinamese… DOI: http://dx.doi.org/10.5772/intechopen.105106*

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 [220–223] as well as an improvement in insulin sensitivity in healthy [220, 222–224], 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 [225–227].

#### **9. Concluding remarks**

Diabetes remains one of the most prevalent diseases of mankind. Despite the many therapeutic options available, this condition is often treated with a variety of traditional medicines in many parts of the world. This chapter has extensively addressed eight plants and plant-derived preparations with hypoglycemic properties, two of which are traditionally used against diabetes by each of the four largest ethnic groups in Suriname. *R. tuberosa* and *G. globosa* are associated with the Afro-Surinamese, *S. cumini* and *A. marmelos* with the Surinamese Hindustani, *S. crispa* and *G. mangostana* with the Surinamese Javanese, and *P. notoginseng* and *C. cassia* with the Surinamese Chinese. As mentioned above, the prevalence of diabetes and other noncommunicable diseases is relatively high in Suriname [35–39], while most Surinamese have largely remained true to their cultural customs [28].

However, as summarized in **Table 2**, despite the availability of many preclinical observations on antidiabetic/hypoglycemic activity of preparations from the plants, the scientific evidence to back up these data is disappointingly meager. Notably, four of the eight plants (*R. tuberosa*, *G. globosa*, *S. crispa*, and *G. mangostana*) had not even undergone clinical testing, while the clinical findings of the remaining four (*S. cumini*, *A. marmelos*, *P. notoginseng*, and *C. cassia*) were in general inconsistent, some reporting positive effects in diabetic patients, others mentioning negative effects. On the bright side, there were in all cases suggestions about the pharmacologically active ingredients and mechanisms that may be involved in the putative antidiabetic/hypoglycemic activities of the plants (**Table 2**). Then again, it remains to be seen whether these findings also apply in the clinic.

These data clearly indicate the shortcomings of the scientific evidence accumulated so far to support the use of these plants against diabetes. This raises not only the possibility that patients treat their disease with substances that may be ineffective, but also that they may run the risk of unknown or unforeseen adverse effects or interactions with allopathic medicines or food constituents. For these reasons, it is necessary to subject these plants to systematic and large-scale clinical trials to definitely establish their roles in the treatment of diabetes. Obviously, these studies must be carried out with standardized preparations and uniform doses and administration schedules. The results from these studies are particularly important to countries such as Suriname, where a large proportion of the population relies on traditional herbal medicinal products.

*Basics of Hypoglycemia*

#### **Author details**

Dennis R.A. Mans Faculty of Medical Sciences, Department of Pharmacology, Anton de Kom University of Suriname, Paramaribo, Suriname

\*Address all correspondence to: dennismans16@gmail.com; dennis\_mans@yahoo.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Hypoglycemic Activity of Plant-Derived Traditional Preparations Associated with Surinamese… DOI: http://dx.doi.org/10.5772/intechopen.105106*

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#### **Chapter 2**

## Hypoglycemia and Brain: The Effect of Energy Loss on Neurons

*Daniel Arturo Martínez-Piña, Gustavo Alexis Alvarado-Fernández, Edith González-Guevara, Carlos Castillo-Pérez, Gerardo Romero-Luna and Jorge Alejandro Torres-Ríos*

#### **Abstract**

Glucose provides the necessary fuel to cover the physiological functions of the organism. In the brain, glucose represents the main energy supply through the generation of adenosine triphosphate, with oxygen and glucose being the main components involved. The imbalance in glucose levels in the central nervous system produces substantial changes in metabolism. Hypoglycemia, or decreased blood glucose levels below 50 mg/dl, is accompanied by symptoms such as decreased performance of cognitive tasks such as verbal fluency, reaction time, arithmetic ability, verbal memory and visual, in addition to excitotoxicity, oxidative stress, neuroinflammation and apoptosis. Hyperglycemia participates in some cardiovascular diseases, neuropathy, nephropathy, retinopathy. Changes in glucose metabolism must be regulated and considered in order to obtain the best treatment for different pathologies, such as infections, non-infections, traumatic, primary or acquired.

**Keywords:** hyperglycemia, hypoglycemia, neuroglycopenia, neuroinflammation, oxidative stress

#### **1. Introduction**

The human brain requires a high and continuous input of energy, which is obtained mainly from glucose, due to its high metabolic rate. Some interesting facts about the brain are that it accounts for only 2% of body weight, but it also requires 15% of cardiac output, 20% of total body oxygen and 25% of serum glucose, which means that the human brain uses up between 5 and 10 g of glucose per hour or 140 g per day on average [1]. Under normal conditions, serum glucose is around 80–90 mg/dl and may increase up to 200 mg/dl after meals. On the other hand, serum glucose may decrease up to 54 mg/dl during prolonged fasting. The concept of hypoglycemia refers to a clinical situation in which patients have a serum glucose value below 50 mg/dl matching with neuroglycopenic symptoms or serum glucose values below 40 mg/dl without any symptoms [1]. The high energy requirements of the human brain employ such complex metabolic strategies to manage energy sources. Glucose enters the central nervous

system through the Blood-Brain Barrier (BBB), a process that requires a transport protein located in the cell membrane [2, 3]. There are two systems of glucose and other monosaccharide transporter proteins: sodium-glucose transporters, also known as SGLTs (sodium-dependent glucose transport), and glucose transporters, also known as GLUTs (glucose transporters). There are several types of GLUT transporters in the human body, but in the central nervous system, there are only two types: GLUT1, which is found in the BBB, and GLUT3, which is found in neurons. Glucose enters cells via GLUT transporters in a process composed of four steps; (1) first, glucose binds to the transporter protein on the outer face of the cell membrane; (2) the transporter protein changes its conformation and glucose enters into the cell membrane; (3) glucose is released into the cytoplasm by the transporter; (4) the transporter returns to its original conformation and its glucose binding site is exteriorized again (**Figure 1**) [4, 5].

The human brain requires a lot of energy to carry out all its functions, this energy comes from different pathways in which glucose and oxygen work together to develop adenosine triphosphate (ATP). The bonds of the ATP molecule are then broken to obtain stored energy, and most of this energy is used for information processing. For example, in the human brain, there are about 10 billion neuronal cells communicated by more than 50 trillion synapses through neurotransmitters that are synthesized in the cerebral cortex in a process that requires about 3.8 × 1012 molecules of ATP [5, 6].

Neuronal and glial cells have distinct functions and are metabolically different from each other [6]. In fact, the gray matter of the human brain uses 10 times more glucose than any other organ in the body. With the known stoichiometry of glucose oxidation (C6H12O6 + 6O2 6CO2 + 6H2O) and its coupled reactions, it is possible to obtain an estimated flux at different points in the metabolic chain. This allows us to know how glucose enters into glycolysis and the Krebs cycle, leading to the release of energy that is then split into small components such as ATP, increasing its molar flux to 31 molecules of ATP for each molecule of glucose [7].

Oxidation of glucose molecules through the tricarboxylic acid cycle develops small amounts of lactate, which plays an important role as a precursor to the process of

#### **Figure 1.**

*Glucose transport from blood vessels to neuronal cells. GLUT (glucose transporters). Modified from Iatreia: 2002;15(3).*

gluconeogenesis in the nervous system. Lactate becomes an energetic compound for the nervous system, which is demonstrated in neuronal and glial uptake, improving ATP synthesis in neurons. Such articles suggest that glucose is stored by the astrocytes and then released as glucose or lactate, to be used by neurons, when energetic requirements increase [8].

#### **2. Cellular and molecular facts of glucose**

Glucose is absorbed by GLUT1 protein transporters and can be stored as glycogen (the most important storage of glycogen is located on astrocytes) or go into glycolysis (**Figure 2**) [9].

#### **2.1 Neurons**

Glucose represents the main source of energy and its metabolic regulation is so important for normal nerve cell functions, including ATP synthesis, regulation of oxidative stress, synthesis of neurotransmitters and neuromodulatory molecules and many processes such as memory, learning and sensitivity and motor functions [10, 11]. The overall performance of neurons, astrocytes and endothelial cells is very important during the transit of energy supplements in the nervous system necessary to cover cellular functions [12]. As mentioned above, neuronal cells require a high amount of energy which is obtained from glucose; also glucose can be obtained directly by neurons or indirectly from astrocytes that converted lactate into glucose previously [13, 14]. In normal conditions, neurons obtain energy from glucose, but

#### **Figure 2.**

*Pathway of glucose from food to ATP in the neuron. The blue color is the area outside the blood-brain barrier, the green color represents only processes in the astrocyte, the yellow color processes in the neuron, and the orange color represents the intramitochondrial pathways.*

during the synaptic activity, they mainly consume lactate as a product of glucose metabolism. In both cases, the overall net brain consumption would be sustained by glucose. Under conditions of glutamatergic synaptic activity, glutamate stimulates GLUT-1-mediated glucose incorporation and glycolysis in astrocytes, followed by the release of lactate into the extracellular space and its capture in neurons, the neuron uptake of glucose is made via the GLUT-3 transporter [9, 15–17].

#### **2.2 Astrocytes**

Astrocytes also need the energy to carry out their functions, these cells play such an important role in brain metabolism by providing lactate as a metabolic substrate when neuronal energy requirements increase. In astrocyte cells, the GLUT-1 transport protein is the main glucose uptake protein. Once glucose enters the astrocyte, it is converted to glucose-6-phosphate (G6P) to undergo glycolysis or be converted to glycogen. Glucogenic enzymes involved in glycogen metabolism, such as glycogen synthase, store backup glycogen. Glycogen phosphorylase and the debranching enzyme metabolize glycogen into G6P to undergo glycolysis when the astrocyte, or near neurons, require energy sources (**Figure 3**) [18, 19].

#### **2.3 Hypoglycemia in neurons and astrocytes**

It has been described that hypoglycemia actively causes neuronal death. When glucose concentration decreases below 1 mM (18 mg/dl), causes energy deficit, the release of excitatory amino acids (aspartate and glutamate) induces the expression of

#### **Figure 3.**

*Glucose metabolism and energy synthesis in astrocytes and neurons. LDH (lactate dehydrogenase), MCT (medium-chain triglycerides), LAC (lactate), ATP (adenosine triphosphate), NAD+ (nicotinamide adenine dinucleotide oxidized), NADH (nicotinamide adenine dinucleotide reduced), H+ (hydrogen), Pyr (pyruvate). Modified from N Engl J Med 2015; 373:187–189.*

#### *Hypoglycemia and Brain: The Effect of Energy Loss on Neurons DOI: http://dx.doi.org/10.5772/intechopen.104210*

excitatory receptors located in neuronal dendrites that produce calcium fluxes, inducing neuronal necrosis. Hypoglycemia constitutes a metabolic brain injury [20, 21].

During hypoglycemia or periods of intense brain activity, glycogen can be used to generate lactate, which is translocated to nearby neuronal cells. Thus, glycogen within astrocytes functions as a backup system in case of hypoglycemia, ensuring neuronal functions and survival during glucose deprivation [22, 23]. In cases of brain ischemia, astrocytes have shown a high resistance, a situation that is explained by its glycogen store. Astrocytes also keep glucose synthesis for longer time periods compared with neuronal cells. Besides, astrocytes lead glycogen to turn into lactate which is moved within neurons when these cells have increased energy requirements or during lack of glucose. However, the amount of mitochondria within astrocyte cells is smaller than the amount of mitochondria within neuronal cells. A single molecule of lactate can generate 10 mM ATP, which is equivalent to 17 molecules of ATP [7, 23]. Several papers suggest that glucose molecules are stored mainly in astrocyte cells and can be released as glucose or lactate to contribute to neuronal metabolism when energy needs increase [8, 22, 23]. Other studies, recently published, suggest that other substrates such as pyruvate, glycogen, ketone bodies, glutamate, glutamine and aspartate can be metabolized by neuronal cells in case of glucose deprivation, supporting neuronal functions and delaying ATP depletion during hypoglycemia [24]. Astrocytes can release purines made of adenine, specifically adenosine (which plays an important role as a neuroprotective molecule) and guanosine which can lead to cell repair after a brain injury (**Figure 3**) [25].

In situations of low glycogen levels, glycogen can modulate some neurotransmitters and also serum glucose levels. These facts are explained by the fact that, during periods of hypoglycemia, glycogen is converted into lactate and reaches nearby neurons and axons where it is used as an energy source, leading to protection against hypoglycemia-induced brain injury and ensuring that neuronal functions supplying energy demands [26].

#### **3. Cellular and molecular neuroglycopenia**

#### **3.1 Calcium and hypoglycemic damage**

As mentioned above, intracellular calcium accumulation promotes lipolysis, increasing the amount of free fatty acids due to phospholipids metabolism, including arachidonic acid, activated by cyclooxygenase enzyme and promoting oxygen reactive species releasing, platelet aggregation and neutrophil chemotaxis, leading to inflammation and direct/indirect cell damage. Calcium accumulation can also activate regulatory mechanisms to keep adequate levels of this ion, such as calsequestrin and chelation promoted by the endoplasmic reticulum and mitochondria [27]. When these mechanisms fail, an ionic overcharge takes place in the mitochondria and the cell membrane polarity is dropped. When the membrane potential is dispelled, the ATP synthase works upside down, metabolizing ATP. Also, it is impossible to generate ATP by Krebs cycle or oxidative phosphorylation. Serum calcium levels decrease during isoelectric periods and return to normal levels after glucose administration. This fact correlates to an increase in intracellular calcium levels and neuronal injury. Besides, proapoptotic factors are released as cytochrome C, caspase 3 and apoptosis-inducing factors. A persistent state of oxidative stress

**Figure 4.** *Example of severe hypoglycemia in the brain.*

is induced by a failure in the I and IV complex of the electron transport chain and release of reactive oxygen species (**Figure 4**) [28].

#### **3.2 Reactive oxygen species and oxidative stress**

Oxygen ions, free radicals and peroxides are very small molecules, which appear as a result of oxygen metabolism, and play an important role in the oxidation-reduction process, activating genes, exchanging ions when their values need to be regulated. The regulating mechanisms to avoid over synthesis of these small molecules include important enzymes groups such as catalase and superoxide dismutase. There are also antioxidant molecules, for example, ascorbic acid, uric acid and glutathione. Oxidative stress can be defined as a metabolic status with overproduction of oxygen reactive species and exceeding the antioxidant molecules' capacity to offset this process. Some important molecules that can be affected by this situation are cell membrane lipids, deoxyribonucleic acid (DNA) and proteins. An increase in catalase and superoxides dismutase enzymes indicate, indirectly, the presence of peroxides and superoxide, respectively. That is because these enzymes are considered important indirect markers of oxidative stress [29].

The glutathione tripeptide functions as a chemical synthesis buffer during oxidation-reduction reactions carried out by the mitochondria. This chemical buffer is made of glycine, glutamate and cysteine. Another chemical buffer that appears in cases of oxidative stress is glutathione in its oxidized form, which is formed by two glutathione molecules linked by a disulfide bond. There is also an increase in nitric oxide synthase, subsequently, nitric oxide becomes reactive when it is combined with superoxides, forming peroxynitrite, a highly reactive molecule with a short half-life, which in addition to oxidizing nearby molecules, can be transformed into nitrotyrosine when reacting with tyrosine residues, increasing immunoreactivity. The neuronal cells located on the Ammon's horn 1 region (CA1), in the hippocampus, promote an increase in zinc levels during long times of hypoglycemia. The glucose reintroduction

*Hypoglycemia and Brain: The Effect of Energy Loss on Neurons DOI: http://dx.doi.org/10.5772/intechopen.104210*

#### **Figure 5.**

*Cell death in neuroglycopenia. DNA (deoxyribonucleic acid), PARP (poly-ADPribose), NMDA (N-methyl-D-aspartate), Mg2 (magnesium), Ca2+ (calcium), Na<sup>+</sup> (sodium), K+ (potassium), nNOS (neuronal nitric oxide synthase), NO+ (derived from oxygen species), ROS (reactive oxygen species), Cit C (cytochrome C), AIF (apoptosis inducing factor).*

to the system promotes zinc vesicles and nitric oxide synthesis that trigger neuronal damage. Zinc activates the NADPH enzyme oxidase (NOX) and poly-ADP ribose (PARP-1) after being translocated to postsynaptic neurons, leading to the production of reactive oxygen species (ROS), depletion of oxidized nicotinamide adenine dinucleotide (NAD+) and lead to neuronal death. The production of ROS by NOS and NOX induces DNA damage and consequent activation of PARP-1, which consumes the NAD+ which is required for glucose oxidation through the glycolytic pathway, as well as activating programmed cell death pathways such as calpain [30]. During hypoglycemia, PARP-1 activation is an important factor involved in neuronal death (it leads to increased nitrotyrosine and products of this polymerase). On the other hand, PARP-1 inhibitors can rescue neurons that would otherwise die after severe hypoglycemia (**Figures 4** and **5**) [31, 32].

#### **3.3 Apoptosis and inflammatory response**

Apoptosis is a type of cell death that depends on energy and various cellular functions in which the membrane retains its integrity. For its activation, specific proteins are required to avoid inflammatory responses, which are divided into intrinsic and extrinsic pathways. The intrinsic activation pathway consists of caspases and calpain. Caspases are classified as initiators, such as caspase 9 and executors, including

caspase 3. The intrinsic pathway starts with the release of cytochrome C from the mitochondrial inner membrane, which increases its concentration in the cytosol and binds APAF1 (apoptotic protease-activating factor 1) protein, dATP and procaspase 9 zymogen [29, 32]. Once bound, this complex becomes an active initiator form of the pathway, caspase 9, which consequently causes the activation of the executioner pathway, procaspases 3 and 7, responsible for promoting apoptosis.

It has been postulated recently that an inflammatory response also participates in hypoglycemic cell damage, this is known due to a study that demonstrates microglial reactivity in the rat of hippocampus 1–7 days after 30 minutes of hypoglycemic isoelectric, with activation of calpain, xanthine oxidase and phospholipase A2.

Tkacs and cols., demonstrated that three hypoglycemic episodes related to 30–35 mg/dl glucose blood levels increased the number of positive cells to TUNEL (apoptosis marker in the arcuate nucleus of the hypothalamus). Subsequently, other authors reported positive degenerative cells to the neuronal death marker Fluoro-Jade B (FJB) after only 1 week of a single hypoglycemia event, particularly in the cerebral cortex, although some were also observed in the hippocampus and striatum [33].

In 1880, blood glucose levels were measured for the first time, which made it possible to understand the different clinical neurological manifestations and their association with low blood glucose levels [34]. It was in 1938, when the surgeon Allen Whipple proposed a triad characterized by hypoglycemia symptoms, decreased venous glucose concentration and the disappearance of these symptoms after the correction of glycemia. Although this description was proposed as criteria to perform or not the insulinomas resection, this triad became widely generalized among the medical community in the face of hypoglycemia events due to any cause. Reversibility of the clinical syndrome is frequent when treatment is initiated, although there are also less fortunate scenarios in which sustained damage to the nervous system is produced, which will depend on the degree of hypoglycemia when treatment is not timely. This situation is directly related to functional prognosis and mortality [34, 35].

The physician must be able to identify the clinical signs of hypoglycemia since the first organ to suffer the consequences is the brain, and we must avoid unfavorable outcomes, such as neuronal damage and death (neuroglycopenia). When the arterial glucose supply is interrupted and the protective mechanisms are overcome, the previously described alterations occur at the level of ionic gradients, neurotransmitter release and reuptake, and oxidative stress, culminating in mitochondrial and cellular dysfunction [36].

There are usually very effective endogenous mechanisms to prevent neuroglycopenia. The first line of defense against falling blood glucose levels is to decrease endogenous insulin production, increasing hepatic glucose production and decreasing its utilization by other peripheral tissues such as muscle and fat tissue [37]. If glucose levels remain low, there will be glucagon secretion, followed by an increase in adrenaline. These counterregulatory mechanisms will be as intense as hypoglycemia severity, resulting in mobilization of glycogen stores, gluconeogenesis and decreased glucose utilization at the peripheral level [38].

A very particular characteristic of the brain is the high consumption of glucose and oxygen, with a high tolerance to periods of transient deficit of these substrates, however, when glucose decreases below 20 mg/dl, there is a cessation of brain electrical activity (hypoglycemic coma). Blood glucose concentrations may decrease to 30% of the normal value, but this supply must be constant, as neuronal glycogen stores are limited and depleted in less than 2 minutes. From this point on, the extent of neuronal damage is directly related to the time the isoelectric period is maintained. Neuronal

death occurs after a period of approximately 15 minutes of inactivity. Repeated episodes of hypoglycemia cause irreversible damage, causing the irreversible cognitive deficit, which correlates to various brain structures, the most sensitive to the damage being the cortex, hippocampus and striatum [39].

#### **3.4 Excitatory amino acids in hypoglycemic damage**

Excitotoxicity refers to the ability of some amino acids (glutamate) to cause neurodegeneration secondary to prolonged stimulation of postsynaptic receptors. This type of toxicity was first described in cerebral vascular disease; later evidence was found in severe hypoglycemia. The mechanism of damage is as follows: extracellular concentrations of glutamate are regulated by reuptake into the synaptic space by specific transporters located in astrocytes and neurons. This reuptake is mediated by sodium, regulated by the electrochemical gradient of ATP-dependent Na/K+ pumps. These ionotropic receptors are classified according to their specific agonist: the N-methyl D-aspartate (NMDA) receptor, permeable to calcium and sodium. The non-NMDA receptors (kainate receptor and a-amino-3-hydroxy-methyloxazole-4propionic acid (AMPA) are sensitive to sodium [40].

Under resting conditions, the NMDA receptor ion channel is blocked by magnesium, which is released during depolarization mediated by non-NMDA aspartate receptordependent ion channels, allowing calcium to enter the intracellular space. Both glutamate and aspartate have been shown to be associated with neuronal damage in hypoglycemia, being released in large amounts during the isoelectric trace [41]. In this situation glutamate is used as a metabolic substrate, favoring the release of aspartate by altering the electrochemical gradient of Na+/K+, promoting the accumulation of intracellular calcium and with it, the release of vesicles by exocytosis with excitatory neurotransmitters. Even with the accumulation of excitatory neurotransmitters, the inhibition of their transporters can limit neurological damage; however, when there is an absence of energetic substrates, neuronal death is induced. As mentioned, neuronal death and cognitive impairment caused by hypoglycemia suggest that they are involved in excitotoxicity and DNA damage.

#### **4. Neuroglycopenia secondary to hypoglycemia**

To avoid neuronal death during a period of hypoglycemia, the brain sets in motion two main regulatory mechanisms: increased cerebral blood flow and the use of alternative substrate pools to glucose [39, 41]. During hypoglycemia, oxygen consumption remains constant, giving rise to the theory that these alternative pools are able to compensate for the lack of glucose, allowing adequate cellular function during relatively short periods of hypoglycemia. The brain can use other substrates for energy, such as lactate, pyruvate and ketone bodies, although the primary substrate in the first instance appears to be glycogen, which seems to be depleted in more than 5 minutes after the onset of the isoelectric period [42].

The nervous system is very susceptible to changes when serum glycemia value is low, which leads to protective mechanisms; on the other hand, when there is hyperglycemia it has a better regulation. The endocrine counterregulatory response mechanisms that are activated when glucose drops below 70 mg/dl, at the level of the pancreatic b-cells the first response is initiated, which consists in the cessation of insulin release and when the glucose level reaches 66 mg/dl, growth hormone and cortisol are released, which stimulate lipolysis in adipose tissue, ketogenesis and gluconeogenesis in the liver. Below 54 mg/dl, glucagon (a hormone produced in pancreatic cells, which stimulates hepatic glucose production through glycogenolysis and gluconeogenesis) and epinephrine are secreted. Epinephrine secreted by the adrenal glands increases glycogenolysis and gluconeogenesis in the liver, stimulates lipolysis and decreases insulin secretion while elevating glucagon release (**Table 1**) [38, 39, 42].

The first modulatory process in hypoglycemia is decreased insulin synthesis. This is followed by an increase in other involved hormones such as GH, ACTH, glucagon, and epinephrine, resulting in the activation of metabolic regulatory pathways such as lipolysis, ketogenesis, and gluconeogenesis.

Recurrent hypoglycemia can cause the loss of these counterregulatory mechanisms and create a vicious cycle increases the risk of severe hypoglycemia with each event. Recurrent hypoglycemia reduces the glucose levels necessary to trigger the autonomic counterregulatory response during a subsequent hypoglycemic period, leading to patients being unable to recognize sympathoadrenal symptoms, leading to the onset of neuroglycopenic symptoms (hypoglycemia unawareness). The unawareness of hypoglycemia and the failure of the autonomic response lead to the so-called hypoglycemia-associated autonomic failure, which increases the risk of severe hypoglycemia by 25 times or more, with high chances of coma, irreversible brain damage and death. Clinical data suggest that about 25% of diabetic patients suffer hypoglycemia without realizing it [37, 39, 42]. Hypoglycemia occurs in 25–30% of diabetic patients, with type 1 diabetics being more affected, followed by type 2 diabetics, although in them it usually happens in advanced stages of the disease. The incidence of hypoglycemia episodes depends on the age and duration of the disease. The mortality rate is between 4 and 10% and is attributable to severe hypoglycemia in type 1 diabetic patients with the long-standing disease (7–30 years), this is because the continuous administration of insulin or insulin-releasing drugs leads to glucose uptake in fat, muscle and liver, inhibiting gluconeogenesis and glycogenolysis, as well as lipolysis and glucagon secretion from pancreatic cells. As a consequence, the first response to hypoglycemia (inhibition of insulin secretion) is lost, glucagon secretion is suppressed, and epinephrine is secreted at lower glucose levels [37, 38, 42].

#### **4.1 Moderate or severe hypoglycemia**

According to histological studies, hypoglycemic coma induces neuronal damage in the cortex, particularly in the insular cortex, hippocampus, caudate nucleus and putamen; lesions have also been identified in the thalamus, globus pallidus and a significant volume decrease in the white matter and gray matter in all cerebral lobes with occipital and parietal predominance. There is a close correlation between the duration of the isoelectric period and the spread of neuronal damage. The most


#### **Table 1.** *Brain protection mechanisms in neuroglycopenia.*

vulnerable brain regions include superficial layers 2 and 3 of the cerebral cortex, CA1, the subiculum and crest of the dentate gyrus, as well as neuronal damage in the dorsolateral region of the striatum [43].

#### **5. Clinical manifestations in neuroglycopenia**

Signs and symptoms for hypoglycemia depend on glucose levels (mild, moderate or severe), frequency and duration of episodes. Symptomatology can be divided into two big groups: The first group included sympathoadrenal or neurogenic symptoms due to the activation of the autonomic nervous system and the release of epinephrine and norepinephrine, triggered in moderate hypoglycemia. The symptoms can be hunger, sweating, tingling, tremors, palpitations and anxiety (the initial symptoms that allow the patient to notice the hypoglycemic state). If glucose levels continue dropping to moderate or severe, the patient would develop the second group of symptoms (neuroglycopenic symptoms) which include blurry vision, confusion, dizziness, irritability, bradylalia, lipothymia, drowsiness, bradypsychia, seizures and coma. However, they do not always present the same way, actually, it is one of the first diseases that mimic brain stroke symptoms, among other acute neurologic diseases (hypoglycemic encephalopathy) [34, 35, 44]. Hypoglycemia recurrence induces the body to adapt, and the clinical signs can be minimal or absent until the glucose levels decrease deeply, taking the patient to an impaired consciousness state (**Table 2**) [29, 44].

Mild hypoglycemia has subtle symptoms which are inconspicuous with cognitive changes. Multiple studies have done experiments on both humans and animals, finding an association between hypoglycemia and cognitive impairment, affecting complex abilities more than simple ones, regulated by the hippocampus [45, 46]. After a severe hypoglycemia episode, the cognitive deterioration in different cerebral domains appears in healthy individuals with glucose blood levels between 2.6 and 3.3 mmol/l [47]. Severe hypoglycemia causes a decrease in the performance of cognitive tasks, such as verbal fluency, reaction time, arithmetic abilities and verbal and visual memory [48]. The cognitive function drop is seen after the activation of the counterregulatory response and the presence of neuroglycopenic symptoms in diabetic


#### **Table 2.** *Clinical manifestations of neuroglycopenia.*

patients, however, this response changes in non-diabetic patients in whom the cognitive function is immediately impaired, even before the counterregulatory neuroendocrine response starts and senses the neuroglycopenic symptoms (**Table 2**) [47, 48].

In 1990, Ryan et al., evaluated the cognitive effects after a hypoglycemic event in children, using the hypoglycemic clamp technique, with a control group with normal glucose levels. Hypoglycemic values were 3.1–3.6 mmol/l and the euglycemic values were from 5.5 mmol/l onwards, noticing a significant decrease in the trail-making test (mental flexibility), attention and decision making in the mild hypoglycemic group. Also, once the glycemic values were restored (>5.5 mmol/l), there was no recovery observed in the attention or reaction time tests, which suggests a long-term neurological effect [49].

Other studies have documented attention, intelligence and memory disturbances in children with a history of severe hypoglycemia [48, 49]. Childhood hypoglycemia represents an essential factor that affects specific cognitive capabilities such as memory, learning, intelligence and attention, being the most vulnerable cognitive domains to hypoglycemia in children [50, 51]. However, no studies have been made comparing the history of hypoglycemia with long-term control groups, therefore, the sequels that may develop are unknown with certainty.

Also, there have been reported mood disorders associated with repeated events of severe hypoglycemia, especially in depressive disorder until 24 hours after the event. Acute hypoglycemia changes the state of mind causing the patient to feel exhausted and reducing the hedonic tone. The consequence of long-term and repetitive periods of moderate hypoglycemia to neuronal damage and cognitive function is not well understood, however, prolonged hypoglycemia with the absence of isoelectricity can also induce neuron death restricted mainly to the cerebral cortex. Glucose blood concentrations of 30–35 mg/dl for 75 minutes can cause significant neuron damage in the medial prefrontal cortex, piriform cortex and orbital cortex [52].

#### **5.1 Imaging in neuroglycopenia**

Objective damage from repeated hypoglycemia events is difficult to document because routine imaging studies are not usually performed in this type of patient, as it is an event that is treated in the emergency room and it usually subsides in a few minutes. However, some studies have evaluated diabetic patients with recurrent hypoglycemia events trying to correlate cognitive alterations and imaging findings in MRI [53]. It has been reported cortical atrophy in type 1 diabetic patients with severe recurrent hypoglycemia events while in patients who do not have recurrent events these findings were not present, nevertheless, these findings were not related to the cognitive alterations. There are also case reports in which the MRI shows a reduction in the white matter of the hippocampus, thalamus and globus pallidus, correlating this with memory loss and anterograde amnesia, however, these findings are not common, which make them statistically insignificant.

#### **6. Neuroglycopenia with and without hypoglycemia in medical scenarios**

The physiology of glucose in the human brain has already been discussed thoroughly, its' way through the blood-brain barrier and molecular, cellular, tissue and systemic conditions, on the other hand, it is important to mention some clinical scenarios where these events take place even though there are not evident and can explain part of the symptoms and prognostic in each entity. This section will briefly *Hypoglycemia and Brain: The Effect of Energy Loss on Neurons DOI: http://dx.doi.org/10.5772/intechopen.104210*

**Figure 6.**

*Hypoglycemia negatively affects diseases of the central nervous system.*

describe neuropathologic things that cause glucose levels alterations at the central nervous system and important treatment aspects (**Figure 6**).

#### **6.1 Glucose brain concentration in the intensive care unit**

The relationship between changes in glucose values and cardiovascular events, such as stroke and acute myocardial infarction, has been well established. Both hyperglycemia and hypoglycemia are factors that vary patient prognosis [54]. Glucose dysregulation is a common situation in neurocritical patients. Since 1849, the association between hyperglycemia and prognosis has been described in patients with cerebral infarction, a situation that has been repeated in more recent studies [55, 56], which also include patients with acute brain injury secondary to other situations such as meningitis and cranioencephalic trauma [57].

From several years, it has been thought that intensive glucose control by continuous infusion, even to near-normal levels, might be beneficial to the patient; however, the NICE-SUGAR study group conducted a randomized clinical trial comparing intensive glucose control (from 81 to 108 mg/dl) with a group in which glucose levels were more permissive (up to 180 mg/dl), with subcutaneous bolus insulin administration. Glucose below 140 mg/dl was associated with increased hypoglycemia events and increased cardiovascular mortality, whereas glucose levels above 180 mg/dl were associated with the worse neurological recovery and increased likelihood of sequelae [58, 59]. Multiple studies have reached the same conclusion, including the SHINE study, in which intensive control compared with the standard modality did not make a significant difference in functional outcome (Rankin scale at 90 days) [60].

Very loose glucose control was associated with worse neurological recovery, although it does not significantly influence mortality in the neurocritical patient, some sequelae may impact functionality [61].

#### **6.2 Brain glucose concentrations in cerebral infarction**

Several clinical trials have shown that cerebral stroke patients with acute elevation of glycemia at the onset of the event suffer worse functional outcomes, longer hospital stay and higher mortality with a higher rate of bleeding after the ischemic event [62]. The definition of hyperglycemia is debated, the reference cohort for different authors usually varies according to the results obtained in clinical trials, where the objective is the correlation between glucose levels and increased mortality, findings are diverse, finding favorable results with levels of 110–155 mg/dl [63, 64]. It has been shown that patients with ischemic stroke who are treated with tissue plasminogen

activator benefit from glucose levels below 140 mg/dl in the first hours of treatment, which correlates with the benefit of the fibrinolytic drug, since patients with adequate initial glycemic control had higher reperfusion rates, smaller infarcts, and better functional prognosis than patients with higher glucose levels, this is independent of chronic glycemic dyscontrol [65, 66]. Although evidence indicates that intensive glucose control does not impact mortality, hypoglycemia could have an impact on the development of neurological damage and long-term sequelae, perpetuating the damage already established by previous injuries in the neurocritical patient [67].

#### **6.3 Brain glucose concentrations in patients with traumatic brain injury**

During traumatic brain injury there is a net decrease in glucose in microdialysis, but an increase in glutamate and lactate/pyruvate in microdialysis, with an adverse effect on the long-term recovery of neurological function [68]. Care should be taken in the management of these patients, as it is known that during traumatic injury there is hyperglycemia, using insulin to control it and decrease brain damage due to hyperglycemia, however, adequate monitoring should be performed, as lowering glucose levels with insulin may induce and aggravate secondary brain injury [69].

A hypothesis suggests that post-traumatic reductions in extracellular glucose levels are not due to ischemia, but are associated with poor neurological outcomes. Neurosurgical data from the microdialysis catheter in uninjured brain tissue with a perfusion rate of 2 uL/min suggest that glucose values of 0.5–1 mmol/L and lactate of 0.6–1.1 mmol/L are considered normal. In patients with epilepsy versus non-epileptic tissue perfused at 2.5 uL/min, mean glucose values of 0.82 ± 0.27 mmol/L and mean lactate levels of 1.3 ± 0.49 mmol/L were observed [70]. In minimally injured brain trauma patients perfused at a rate of 2 uL/min and under conditions of normal intracranial pressure and normal tissue oxygenation, reports of mean glucose values have ranged from 0.5 to 1.1 mmol/L, demonstrating that glucose variations are not significant during direct trauma [71]. The extracellular glucose level is generally reduced after severe traumatic brain injury and is associated with poor neurological recovery, but is not associated with ischemia [72].

Due to these findings, blood glucose control in patients with traumatic brain injury has recently been the subject of much research [68, 72]. A retrospective study included a total of 228 patients with severe trauma who were treated with insulin. In the first week (acute stage), a blood glucose target of 90–144 mg/dL (5–8 mmol/L) was associated with a reduced mortality rate and a decrease in intracranial pressure (ICP) compared with a blood glucose target of 63–117 mg/dL (3.5–6.5 mmol/L). However, in the second week, the groups appeared to have the reverse results: compared to the target group of 5–8 mmol/L, the 3.5–6.5 mmol/L group demonstrated a lower incidence of ICP and a reduction in infectious complications. Therefore, slightly higher blood glucose (5–8 mmol/L) appears to provide benefits during the first week, whereas lower blood glucose (3.5–6.5 mmol/L) may be more favorable during the later stages of recovery [69, 72]. Another study showed that blood glucose < 6–11 mmol/L could reduce mortality in patients with mild trauma, whereas, in severe cases, the ideal blood glucose target was 7.77–10.0 mmol/L.

Both hyperglycemia and hypoglycemia are harmful [70, 73]. Therefore, methods to improve intensive insulin therapy without inducing secondary complications should be investigated, and attention should also be focused on the prevention of hypoglycemia in patients with head injury [73]. It can be concluded that, in the first

few days following traumatic brain injury, patients benefit most from less strict glucose control, and that, past this acute period, blood glucose targets should be modified.

#### **6.4 Hypoglycorrhachia without hypoglycemia**

An objective way to demonstrate neuroglycopenia without symptoms is by measuring glucose in the cerebrospinal fluid (CSF). There are multiple etiologies that lower glucose centrally and are recognized not by the symptomatology of neuroglycopenia but by the characteristic symptoms of each disease and the presence of hypoglycorrhachia (there are multiple definitions, however, the most accepted is CSF glucose/serum glucose ratio ≤ 0.5, and < 40 mg/dl is considered severe) [74, 75]. The etiologies are diverse in both children and adults (**Table 3**) [74–76]. Treatment is disease-specific and hypoglycorrhachia is not specifically treated.

#### **6.5 COVID-19**

Neuro-COVID has been described for its clinical manifestations and findings in acute neurological disease, and the data that have caused the most impact when talking about encephalitis secondary to COVID-19 is hypoglycorrhachia and changes in the electroencephalogram [77]. Based on the above, our team conducted an investigation during the current SARS-CoV2 pandemic in 30 patients with a diagnosis and positive polymerase chain reaction for SARS-CoV2, without any obvious neurological manifestations, and performed a clinical history, complete physical and neurological examination, lumbar puncture and electroencephalogram, obtaining the following results: We found a high prevalence of minor neurological manifestations, such as headache, anosmia, dysgeusia and hypoaesthesia predominating in the early stages [78]. Other frequent abnormal findings were in the CSF with hypoglycorrhachia >70% and less frequently in the electroencephalogram of the scalp with focal and generalized dysfunction in <20%.


#### **Table 3.**

*Diseases with hypoglycorrhachia without neuroglycopenia.*

#### **7. Conclusion**

Glucose is the main fuel for the appropriate functioning of the central nervous system. It has been described the main mechanism of entry and use of glucose at the molecular and cellular levels. We emphasize that neurons and astrocytes interact to form common metabolic cooperation generating a neuroprotective effect to avoid hypoglycemic coma or a major brain injury that leads to cellular death. We cannot forget that when a patient has already had neuroglycopenia secondary to hypoglycemia, he/she already has a change in his/her metabolism and recurrence becomes more frequent with each episode, which is why some insulin-dependent diabetics die. The management of glucose in critically ill patients or at the brain level is different and the ideal treatment and glucose values at central and serum levels are not clear. Central nervous system diseases that cause hypoglycorrhachia are treated by etiology and not by low central glucose. Finally, at the time of writing this chapter we faced with the fact that the amount of published information is old and repetitive, it is important to continue research on the damage, prevention and prognosis of glucose levels at the central level in different scenarios.

#### **Acknowledgements**

Architect Dulce Maria Gallardo Rocha and Engineer Luis Miguel Vaquera Ortiz for making and editing the images and tables used in this chapter.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Appendices and nomenclature**


*Hypoglycemia and Brain: The Effect of Energy Loss on Neurons DOI: http://dx.doi.org/10.5772/intechopen.104210*


#### **Author details**

Daniel Arturo Martínez-Piña1 \*, Gustavo Alexis Alvarado-Fernández2 , Edith González-Guevara1 , Carlos Castillo-Pérez1 , Gerardo Romero-Luna1 and Jorge Alejandro Torres-Ríos1

1 National Institute of Neurology and Neurosurgery, Mexico City, Mexico

2 Hospital Gustavo A Rovirosa Perez, Villahermosa, Mexico

\*Address all correspondence to: daniel\_264mx@hotmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 2
