Essay: The effect of Hypoxis hemerocallidea on insulin secretion and digestion enzymes

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1 Introduction

The blood glucose level is regulated as part of metabolic homeostasis (Young, 1977). The normal range of glucose in the plasma is regulated between 3.5-8.0 mM (Arciero et al., 1999). The level of the sugar in the blood outside the normal range may be indicative of a medical condition. A persistently high level in blood glucose is referred to as hyperglycemia and low glucose levels are referred to as hypoglycemia (Colberg & Colberg, 2009; Lee et al., 2005). Glucose transported from the intestines or liver to the body cells is made available for uptake by absorption cells and metabolism (Reddy, 2012).

The islets of Langerhans in the pancreas coordinates the secretion of insulin and glucagon (Lowell & Shulman, 2005; Quesada et al., 2008). In the event that the blood glucose levels rise the β-cells import and oxidise glucose to support mitochondrial ATP synthesis. This process stimulate a rise in the cytoplasmic ATP/ ADP ratio, which consequently induces the Ca2+ uptake from mitochondria followed by a release of insulin (Maechler et al., 2010; MacDonald et al., 2005). After its release the insulin ensures the uptake of glucose from sensitive tissues, metabolism and storage of glucose as glycogen or lipids. Insulin has the ability to counteract the effects of glucagon in the liver. This occurs by inhibition of gluconeogenesis and glycogenolysis. Low blood glucose levels prompt the secretion of glucagon which in turn induces glyconeogenesis and glucose mobilization in the hepatic tissue. These processes then restores euglycemia and at the main time prevent insulin action (Quesada et al., 2008).

In the event that there is a disruption in the coordinated secretion of insulin and glucagon, it may lead to lasting pathological effects, including the development of type1 diabetes (T1DM) and type2 diabetes (T2DM). Both T1DM and T2DM are characterized by gradual failure and destruction of the β-cells. T2DM develops via a complex interplay between genetics and environmental factors such as exposure to toxins, diet and alcohol consumption (Cnop et al., 2005). T1DM is characterized by an auto-immune assault, which occurs with the invasion of the islets by mononuclear cells and induction of intra-islet inflammation and cell apoptosis (Knip et al., 2005). Development of T1DM can also be facilitated by exposure to chemicals. Chemical substances such as alloxan and streptozotocin are often administered to selectively eradicate β cells and induce T1DM. The two chemical substances eradicate β cells by inducing oxidative stress and damage by disrupting pancreatic ion transport and calcium levels (Szkudelski, 2001).

The major source of blood glucose is dietary carbohydrates such as starch, which are hydrolyzed by α-glucosidases and pancreatic α-amylase, so as to be absorbed by the small intestine. Inhibitors of the enzymes could retard the uptake of dietary carbohydrates, which suppress postprandial hyperglycaemia. Alpha-glucosidase inhibitors such as acarbose, miglitol, and voglibose are known to minimize postprandial hyperglycemia primarily by interfering with the activity of carbohydrate-digesting enzymes and decrease glucose absorption (Maurus et al., 2005).

Hypoxis hemerocallidea (HH) is one of the most commonly used medicinal plants in South Africa (Nair et al., 2007). It is used for the treatment of numerous ailments which include urinary tract infections, heart disease, infertility and anxiety (Brown et al., 2008). Due to its usefulness in traditional medicine, Hypoxis hemerocallidea has attracted a lot of interest in scientific studies (Nair et al., 2007). Hypoxis extracts contain phytosterols which are thought to be the main pharmacological ingredient responsible for its anti-lipidemic, anti-diabetic and anti-inflammatory properties (Boukes et al., 2008). An aqueous extract of Hypoxis hemerocallidea was found to exhibit a significant reduction in the blood glucose levels of fasted normal and Streptozotocin (STZ) induced diabetic rats (Mahomed & Ojewole, 2003). It is thought that the blood glucose lowering effect observed is due to the presence of phytosterols and/or sterolin. The mechanism of the blood glucose lowering action is still not well understood. Ojewole (2006) in a study in which an aqueous extracts of Hypoxis hemerocallidea were orally administered found anti-diabetic effects starting at 100 mg/kg in both normoglycaemic and hypoglycaemic rats.

1.1 The purpose of the study

The plant Hypoxis hemerocallidea, also known as the African potato, is commonly used as a traditional medicine to treat diabetes in South Africa. There are many mechanisms that leading to low blood glucose level, and one of these mechanisms is increase insulin secretion. The purpose of this study is thus to explore the effect of Hypoxis hemerocallidea on insulin secretion and digestion enzymes.

1.1.1 Specific objectives

• To determine the potential toxicity of Hypoxis hemerocallidea and glucose on pancreatic RIN5-F cell viability

• To determine whether Hypoxis hemerocallidea can increase insulin secretion from the pancreatic RIN5-F.

• To determine whether Hypoxis hemerocallidea can inhibit the activity of α-amylase and α -glucosidase.

Chapter II

2 Literature review

The body naturally regulates blood glucose levels as part of metabolic homeostasis (Young, 1977). The glucose is absorbed by the intestines and released into the blood (Magistretti & Pellerin, 1999; Miller et al., 1995). Regardless of the body situation such as starvation, intense physical activities and intake of large quantities of food, the normal level of glucose in the plasma is 3.5-8.0 mmol/L. (Arciero et al., 1999). To control blood sugar, the body has three hormones: glucagon, insulin and epinephrine (Lotfy, 2012). The level of the sugar in the blood outside the normal range may be an indicator of a medical condition. A persistently high blood glucose are forwarded to as hyperglycemia and low levels in glucose are referred to as hypoglycaemia and (usually less than 3.5 mmol/L) (Colberg & Colberg, 2009; Lee et al., 2005).

Usually the glucose is derived from 2 sources, the intestinal absorption that follows the digestion of carbohydrates nutrition and glucose released into the circulation from the kidney and liver after gluconeogenesis process (Giugliano et al., 2008). Glucose is transported from the intestines or liver to body cells via the blood, and is made available for uptake by the cells (Reddy, 2012). Glucose levels are usually lowest in the morning before the first meal of the day and rise after meals for an hour or two by a few millimolar (Colberg & Colberg, 2009; Reddy, 2012). Glucose metabolisms take place in the muscles and liver (König et al., 2012). The operation that by which simple sugars found in many foods are processed and used to produce energy in the form of ATP (Magistretti & Pellerin, 1999; Miller et al., 1995).The glucose absorption by different body tissues occurs under the effect of two factors which are the accessibility of glucose and the physiological conditions of the tissue. These two systems in which glucose absorption occur are simplify transport (a passive way) down the glucose concentration regression, and secondary active diffusion against glucose concentration regression (an active indirect way that wants adenosine triphosphate (ATP), as origin of energy). (Lotfy, 2012).

There is two hormones secreted from the pancreas are mainly responsible for blood glucose regulation, insulin and glucagon, insulin is the dominant glucoregulatory hormone, which regulate the blood glucose level in the fasting state (Rizza et al., 1985). While the glucagon considered as a potent hyperglycemic hormone, which is work exclusively on the liver to elevate hepatic glucose production within minutes. Ingestion of carbohydrate elicits a rapid rise in insulin concentration and a reduction in glucagon concentration. The increase in insulin concentrations happen before raising the blood glucose concentrations is thought to be mediated largely by hormonal signals arising in the digestive system (Aronoff et al., 2004; Kuznetsov, 1978).

2.1 The Pancreas and blood glucose level control

The pancreas is a glandular organ in the upper part of the abdomen, but serves as two glands in one: a digestive exocrine gland and a hormone-producing endocrine gland. Working as an exocrine gland, the pancreas secretes enzymes to smash the lipids, proteins and carbohydrates in nutriment (Olubummo, 2010). It weighs between 70 g and 110 g (Gromada et al., 2007; Nobukawa, 2007). The pancreas is attached to the duodenum, the first part of the small intestine via the common pancreatic bile duct. The gland is also extended towards the spleen (Figure 2.1.).

The Langerhans islets (Figure 2.2.) consisting of insulin releasing β-cells (65-90 %) forming the core of the islet, glucagon-releasing alpha-cells (15-20 %) (Zhou et al., 2011), pancreatic polypeptide cells producing (1 %) PP and somatostatin-producing delta-cells (3-10 %), generalley it located on the surface (Elayat et al., 1995). β-cells, which couple nutrients metabolism with electrical activity to modulate the produce and release of insulin, have been most of the time studied. The islets of Langerhans play an important role in glucose metabolism and organize of blood glucose concentration (Jo et al., 2007).

2.1.1 Pancreatic hormones Insulin

Insulin is anabolic hormone which is excreted in response to elevate blood glucose and amino acids following to uptake of a meal. The other functions of insulin with several body tissues is controls the metabolism of lipids, carbohydrates, and amino acids within several body tissues (Britton et al., 2002; Saltiel & Kahn, 2001). As many hormones, insulin exerts its activity through obligated to certain receptors located on many cells of the body, including liver, fat and muscle cells (Aronoff et al., 2004). The effective action of insulin is decrease blood glucose level. β- cells can respond quickly to spikes in blood glucose level by excrete some of its stored insulin while simultaneously generating more of the hormone (Wilcox, 2005). Insulin structure

The structure of human insulin as seen in Figure 2.3 consists of 51 amino acids forming two polypeptide chains (A and B) (Lotfy, 2012). The A-chain is the smaller one and formed from 21 amino acids while the B-chain is second one and larger, which consisting of 30 amino acids. Both of them A-chains and B-chains are attached together through two disulphide links set between cysteine amino acids. In the chain- A similar inner disulphide link is set between two cysteine amino acids. The main action of these disulphide links is to give the three-dimensional form of insulin molecule and guarantee the precise physiological function of insulin hormone (Weise et al., 2009).

Figure ‎2.3. Diagram showing the structure of human insulin A-chain and B-chain

( Adapted from Lotfy, 2012). Insulin synthesis

Insulin is a spherical protein hormone with low molecular weight, around 5800 KD (Lotfy, 2012). Many factors such as acetylcholine, fatty acids, pituitary adenylate cyclase-activating polypeptide (PACAP), amino acids, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are effective in insulin biosynthesis and secretion. Translation, gene transcription, and post-translational modification happen in the Golgi apparatus which effect on insulin release from the secretory granules (Xu et al., 2003).The main task of the β-cell is to produce, store and execrate the insulin. The insulin granules is consisting of two polypeptide chains, A and B, which are not created as single polypeptide chains but are formed by specific proteolytic processing of a bigger precursor, proinsulin (Steiner, 2004).

Through a process of proteolysis, recently synthesised of proinsulin in the Golgi apparatus is tardily converted to the insulin granules. The recently formed storage granules are imported from the Golgi apparatus to the β-cell cytoplasm waiting for the secretory signals. These secretory granules include mainly mature insulin with minor quantity of unconverted proinsulin (Wicksteed et al., 2001; Wilcox, 2005). The main effective signal in insulin synthesis via β-cell is the blood glucose concentration. Hypoglycemia concentration (2-4 mM), leads to reduced synthesis level of proinsulin. On the other side, hyperglycemia concentration (4-6 mM), it causes an improvement of proinsulin synthesis (Steiner et al., 2009; Brandenburg, 2008). Insulin secretion

The main function of β-cells is to maintain glucose homeostasis within the body via secretion of insulin in response to elevate blood glucose concentration (DeFronzo, 2004). Insulin secretion can be divided into two phases; the first phase of insulin releases the KATP channel dependent insulin secretion (Figure2.5). In humans the glucose is taken up into b-cell via glucose transporter one (GLUT1) but in mice by glucose transporter two (GLUT2) (Hiriart and Aguilar-Bryan, 2008). Glucose is then metabolised by glycolysis and the tricarboxylic acid (TCA) cycle (Herman and Kahn, 2006). Both pathways provide substrates (FADH2 and NADH) for the respiratory chain within mitochondria to produce ATP. ATP is moved into the cytoplasm, where it binds to the Kir6.2 subunit of the KATP – channel (Klingenberg, 2008). The binding of ATP causes channel closure, resulting in the depolarisation of the plasma membrane. The depolarisation triggers the opening of the L-type voltage-gated Ca+ channels, which leads to the influx of Ca2+ ions. Calcium triggers the exocytosis of insulin secretory vesicles and results in the release of insulin from beta cells (Straub and Sharp, 2002). As Ca+ uptake and insulin release are dependent on potassium channel closure by ATP, this corridor is called the KATP channel dependent insulin secretion pathway.

The second phase of insulin secretion is called KATP -channel independent insulin secretion, as insulin secretion occurs despite the potassium channel being open or otherwise dysfunctional (Tengholm and Gylfe, 2009). The second phase involves augmented insulin release in response to elevated intracellular calcium levels. This mechanisms are still unknown but are thought to involve changes in actions and concentrations of cAMP, phospholipase C and plasma membrane phosphoinositides (Straub and Sharp, 2002; Tengholm and Gylfe, 2009). Poorly defined metabolic coupling pathways such as generation of mitochondrial NADH, malonyl-CoA and cytosolic long chain-CoA esters are also 5 required (Prentki et al., 1997) Insulin resistance

Insulin resistance might happen either at the level of downstream signalling or at the connecting stage of insulin to the receptor (Wilcox, 2005). Lifestyle habits or several environmental factors are implicated in the development of insulin resistance in a person. Hyperinsulinemia, glucose intolerance, hypertension and dyslipidemia stimulate the insulin resistance syndrome (Haffner et al., 1992; DeFronzo & Ferrannini, 1991). High blood glucose is associated with insulin insufficiency once hyperglycaemia has developed glucose toxicity. This can stimulates insulin resistance and reduced pancreatic β-cell function. It has been expected that a 50 % decrease in β-cell function in the existence of insulin resistance may causes hyperglycaemia (Butler et al., 2003; Buchanan et al., 2002). As soon as hyperglyceamia evolve, immediately the glucose itself leads to loss of glucose stimulate-insulin release and disruption in glucose elimination (glucose toxicity), which performs to exacerbation of the disease condition. Adipose tissue plays a master role in the state of insulin resistance via production the adipsin, complement factor B, and acylation-stimulating protein. Besides that, the adipose tissue also helps in triglyceride composition and they are also involved in the excess of paracrine signalling (Xu et al., 2003; Fantuzzi, 2005). In muscle, fat and liver cells, the impedance to subjectivity insulin is compensated by the high concentration of serum insulin combination with normal or high blood glucose levels (Ahmed & Thornalley, 2007).

Type tow diabetes mellitus (T2DM) is described by a 20-50 % lessening in β-cell mass and this might be factor in disadvantage insulin secretion. Progressive damage of β-cell function is correlated with insulin resistance in skeletal muscle and in the formation of islet myeloid residue in the pancreas. This could stimulate pancreatic β-cell death in vitro (Jun et al., 1999; Prudente et al., 2009). In the primary stages of insulin secretion, the pattern of death is the initial defect followed by a drop in glucose to stimulate non-glucose signals, and finally β-cell death that demand insulin therapy (Jun et al., 1999; Poitout & Robertson, 1996). Insulin resistance and insulin secretion are hence correlated at various levels; however, it is unclear which disadvantage is primary in the aetiology of diabetes (Jun et al., 1999; Robertson et al., 2003).

T2DM is characterized by the presence of low affinity insulin receptor and hybrid receptors which when over expressed are also proposed to contribute to insulin resistance (Prudente et al., 2009). Hybrid receptors are formed when fusion occurs in between the insulin and insulin growth factor (IGF) receptors (Slaaby et al., 2006) The insulin receptor is found to be negatively correlated with insulin sensitivity in vivo as it has greater affinity for insulin like growth factor (ILGF) than insulin (Federici et al., 1998; Jones & Clemmons, 1995). Recent studies have also suggested that insulin resistance is caused by poor foetal and postnatal nutrition, leading to β-cell dysfunction and insulin resistant tissues and thus can be detected by low birth weight of the child (Wilcox, 2005).

The major causes of insulin resistance in T2DM are defects in glucose oxidation and glycogen synthesis in skeletal muscle (DeFronzo & Tripathy, 2009). It was observed that it has impaired insulin-stimulated glucose uptake and moreover, lipolysis is increased (Jones & Clemmons, 1995; Fantuzzi, 2005). This is achieved by reducing glucose oxidation through the glucose fatty acid cycle in the muscle. The elevated levels of circulating free fatty acids induce insulin resistance. Greater levels of free fatty acids can also induce insulin resistance by reducing hepatic clearance of insulin and by enhancing gluconeogenesis (Boden & Shulman, 2002; Kahn et al., 2006). It has been suggested that long chain fatty acids are actively involved in directly affecting the glycogen synthase activity and can also modulate the transcription of pancreatic β-cell transcription factor HNF-4α. Increased expression of cytokines may also result in insulin resistance (Plomgaard et al., 2005). When tumor necrosis factor of the (TNFα) is over expressed in obese people, it inhibits the phosphorylation of the insulin receptor and insulin receptor substrate (IRS-1), which results in blocking the insulin-signalling cascade in the adipose tissue (Hotamisligil, 1999; Plomgaard et al., 2005). Glucagon

Glucagon is a polypeptide hormone containing of a single polypeptide series of 29 amino acids. The effects of glucagon appear on liver by connecting to hepatic cell membrane receptor and initiates a sequence of intracellular reactions through cAMP as a second intracellular messenger to stimulate or discouragement either phosphatase or kinase enzymes (Jiang & Zhang, 2003). These effects in turn prevents glycogenesis, supress glycogenolysis and promote glucose synthesis (Lotfy, 2012). From the other side, glucagon elevates β-oxidation of non-esterified fatty acids and decreases triglyceride synthesis leading to ketogenesis. Glucagon also prevent coenzyme reduction, which leads to decrease of cholesterol synthesis in liver cells (Lotfy, 2012; Jiang & Zhang, 2003). The interaction between insulin and glucagon

Insulin and glucagon have antagonistic actions on substrate fluctuations, which are controlled by the insulin-glucagon ratio. The normal molar ratio is 2:1. Consequently, it is converted to 1:2 when there is a demand for mobilization of endogenous substrates (Adkins-Marshall et al., 1990). A decrease in insulin release and the increase in glucagon release can lead to glycogenolysis and gluconeogenesis in the liver and lipolysis in adipose tissue. There is a non-esterified fatty acids needed for β-oxidation (Adkins-Marshall et al., 1990; Lotfy, 2012). After a meal, the insulin-glucagon ratio is elevated to about 10:1, mainly due to enhanced insulin release. This leads to activation of glucose uptake associated with glucose oxidation and conversion of glucose to glycogen in either liver or muscle ( Lotfy, 2012). The pancreatic endocrine action is controlled through many factors including glucose. This control involves the parasympathetic nervous system that enhances insulin and glucagon release, while the sympathetic pathway enhances glucagon uptake but reduces insulin release (Nonogaki, 2000). Somatostatin

Pancreatic somatostatin is a neuropeptide consisting of 14 amino acids (SS14) (Figure 2.6). Somatostatin is manufactured in the form of prosomatostatin via δ-cells of islets of Langerhans, It also manufactured by intestinal cells and originally was find out as a hypothalamic neuropeptide. Somatostatin (SS14) is a strong suppressor of the liberation of glucagon, insulin and pancreatic polypeptide, there is several factors helps to shot the somatostatin from either δ-cells of the pancreas or intestine such as ketone bodies, amino acids, glucose, cholecystokinin secretion and gastrin hormones (Montminy & Bilezikjian, 1987). Somatostatin liberation is encouraged by insulin only at increased blood glucose levels. Since somatostatin has a restrained effect on insulin manufacture and secretion, insulin can prevent its own release via stimulate somatostatin secretion (Gonzalez & Montminy, 1989; Lotfy, 2012).

In the case of increased body physical activity with reduced blood glucose level, somatostatin decreases the secretion of growth hormones and thyroid stimulating hormone. Somatostatin reduces the volume of blood reaching the stomach and spleen and inhibits the secretion of hydrochloric acid from the stomach and digestive enzymes from the pancreas (Van Op den Bosch et al., 2009). On the other hand, a decreased blood glucose level induces somatostatin via glucagon-mediated release secretion. Generally, it appears that there is a negative feedback relationship of somatostatin with either glucagon or insulin (Muroyama et al., 2004). Somatostatin may be an additional treatment of diabetes mellitus through its suppressing effect on glucagon release (Muroyama et al., 2004; Bosch et al., 2009). Pancreatic polypeptide (PP)

Pancreatic polypeptide (PP) is a peptide consisting of 36 amino acids secreted and produced by PP cells of the pancreas which are primarily located in the islets of Langerhans, which is part of a family of peptides that also includes neuropeptide Y (NPY) and peptide YY (Lotfy, 2012). The essential function of PP is to reduce the release of pancreatic bicarbonate and proteins (Clark et al., 1984; Tatemoto et al., 1982). After a meal, the secretion of PP is stimulated by the decrease in blood glucose level (Lotfy, 2012). The PP release is stimulated by the vagal cholinergic reflex. Accordingly, PP may induce vagal stimulation of the pancreas and many organs in the gut. The PP secretion after a meal leads to reduction of food ingestion via decreasing the rate of stomach-emptying ( Lotfy, 2012).

2.2 Diabetes Mellitus (DM)

Diabetes Mellitus is one of the pancreatic diseases defined as a chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. Hyperglycemia is a common consequence of uncontrolled diabetes and over time leads to serious damage to many of the body’s systems, especially the nerves and blood vessels (Sugihara et al., 2008).

Diabetic prevalence for all age-groups across the world has been found to be 2.8 % in 2000 and an estimated to increase to 4.4 % in 2030 (Wild et al., 2004). This is further supported by a study finding which speculate that the total number of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030 (Deshpande et al., 2008). Men have a higher diabetic prevalence compared to women. There are however more women with diabetes than there are men (Wild et al., 2004).

In 1980, the World Health Organisation (WHO 2003) classified diabetes into type 1 diabetes mellitus (T1DM), an auto-immune disease resulting in the destruction of pancreatic β-cells and type 2 diabetes mellitus (T2DM). A strong association exists with obesity occurs as a result of failing pancreatic β-cell function, responsible for the production of insulin, often alongside insulin resistance. The WHO as well categorized DM into other types such as malnutrition-related diabetes, which is now careless from the new classification because it’s anonymous disease which is diagnosed during pregnancy (gestational diabetes). (WHO 2006) ultimately official the classification suggested by the American Diabetes Association (ADA).

Persistent high blood glucose levels could result in the glycosylation of proteins which can lead to the irreversible damage as present in diabetes, of tiny blood vessels and nerve endings especially in the areas of from the heart, retina and renal glomerulus (Deshpande et al., 2008). Macrovascular complications which affect the larger blood vessels in the body are common among T2DM patients. These patients are more likely to suffer from hypertension and coronary heart diseases (CHD) including, atherosclerosis and thrombosis. About 75 % of macrovascular diabetic mortality is due to coronary heart disease (Deshpande et al., 2008).

It has been found to manage diabetes mellitus it is beneficial to monitor a patient’s eating and exercise to determine the optimum insulin dosage required for that patient.

To control a patient’s nutriment it is extremely important to monitor the amount of carbohydrates which plays a critical role in determining the blood glucose level. Research has confirmed that when diabetic patients can control their blood glucose levels effectively they will reduce risks in developing many of the health complications well known in diabetes mellitus (Deshpande et al., 2008).

2.3 Carbohydrate digestion

Carbohydrates are organic compounds, including sugars and starches that serve as a major energy source for the body (Huber et al., 2005; Zhang et al., 2010). Carbohydrate digestion begins in the oral cavity with salivary amylase and then continues in other parts of the gastrointestinal tract, particularly in the small intestines. (Roberfroid, 2004; Huber et al., 2005).

Most of the digestion enzymes are hydrolases, which is execrated by the salivary glands and gastric glands. The effect of the digestive enzymes are identical to those of the lysosomal enzymes, excluding that they have different pH optima (Thornhill et al., 2008). Lysosomal enzymes are generally active at acidic pH, while the digestive enzymes except pepsins have their activity optima at a pH of 6.5 to 7.5. Abundant of the digestive enzymes have measly names such as trypsin and pepsin due to they were the first enzymes to be discovered before the systematic terminologies was developed. Table 2.1 shows the sources, activators, substrates, actions and end products of the enzymes of digestion (Deguara et al., 2003; Gawlicka et al., 2000).

2.4 The digestion enzymes

The α- amylase and α-glucosidase helps in the breakdown of complex carbohydrates (oligosaccharides and starch) in the digestive tract into simple sugars such as glucose, sucrose and maltose (Dong et al., 2012). Therefore, one of the important treatments for high postprandial glucose levels is to delay the absorption of glucose using the hydrolysing enzymes inhibitor such as α- amylase and α-glucosidase.

2.4.1 Alpha-amylase

Alpha-amylase is a digestive enzyme that hydrolyses alpha -1, 4 bonds of large polysaccharides such as starch and glycogen by converting them into smaller products which are glucose and maltose. Alpha-amylase is widespread among living organisms (Maurus et al., 2005). In the digestive systems of humans and many other mammals, pancreatic amylase is secreted by the pancreas into the small intestine. On the other hand, α -amylase is produced by the salivary glands and is synthesized in the serous acinar cells of the saliva glands. It is then stored in secretory granules inside the cells, and then released from the salivary cells especially with an increase in response to taste or chewing motions of the jaw (Maurus et al., 2005).

Under the impact of vegal stimulation the alpha-amylase dealing with carbohydrate digestion disorders such as obesity and diabetes (Bayramoǧlu et al., 2004; Butterworth et al., 2011). α -Amylase (EC is an endoglycosidase, which hydrolyses the polysaccharide and starch . Even though found in many of organisms, the primary sequences of α-amylases show poor serial homology. on the other hand, the three-dimensional structures of enzymes are found to be uncommonly conserved in organisms ranging from microbial to mammalian(Janeček et al., 2014; Kandra, 2003). Among the most prominent the structural similarities spotted the common existence of three domains in the enzyme structure. Domain A consists of an α/β keg and contains the effective site; domain B protrudes from the side of domain A and consist of the calcium binding site; and domain C forms a structurally independent antiparallel β-barrel (Maurus et al., 2005; Kandra, 2003). The identical structural features of human pancreatic α-amylase are explained in Figure 2.7.

Figure ‎2.7. Diagram showing the structural features of human pancreatic α-amylase

(Adapted from Maurus et al., 2005).

Alpha-amylase begins the process of starch digestion. It takes starch chains and breaks them into short saccharides with two or three glucose units. Two similar types of amylase are made in the human body; one is secreted in saliva, where it starts to break down starch grains into smaller pieces when food is chewed, and the other is secreted by the pancreas, where final digestion of the carbohydrates is completed. These saccharides are broken into individual glucose units by a collection of enzymes that are tethered to the walls of the intestine (Yilmazer-Musa et al., 2012; Lordan et al., 2013).

2.4.2 Alpha-Glucosidases Enzyme

Alpha-glucosidase is an enzyme that breaks down starch and disaccharides to glucose and maltose (Lu & Sharkey, 2006), and is also called alpha-1, 4-glucosidase EC (Figure 2.8) (Woo & Wynne, 2011) which is located in the brush border of the small intestine and acts upon 1,4-alpha bonds (Sun & Henson, 1990).

Alpha-Glucosidase is involved in carbohydrate breakdown. It plays a crucial role in diabetes and also in viral infections and cancer. Alpha-glucosidase delays the hydrolysis of carbohydrates and alleviate postprandial hyperglycemia (Hemmerich, 2001; Kumar et al., 2011).

2.5 Glucose metabolism

Once glucose has been transported into the beta cells it enters glycolysis in the cytoplasm where it is metabolised to pyruvate (Herman and Kahn, 2006). Pyruvate enters mitochondrial matrix where it acts as a substrate for pyruvate carboxylase, which converts pyruvate to oxaloacetate, and for pyruvate dehydrogenase, which converts it to acetyl-CoA (Herman and Kahn, 2006). Both oxaloacetate and acetyl-CoA are substrates for the TCA cycle that provides NADH and FADH2 for the mitochondrial respiratory chain (Wollheim and Maechler, 2002).

2.6 Mitochondrial function in beta cells

Mitochondrion is double-membrane organelles with multiple essential cellular functions. The main function of this to produce energy in the form of ATP from acetyl CoA derived from, fats, carbohydrates and proteins (Dimmer et al., 2002). ATP is the universal currency of energy in the cell. It is an energy-rich molecule because it contains two phosphoanhydride bonds. Energy is released when these bonds are broken. ATP can be synthesized from adenosine diphosphate (ADP) by two processes, which are substrate-level phosphorylation and oxidative phosphorylation. Substratelevel phosphorylation is the process by which ATP is formed from the direct phosphorylation of ADP (Klingenberg, 2008). All of these processes related to cell energy production and utility, therefore, mitochondrion is the power plant of cells. The primary or secondary alterations in mitochondria related signalling pathways could be explained multiplicity of organelle functions and va-riability in the pathophysiology (Dimmer et al., 2002; Klingenberg, 2008). Around 90% of cellular ATP is generated by oxidative phosphorylation, a process via which ATP is formed as electrons are transferred from nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) to molecular oxygen, by a series of electron carriers that make up the electron transport chain (ETC) (Wollheim and Maechler, 2002). Carbohydrates are converted to pyruvate through glycolysis, which is held in the cytosol. Pyruvate is subsequently actively transported across the inner mitochondrial membrane, and into the mitochondrial matrix where it is oxidised and changed it to acetyl CoA by pyruvate dehydrogenase. It is well established that mitochondrial function is required for normal glucose-stimulated insulin secretion from pancreatic b cells. In addition, maternally inherited deformities in mitochondrial DNA that disturb mitochondrial function are known to cause an insulin-deficient form of diabetes like T1DM (Lowell and Shulman, 2005).

2.7 Medicinal plants used to control blood glucose level

Despite considerable progress in the treatment of diabetes by oral hypoglycemic agents, the search for newer drugs continues because the existing synthetic drugs have several limitations. Traditional treatments are prescribed by practitioners of alternative medicine or sometimes taken by patients as supplements to conventional therapy. Hypoglycemic action of some traditional treatments has been confirmed in animal models and T2DM (Arumugam et al., 2013).

Herbal medicine plants having anti diabetic properties could be a useful source for the development of safer and effective oral hypoglycemic products. More than 400 traditional plants are used in the treatment of diabetes mellitus. The herbal drugs with antidiabetic activity are yet to be commercially formulated as modern medicines; moreover, they have been acclaimed for their therapeutic properties in the traditional systems of medicine (Arumugam et al., 2013). Only a small number of these have received scientific and medical evaluation to assess their efficacy. Traditional treatments may provide valuable clues for the development of new oral hypoglycemic agents and simple dietary adjuncts (Arumugam et al., 2013). Table 2.2 shows the most important medicinal plants used for the control of blood glucose level (Kavishankar, 2011).

2.8 Hypoxis hemerocallidea (HH)

Hypoxis hemerocallidea (HH) is one of southern Africa’s most important and popular medicinal plants (Nicoletti et al., 1992). HH has a long history of traditional use for a diversity of ailments and more recently has been the subject of several scientific studies. In many parts of Africa the corms of this attractive yellow flowered herb have been used in the treatment of urinary tract diseases, prostate hypertrophy and cancer (Mahomed & Ojewole, 2003). HH is geophytic and overcome winter conditions in the form of an underground rootstock called a corm. It also has adventitious roots attached to the corms that are thick, fleshy and which arise from the base of young corms. The flowering stems are unbranched, with 2-12 flowers per stalk. Flowers are symmetrical with 6 petals, which are bright yellow, giving the plant its common name Yellow Stars, shown in Figure 2.9 (Nair, 2006; Nair & Kanfer, 2006).

The corms of these plants are graded on size. The small (200 g) corms are generally from one year old seedlings and the medium corms (450 g) are at least three years old, whereas the large corms (800 g) are older(Nair, 2006). The fleshy corms of HH are yellow in colour on the inside (Figure 2.10), but soon turn to dark brown due to oxidation, when exposed to air (Nair, 2006). The uses of this plant can be attributed to a few of the medicinal compounds found in the plant of which hypoxoside, sitosterol, and its aglycone derivative rooperol are the most well-known compounds (Street & Prinsloo, 2012).

Vernacular names

The family name of Hypoxis hemerocallidea is Hypoxidaceae.

The most common names for HH are Star Lily, Yellow Stars, Afrika-patat, Sterretjie, African Potato, Inkomfe and Ilabatheka (Street and Prinsloo, 2012).

2.8.2 Geographical distribution

In South Africa, the genus is distributed in five provinces, namely, Eastern Cape, KwaZulu-Natal, Limpopo, Mpumalanga and Gauteng but it is also found in Lesotho, Swaziland, Mozambique, and Zimbabwe (Singh, 2007). There are reports of its existence in various other countries including Madagascar, New Zealand, Malawi, America, Mauritius and other Central Africa countries (Mogatle, 2008).

2.8.3 Botanical classification

The particular nomenclature for Hypoxis depends on leaf figurers, leaf venation, flower figurers and inflorescence (Singh, 2007). In Africa there are 30 types of Hypoxis. Most of these kinds tend to become common endemic to southern Africa. Hypoxia hemerocallidea found in the Eastern Cape region of South Africa (Mogatle, 2008). Most of the species are arranged under one of names are presented below:

• Hypoxis angustifolia var buchananii.

• Hypoxis argenta var sericea.

• Hypoxia colchicifolia.

• Hypoxia floccose.

• Hypoxis hemerocallidea.

• Hypoxia longifolia.

• Hypoxis obtuse.

• Hypoxia ridicule.

• Hypoxis ridigula var pilosissima.

2.8.4 Traditional forms

Hypoxis hemerocallidea have been used traditionally for a wide range of purposes by different tribes of Southern Africa. They have been used by the Zulu tribe as an internal parasiticide, purgative and to treat delirium. The Maniyaka tribe applied the ash to treat wounds, whereas the Karanga tribe used it as a remedy for bilious vomiting, anorexia, abdominal pain and fever (Botha & Penrith, 2008).

The corm of the plant has been used in folk medicine to treat a variety of diseases which include the common cold, flu, hypertension, adult-onset diabetes, psoriasis, urinary tract infections, testicular tumours and prostate hypertrophy. HH is used to build up the immune system of patients suffering from HIV/AIDS, anticancer, antidiabetic, antimicrobial, antioxidant, and anti-inflammatory treatment (Mogatle, 2008). Table 2.3 shows the most important traditional uses of HH.

2.8.5 Aspects of the use, pharmacology and phytochemistry

HH contains many of chemical constituents; of which hypoxoside, rooperol, and the phytosterol, β-sitosterol are the main ones (Muwanga, 2006; Boukes and van de Venter 2011; Sathekge, 2011). These main chemical agents contribute to the wide array of pharmaceutical properties that extracts of HH provides has been described as a plant-medicine for modern diseases of mankind (Owira and Ojewole, 2009).

Hypoxoside is the measly name for (E)-1, 5 bis (4′-B-D-glucopyranossyloxy-3′-hydroxyphenyl) pent-1-en-4-yne which is a norlignan diglucoside secluded from the

rootstock of the family Hypoxidaceae. High existence in concentration of phytosterols such as -sitosterols has confirmation to be effective against benign prostate hypertrophy, and a sturdy decoction of the rootstocks is also used as a laxative (Mills, Cooper, et al., 2005; Steenkamp, 2003). Rooperol could be acquired by handling hypoxoside with a -glucosidase to detach the attached glucose groups. Besides to hypoxoside and rooperol, the rootstocks are used predominantly as sources of dosage for a large array of diseases. The rootstocks also notify to consist of -sitosterols, monterpene glycosides, stigmastanols, sterol andstanols (Street & Prinsloo, 2012). The outcome of the chemical analysis of HH showed that the species have various classes of secondary metabolites namely; saponnins, glycosides, polyphenols, steroids and tannins. The rootstock of HH has earned three cytokinins identified as zeatinriboside, zeatinglucoside and zeatin (Street & Prinsloo, 2012).

2.8.6 Toxicity

A lethal dose (LD50) in mice was found to be 1948 ± 57 mg/kg of HH aqueous extract after oral administration (Ojewole, 2006). A lower dose (≤ 1600 mg/kg) of HH aqueous extracts is safe while relatively higher doses were toxic and/or lethal to the mice (Ojewole, 2006). A clinical trial was conducted involving 24 cancer patients at Karl Bremer Hospital, Bellville, South Africa (Smit et al., 1995), where the toxicity of hypoxoside, which was administered in the form of a hypoxis plant extract, was assessed. The patients were given 1200 – 3200 mg standardised hypoxis plant extract (50-55% hypoxoside content) /day, in three divided doses. Based on haematological and biochemical tests it was concluded that the dose administrated was not toxic (Mogatle, 2008).

2.8.7 Registered Patents

Several patents of Hypoxis, hypoxoside, rooperi and rooperol have been registered in the Europe and the USA. A patent registered under the title (method of treating viral infections) was registered by Liebenberg (Mogatle, 2008). That related to bulbous of the family of hypoxidaceae in preparation of medicament to treat viral infection by cutting the rate of reduction of T lymphocytes The patents include methods of extraction and preparation of derivatives (Mogatle, 2008).

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