The effect of Oral anti diabetic drugs

Introduction

Type 2 diabetes (DM2) and associated cardiovascular diseases and cancer are an increasing problem around the globe, especially in the developed world (Beaglehole and Yach, 2003). Currently, in the Netherlands the prevalence of DM2 is approximately 3.5% and this number is expected to increase by at least 32% in the next decades. This is due to the changing demographic characteristics (more elderly people), increasing problem of overweight and the improved and early detection of patients with DM2 (Baan and Poos, 2007).

Diet and exercise is the first step in the treatment of DM2. If these measures alone fail to sufficiently control blood glucose level, starting oral drugs therapy is recommended (Rutten, et al 2006). To date about six classes of oral antihyperglycemic drugs are available. They include; Biguanides e.g metformin, Sulphurnylurea eg tolbutamide, Glinidines eg repaglinide, Thiazolidinediones eg pioglitazone, Dipeptidylpeptidase inhibitors eg sitagliptin, and Alpha glucosidase inhibitors eg Acarbose, Miglitol and Voglibose. (Nathan, 2007).

The diagnosis of DM2 is not clear-cut, but merely the result of an arbitrarily chosen point somewhere between the absence of insulin resistance and normal insulin secretion, and advanced peripheral insulin resistance and absence of insulin production. Therefore, the optimal moment to start treatment is not unequivocal. Specific criteria have been defined for those people who have raised post-prandial and/or fasting blood glucose, but who do not meet the criteria for DM2. This condition is referred to as ‘impaired glucose tolerance’ (IGT) when post-prandial blood glucose levels are elevated, and ‘impaired fasting blood glucose’ (IFBG) in case of elevated fasting blood glucose.

Alpha-glucosidase inhibitors (AGIs) are drugs that inhibit the absorption of carbohydrates from the gut and may be used in the treatment of patients with type 2 diabetes or impaired glucose tolerance. There is currently no evidence that AGIs are beneficial to prevent or delay mortality or micro- or macrovascular complications in type-2 diabetes. Its beneficial effects on glycated hemoglobin are comparable to metformin or thiazolidinediones, and probably slightly inferior to sulphonylurea. In view of the total body of evidence metformin seems to be superior to AGIs.

AGIs reversibly inhibit a number of alpha-glucosidase enzymes (e.g, maltase), consequently delaying the absorption of sugars from the gut (Campbell et al., 1996). In a recent study among healthy subjects it was suggested that the therapeutic effects of AGIs are not only based on a delayed digestion of complex carbohydrates, but also on metabolic effects of colonic starch fermentation (Wachters-Hagedoorn et al., 2007). Acarbose (Glucobay) is the most widely prescribed AGI. The other AGIs are miglitol (Glyset) and voglibose (Volix, Basen). AGIs might be a reasonable option as first-line drug in the treatment of patients with DM2 as it specifically targets postprandial hyperglycemia, a possible independent risk factor for cardiovascular complications (Ceriello, 2005). Although rare cases of hepatic injury were described, AGIs are expected to cause no hypoglycemic events or other life-threatening events, even at overdoses, and cause no weight gain (Chiasson et al., 2003).

AGIs are not necessarily a drug in the form of a pill as it may also be given as ‘smart food’ or as a food supplement. For example, a soy-bean derived touchi extract, a traditional Chinese food in the form of a paste, has shown to have alpha-glucosidase inhibiting properties and reduce blood glucose levels (Fujita et al., 2001).

1.1 Biochemistry of alpha glucosidase

Alpha glucosidase is a glucosidase that acts on 1,4-alpha bonds. It breaks down starch and disaccharides to glucose. Examples of alpha glucosidase includes; glucoinvertase, glucosidosucrase, alpha –D- glucosidase, alpha-glucopyranosidase, alpha-glocoside hydrolase, alpha-1,4-glucosidase, alpha-D- glucoside glucohydrolase.

Alpha-glucosidase hydrolyzes terminal non-reducing 1-4 linked alpha-glucose residues to release a single alpha-glucose molecule. Alpha- glucosidase is a carbohydrate hydrolase that releases alpha glucose. The substrate selectivity of alpha glucosidase is due to subsite affinities of the enzymes active site.

Alpha glucosidases can potentially be split according to primary structures into two families. The gene coding for human lysosomal alpha-glucosidase is about 20 kb long and it’s structure has been cloned and confirmed.

·         Human lysosomal alpha-glucosidase has been studied for the significance of the Asp-518 and other residues in proximity of the enzyme’s active site. It was found that substituting Asp-513 with Glu-513 interferes with posttranslational modification and intracellular transport of alpha-glucosidase’s precursor. Additionally, the Trp-516 and Asp-518 residues have been deemed critical for the enzyme’s catalytic functionality.

·         Kinetic changes in alpha-glucosidase have been shown to be induced by denaturants such as guanidinium chloride (GdmCl) and SDS solutions. These denaturants cause loss of activity and conformational change. A loss of enzyme activity occurs at much lower concentrations of denaturant than required for conformational changes. This leads to a conclusion that the enzyme’s active site conformation is less stable than the whole enzyme conformation in response to the two denaturants.

Two proposed mechanisms include a nucleophilic displacement and an oxocarbenium ion intermediate.

      

Figure 1: Alpha-glucosidase in complex with maltose and NAD+

Example of an alpha-glucosidase catalyzed reaction

• Rhodnius prolixus, a blood-sucking insect, forms hemozoin (Hz) during digestion of host hemoglobin. Hemozoin synthesis is dependent on the substrate binding site of alpha-glucosidase.

• Trout liver alpha-glucosidases were extracted and characterized. It was shown that for one of the trout liver alpha-glucosidases maximum activity of the enzyme was increased by 80% during exercise in comparison to a resting trout. This change was shown to correlate to an activity increase for liver glycogen phosphorylase. It is proposed that alpha-glucosidase in the glucosidic path plays an important part in complementing the phosphorolytic pathway in the liver’s metabolic response to energy demands of exercise (Mehrani et al., 1993).

• Yeast and rat small intestinal alpha-glucosidases have been shown to be inhibited by several groups of flavonoids.

Alpha-glucosidases can potentially be split, according to primary structure, into two families.

1.1.1 Diseases associated with alpha glucosidase enzymes

·         Diabetes: Luteolin has been found to be a strong inhibitor of alpha-glucosidase. The compound can inhibit the enzyme up to 36% with a concentration of 0.5 mg/ml. These results hint that luteolin has potential to suppress postprandial hyperglycemia in non-insulin dependent diabetes mellitus patients and there is value in pursuing a greater understanding of luteolin’s potential for treatment (Kim et al., 2000). Acarbose, another alpha-glucosidase inhibitor competitively and reversibly inhibits alpha-glucosidase in the intestines. This inhibition lowers the rate of glucose absorption through delayed carbohydrate digestion and extended digestion time. It has been determined that acarbose may have the capability to permanently or temporarily stop developing diabetic symptoms.

Hence, alpha-glucosidase inhibitors (like Acarbose), are used as anti-diabetic drugs in combination with other anti-diabetic drugs.

·         Pompe Disease: a disorder in which alpha-glucosidase is deficient. In 2006, the drug Alglucosidase alfa became the first released treatment for Pompe Disease and acts as an analog to alpha-glucosidase. Further studies of alglucosidase alfa revealed that imino sugars exhibit inhibition of the enzyme. It was found that one compound molecule binds to a single enzyme molecule. It was shown that 1-deoxynojirimycin (DNJ) would bind the strongest of the sugars tested and blocked the active site of the enzyme almost entirely. The studies enhanced knowledge of the mechanism by which alpha-glucosidase binds to imino sugars.

·         Azoospermia: Diagnosis of azoospermia has potential to be aided by measurement of alpha-glucosidase activity in seminal plasma. Activity in the seminal plasma corresponds to the functionality of the epididymis.

·                     Anti-Viral Agents: Many animal viruses possess an outer envelope composed of viral glycoproteins. These are often required for the viral life cycle and utilize cellular machinery for synthesis. Inhibitors of alpha-glucosidase show that the enzyme is involved in the pathway for N-glycans for viruses such as HIV and human hepatitis B virus (HBV). Inhibition of alpha-glucosidase can prevent fusion of HIV and secretion of HBV.

1.2       Inhibitors and mechanism of action

Alpha-glucosidase inhibitors are oral anti diabetic drugs used for diabetes mellitus type 2 that work by preventing the digestion of carbohydrates (such as starch and table sugar) Carbohydrates are normally converted into simple sugars(monosaccharides), which can be absorbed through the intestine. Hence, alpha-glucosidase inhibitors reduce the impact of carbohydrates on blood sugar.

Examples of alpha-glucosidase inhibitors include:

·         Acarbose

·         Miglitol

·         Voglibose

Even though the drugs have a similar mechanism of action, there are subtle differences between acarbose and miglitol. Acarbose is an oligosaccharide, whereas miglitol resembles a monosaccharide. Miglitol is fairly well absorbed by the body, as opposed to acarbose. Moreover, acarbose inhibits pancreatic alpha-amylase in addition to alpha-glucosidase.

There are a large number of plants with Alpha-glucosidase inhibitor action. For example, research has shown the culinary mushroom Maitake (Grifola frondosa) has a hypoglycemic effect. The reason Maitake lowers blood sugar is because the mushroom naturally contains an alpha glucosidase inhibitor. Another plant attracting a lot of attention is Salacia oblonga.

Alpha-glucosidase inhibitors are used to establish greater glycemic control over hyperglycemia in diabetes mellitus type 2, particularly with regard to postprandial hyperglycemia. They may be used as monotherapy in conjunction with an appropriate diabetic diet and exercise, or they may be used in conjunction with other anti-diabetic drugs.

Alpha-glucosidase inhibitors may also be useful in patients with diabetes mellitus type 1; however, this use has not been officially approved by the Food and Drug Administration.

1.2.1 Mechanism of action

Alpha-glucosidase inhibitors are saccharides that act as competitive inhibitors of enzymes needed to digest carbohydrates: specifically alpha-glucosidase enzymes in the brush border of the small intestines. The membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the small intestine.

Acarbose also blocks pancreatic alpha-amylase in addition to inhibiting membrane-bound alpha-glucosidases. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine.

Inhibition of these enzyme systems reduces the rate of digestion of carbohydrates. Less glucose is absorbed because the carbohydrates are not broken down into glucose molecules. In diabetic patients, the short-term effect of these drugs therapies is to decrease current blood glucose levels: the long term effect is a small reduction in hemoglobin level.

Since alpha-glucosidase inhibitors are competitive inhibitors of the digestive enzymes, they must be taken at the start of main meals to have maximal effect. Their effects on blood sugar levels following meals will depend on the amount of complex carbohydrates in the meal.

1.2.2 Side effects/ precautions

Since alpha-glucosidase inhibitors prevent the degradation of complex carbohydrates into glucose, the carbohydrates will remain in the intestine. In the colon, bacteria will digest the complex carbohydrates, thereby causing gastrointestinal side effects such as flatulence and diarrhea. Since these effects are dose-related, it is generally advised to start with a low dose and gradually increase the dose to the desired amount. Pneumatosis cystoides intestinalis is another reported side effect. If a patient using an alpha-glucosidase inhibitor suffers from an episode of hypoglycemia, the patient should eat something containing monosaccharides, such as glucose tablets. Since the drug will prevent the digestion of polysaccharides (or non-monosaccharides), non-monosaccharide foods may not effectively reverse a hypoglycemic episode in a patient taking an alpha-glucosidase inhibitor. 

CHAPTER TWO

2.0 Diabetes Mellitus

Diabetes mellitus (DM) or simply diabetes, is a group of metabolic diseases in which a person has high blood sugar (WHO, 2014). This high blood sugar produces the symptoms of frequent urination, increased thirst, and increased hunger. Untreated, diabetes can cause many complications. Acute complications include diabetic ketoacidosis and nonketotic hyperosmolar coma. Serious long-term complications include heart disease, kidney failure, and damage to the eyes.

Diabetes is due to either the pancreas not producing enough insulin, or because cells of the body do not respond properly to the insulin that is produced (Shoback et al., 2011). There are three main types of diabetes mellitus (WHO, 2013).

Insulin is the principal hormone that regulates the uptake of glucose from the blood into most cells of the body, especially liver, muscle, and adipose tissue. Therefore, deficiency of insulin or the insensitivity of its receptors plays a central role in all forms of diabetes mellitus.

The body obtains glucose from three main places: the intestinal absorption of food, the breakdown of glycogen, the storage form of glucose found in the liver, and gluconeogenesis, the generation of glucose from non-carbohydrate substrates in the body (Shoback et al., 2011). Insulin plays a critical role in balancing glucose levels in the body. Insulin can inhibit the breakdown of glycogen or the process of gluconeogenesis, it can transport glucose into fat and muscle cells, and it can stimulate the storage of glucose in the form of glycogen (Shoback et al., 2011).

Insulin is released into the blood by beta cells (β-cells), found in the islets of Langerhans in the pancreas, in response to rising levels of blood glucose, typically after eating. Insulin is used by about two-thirds of the body's cells to absorb glucose from the blood for use as fuel, for conversion to other needed molecules, or for storage. Lower glucose levels result in decreased insulin release from the beta cells and in the breakdown of glycogen to glucose. This process is mainly controlled by the hormone glucagon, which acts in the opposite manner to insulin (Kim et al., 2012).

If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin (insulin insensitivity or insulin resistance), or if the insulin itself is defective, then glucose will not be absorbed properly by the body cells that require it, and it will not be stored appropriately in the liver and muscles. The net effect is persistently high levels of blood glucose, poor protein synthesis, and other metabolic derangements, such as acidosis (Shoback et al., 2011).

When the glucose concentration in the blood remains high over time, the kidneys will reach a threshold of reabsorption, and glucose will be excreted in the urine (glycosuria), (Robert et al., 2012). This increases the osmotic pressure of the urine and inhibits reabsorption of water by the kidney, resulting in increased urine production (polyuria) and increased fluid loss. Lost blood volume will be replaced osmotically from water held in body cells and other body compartments, causing dehydration and increased thirst (polydipsia), (Shoback et al., 2011).

All forms of diabetes increase the risk of long-term complications. These complications typically develop after many years (10–20), but may be the first signs or symptoms in those who have otherwise not received a diagnosis before that time.

The major long-term complications relate to damage to blood vessels. These complications can be grouped into microvascular disease (damage to small blood vessels) and macrovascular disease (damage to larger arteries).

The primary microvascular complications of diabetes include damage to the eyes, kidneys, and nerves (WHO, 2014). Damage to the eyes, known as diabetic retinopathy, is caused by damage to the blood vessels in the retina of the eye, and can result in gradual vision loss and potentially blindness (WHO, 2014).  Damage to the kidneys, known as diabetic nephropathy, can lead to tissue scarring, urine protein loss, and eventually chronic kidney disease, sometimes requiring dialysis or kidney transplant (WHO, 2014). Damage to the nerves of the body, known as diabetic neuropathy, is the most common complication of diabetes. The symptoms can include numbness, tingling, pain, and altered pain sensation, which can lead to damage to the skin. Diabetes-related foot problems (such as diabetic foot ulcers) may occur, and can be difficult to treat, occasionally requiring amputation. Additionally, proximal diabetic neuropathy causes painful muscle wasting and weakness.

The primary macrovascular complications of diabetes include coronary artery disease (angina and myocardial infarction), stroke, and peripheral vascular disease. About 75% of deaths in diabetics are due to coronary artery diseases.

Diabetes mellitus is classified into four broad categories: type 1, type 2, gestational diabetes, and "other specific types" (Shoback et al., 2011).  The "other specific types" are a collection of a few dozen individual causes (Shoback et al., 2011).  The term "diabetes", without qualification, usually refers to diabetes mellitus.

 2.1.1 Type 1 diabetes mellitus

Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas, leading to insulin deficiency. This type can be further classified as immune-mediated or idiopathic. The majority of type 1 diabetes is of the immune-mediated nature, in which a T-cell-mediated autoimmune attack leads to the loss of beta cells and thus insulin (Rother, 2007).  It causes approximately 10% of diabetes mellitus cases in North America and Europe. Most affected people are otherwise healthy and of a healthy weight when onset occurs. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages. Type 1 diabetes can affect children or adults, but was traditionally termed "juvenile diabetes" because a majority of these diabetes cases were in children.

"Brittle" diabetes, also known as unstable diabetes or labile diabetes is a term that was traditionally used to describe the dramatic and recurrent swings in glucose levels, often occurring for no apparent reason in insulin-dependent diabetes. This term, however, has no biologic basis and should not be used. Still, type 1 diabetes can be accompanied by irregular and unpredictable hyperglycemia, frequently with ketosis, and sometimes with serious hypoglycemia. Other complications include an impaired counterregulatory response to hypoglycemia, infection, gastroparesis (which leads to erratic absorption of dietary carbohydrates), and endocrinopathies (e.g., Addison's disease). These phenomena are believed to occur no more frequently than in 1% to 2% of persons with type 1 diabetes.

Type-1 diabetes is partly inherited, with multiple genes, including certain HLA genotypes, known to influence the risk of diabetes. In genetically susceptible people, the onset of diabetes can be triggered by one or more environmental factors, such as a viral infection or diet. There is some evidence that suggests an association between type 1 diabetes and Coxsackie B4 virus. Unlike type 2 diabetes, the onset of type 1 diabetes is unrelated to lifestyle.

2.1.2 Type 2 diabetes mellitus

Type 2 diabetes mellitus is characterized by insulin resistance, which may be combined with relatively reduced insulin secretion (Shoback et al., 2007). The defective responsiveness of body tissues to insulin is believed to involve the insulin receptor. However, the specific defects are not known. Diabetes mellitus cases due to a known defect are classified separately. Type 2 diabetes is the most common type.

In the early stage of type 2, the predominant abnormality is reduced insulin sensitivity. At this stage, hyperglycemia can be reversed by a variety of measures and medications that improve insulin sensitivity or reduce glucose production by the liver.

Type 2 diabetes is due primarily to lifestyle factors and genetics, (Riserus et al., 2009). A number of lifestyle factors are known to be important to the development of type 2 diabetes, including obesity (defined by a body mass index of greater than thirty), lack of physical activity, poor diet, stress, and urbanization,  (Shoback et al., 2007).  Excess body fat is associated with 30% of cases in those of Chinese and Japanese descent, 60-80% of cases in those of European and African descent, and 100% of Pima Indians and Pacific Islanders. Those who are not obese often have a high waist–hip ratio (Shoback et al., 2007).

Dietary factors also influence the risk of developing type 2 diabetes. Consumption of sugar-sweetened drinks in excess is associated with an increased risk (Malik et al., 2010). The type of fats in the diet is also important, with saturated fats and trans fatty acids increasing the risk and polyunsaturated and monounsaturated fat decreasing the risk (Riserus et al., 2009). Eating lots of white rice appears to also play a role in increasing risk, (HU et al., 2012). A lack of exercise is believed to cause 7% of cases, (Lee et al., 2012).

2.1.3 Gestational diabetes

Gestational diabetes mellitus (GDM) resembles type 2 diabetes in several respects, involving a combination of relatively inadequate insulin secretion and responsiveness. It occurs in about 2-10% of all pregnancies and may improve or disappear after delivery. However, after pregnancy approximately 5-10% of women with gestational diabetes are found to have diabetes mellitus, most commonly type 2. Gestational diabetes is fully treatable, but requires careful medical supervision throughout the pregnancy. Management may include dietary changes, blood glucose monitoring, and in some cases insulin may be required.

Though it may be transient, untreated gestational diabetes can damage the health of the fetus or mother. Risks to the baby include macrosomia (high birth weight), congenital cardiac and central nervous system anomalies, and skeletal muscle malformations. Increased fetal insulin may inhibit fetal surfactant production and cause respiratory distress syndrome. Hyperbilirubinemia may result from red blood cell destruction. In severe cases, perinatal death may occur, most commonly as a result of poor placental perfusion due to vascular impairment. Labor induction may be indicated with decreased placental function. A Caesarean section may be performed if there is marked fetal distress or an increased risk of injury associated with macrosomia, such as shoulder dystocia.

 2.1.4 Other types

Prediabetes indicates a condition that occurs when a person's blood glucose levels are higher than normal but not high enough for a diagnosis of type 2 DM. Many people destined to develop type 2 DM spend many years in a state of prediabetes.

Latent autoimmune diabetes of adults (LADA) is a condition in which type 1 DM develops in adults. Adults with LADA are frequently initially misdiagnosed as having type 2 DM, based on age rather than etiology.

Some cases of diabetes are caused by the body's tissue receptors not responding to insulin (even when insulin levels are normal, which is what separates it from type 2 diabetes); this form is very uncommon. Genetic mutations (autosomal or mitochondrial) can lead to defects in beta cell function. Abnormal insulin action may also have been genetically determined in some cases. Any disease that causes extensive damage to the pancreas may lead to diabetes (for example, chronic pancreatitis and cystic fibrosis). Diseases associated with excessive secretion of insulin-antagonistic hormones can cause diabetes (which is typically resolved once the hormone excess is removed). Many drugs impair insulin secretion and some toxins damage pancreatic beta cells. The ICD-10 (1992) diagnostic entity, malnutrition-related diabetes mellitus (MRDM or MMDM, ICD-10 code E12), was deprecated by the World Health Organization when the current taxonomy was introduced in 1999, (WHO, 1999).

Other forms of diabetes mellitus include congenital diabetes, which is due to genetic defects of insulin secretion, cystic fibrosis-related diabetes, steroid diabetes induced by high doses of glucocorticoids, and several forms of monogenic diabetes.

2.2 Causes and symptoms of diabetes mellitus

The exact cause of diabetes is unknown but it is believed that some factors are known to increase one’s chances of becoming diabetic. These factors are known as risk factors. They include;

·        Obesity:   Statistically, it has been proven that three quarters of diabetic patients, especially those with type II diabetes are obese. Scientifically, it has been proven that 10kg loss of weight can reduce fasting blood sugar level by almost 50md/dl.

·        Family History: A person with a family history of diabetes has an increased chance of suffering from the condition.

·        Lack of activity

·        Poor diet

·        Stress etc

·        The classic symptoms of untreated diabetes are weight loss, polyuria (frequent urination), polydipsia (increased thirst), and polyphagia (increased hunger), (Cooke et al., 2008). Symptoms may develop rapidly (weeks or months) in type 1 diabetes, while they usually develop much more slowly and may be subtle or absent in type 2 diabetes.

·        Prolonged high blood glucose can cause glucose absorption in the lens of the eye, which leads to changes in its shape, resulting in vision changes. Blurred vision is a common complaint leading to a diabetes diagnosis. A number of skin rashes that can occur in diabetes are collectively known as diabetic dermadromes.

2.3 Prevention and management of diabetes mellitus

There is no known preventive measure for type 1 diabetes. (WHO, 2013).

Type 2 diabetes on the other hand can often be prevented by a person being of normal body weight, physical exercise, and following a healthy diet (WHO, 2013).

Dietary changes known to be effective in helping to prevent diabetes include a diet rich in whole grains and fiber, and choosing good fats, such as polyunsaturated fats found in nuts, vegetable oils, and fish.

Limiting sugary beverages and eating less red meat and other sources of saturated fat can also help in the prevention of diabetes.
Active smoking is also associated with an increased risk of diabetes, so smoking cessation can be an important preventive measure as well (Willi et al., 2007).
The management of diabetes mellitus can be best carried out during the early stages of the disease, when the consequences can still be controlled and minimized. The approach will require an early determination of the symptoms of the disease and the use of insulin injections and drugs that inhibit the action of alpha glucosidase enzymes (AGIs)                                             

CHAPTER THREE

3.0 Mechanism of action of acarbose as an inhibitor of α-glucosidase activity

Acarbose is an oligosaccharide derived from the Actinoplanes strain of fungi. The mechanism of action is predominantly through competitive, reversible inhibition of intestinal brush border alpha-glucosidase, with a weaker effect on pancreatic alpha-amylase. The overall effect is the reduction in production and absorption of monosaccharides in the small intestine (figure 1). The activity of alpha-glucosidase varies between individuals with the dosage of acarbose adjusted according to clinical response and side effects. The duration of action is up to six hours. It is effective when ingested at the onset of a meal and the advice is to take it at the first bite of the meal. The delay in the absorption of carbohydrates leads to a reduction in postprandial hyperglycemia. Additionally, acarbose produces a mild reduction in fasting hyperglycemia. It reduces both fasting and postprandial insulin levels. Hypoglycemia occurring during treatment with acarbose must be treated with glucose only, and not sucrose, as a consequence of its mechanism of action.

Source: Br. J Cardiol (c) 2011 Medinews (Cardiology) Limited.

Figure 2. Pharmacological action of acarbose. (A) shows polysaccharides and oligosaccharides broken down by alpha-glucosidase at the small intestine brush border to monosaccharides, which are easily absorbed. (B) shows acarbose working by competitive, reversible inhibition of intestinal brush border alpha-glucosidase with a weaker effect on pancreatic alpha-amylase. The overall effect is the reduction in production and absorption of monosaccharides in the small intestine. In patients with diabetes this results in a decrease in postprandial hyperglycaemia.

Acarbose can be used as an adjunct to diet and exercise as monotherapy when other oral antidiabetic agents are contraindicated, or in any combination of oral antidiabetic drugs and insulin in the management of type 2 diabetes mellitus. There is a 0.4–1% reduction in glycosylated haemoglobin (HbA_1c) with acarbose monotherapy, and up to a 0.65% reduction with combination therapy with other antidiabetic medications. Triglycerides and low-/high-density lipoprotein (LDL/HDL) cholesterol ratio have decreased with acarbose in some studies. Acarbose monotherapy is not associated with any significant change in weight.

It is especially used in reducing postprandial hyperglycaemia. It is used in situations where there is a discrepancy between the blood glucose values obtained on self-monitoring of blood glucose values and the HbA_1c. A mildly elevated fasting glucose and a disproportionately high HbA_1c suggest postprandial hyperglycaemia. It also reduces reactive hypoglycaemia by delaying the glucose absorption peak.

It is approved for use in impaired glucose tolerance to delay or halt the progression to type-2 diabetes. Acarbose has been shown to reduce postprandial glucose levels in insulin treated diabetes, including type 1 diabetes when it is used as an adjunct to insulin, but the reduction in HbA_1c noted in this group has been very marginal and not consistent. Acarbose is a safe drug and the beneficial effects of acarbose in improving glycaemic control have been shown in several studies.

The mechanism by which acarbose increases insulin sensitivity is probably based on lowering fasting and postprandial hyperglycemia and decreasing glucose toxicity (Qualmann et al., 1995) In addition, a decrease in post-challenge hyperinsulinaemia is considered by some authorities to contribute to insulin sensitivity (Lebowitz, 1998). Other investigators have reported improvements in insulin sensitivity following a rise of the incretin hormone, GLP-1, and the 'priming' effect it induces (Nauck et al., 1997).

3.1 α-Glucosidase inhibition and intestinal hormones

Considerable interest has recently focused on the incretin hormones. Acarbose inhibits the post-prandial release of gastric inhibitory polypeptide (GIP) in the duodenum and jejunum and increases the response of GLP-1 in the distal intestine, ileum and colon during the late postprandial period (60 to 240 min), (Requejo et al., 1990). GLP-1 primes ß-cells and makes them more sensitive to glucose, thus increasing their secretion of insulin in response to glucose load and improving insulin sensitivity. In addition, GLP-1 delays gastric emptying and stimulates satiety. The increase in GLP-1 following acarbose treatment is therefore a reliable marker of delayed and more distal intestinal absorption of carbohydrate, and a modulator of decreased postprandial hyperglycemia.

Treatment with acarbose is associated with several changes in lipid profile. Serum triglycerides, very low-density lipoprotein (VLDL) concentration and free fatty acids are frequently elevated in obese patients with insulin-resistant type 2 diabetes. Several studies have documented a dose-dependent reduction in blood lipids with acarbose in this patient population (Hillebrand et al., 1979, Nestel et al., 1985 and Clissold et al., 1998).

Lowering of total serum triglycerides is primarily mediated via a reduction in the biosynthesis of VLDL (Nestel et al., 1985) and is secondary to acarbose-induced attenuation of postprandial hyperinsulinaemia. Mean triglycerides decreased significantly (from 5.8 mmol/L to 3.6 mmol/L) when acarbose 50mg twice daily was given as an adjunct to dietary therapy in 30 nondiabetic patients with hypertriglyceridaemia for a total period of 16 weeks (Malaguamera et al.,  1999). The same beneficial effect was seen in 18 non-diabetic patients with familial hypertriglyceridaemia (FH); mean serum triglycerides dropped significantly (p < 0.05) from 5.8 ± 4.1 to 3.6 1.2 mmol/L after 2 months' treatment with acarbose 50mg twice daily (Malaguamera et al., 1999).

The response of fasting triglyceride levels to acarbose is related to dietary fat intake and an overall improvement of metabolic control (Reaven et al., 1990). Maruhama et al. reported a significant (p < 0.05) mean decrease in fasting serum triglycerides (from 1.92 ± 0.31 mmol/L to 145 ± 0.21 mmol/L) in obese hyperinsulinaemic patients following acarbose 100mg three times daily for 1 month.

Carbohydrate-induced postprandial triglyceride overproduction is reduced for several hours by acarbose, through a slowing of the impact of glucose on liver metabolism (Hanefeld et al., 1991 and Baron et al., 1987). Similar results were reported by Kado et al. who demonstrated a significant (p < 0.01) reduction of the post-prandial rise of serumtriglycerides and lipoprotein remnants in the postprandial phase in 20 normal weight patients with type 2 diabetes, following a 300 kcal test meal (21.1% protein, 22.5% fat, 49.6% carbohydrate) and a single dose of acarbose 100mg.

Since acarbose does not interfere with intestinal lipid absorption, the most likely mechanism for its hypo triglyceridaemic action is a slower hepatic uptake of precursor molecules for de novo lipogenesis. Dietary carbohydrates are key precursors of lipogenesis and insulin plays a central role in postprandial lipid metabolism. Thus, acarbose may also contribute to triglyceride inhibition by interference with endogenous triglyceride synthesis. Suppression of intestinal lipogenesis by acarbose has also been suggested as a plausible explanation. (Kado et al., 1998).

Inconsistent effects of acarbose on serum cholesterol have been reported. Total cholesterol concentrations were not significantly altered in studies reported by Homma et al., and Nestel et al., whereas other studies have documented a significant reduction (Maruhama et al., 1995 and Leonhardt 1991). An increase in the low-density lipoprotein/high-density lipoprotein (LDL/HDL) cholesterol ratio of 26.8% was evident following treatment of 96 patients with type 2 diabetes with acarbose 100mg three times daily for 24 weeks in the Essen-II Study (Hoffmann et al., 1997). Plasma levels of apolipoprotein A-I and A-II decreased significantly during acarbose treatment, whereas plasma apolipoprotein B remained unchanged. (Couet et al., 1989).

In hyperinsulinaemic, overweight patients with impaired glucose tolerance, acarbose 300mg daily reduced LDL-cholesterol significantly (p < 0.05) from 4.40 ± 0.30 mmol/L to 3.40 ± 0.27 mmol/L after 4 weeks. HDL-cholesterol remained unchanged (Maruhama et al., 1980).There was a marked increase of intestinal anaerobic bacteria (bifidobacter and acidophilus), probably as a result of undigested carbohydrates in the lower part of the bowel.

National Institute for Health and Clinical Excellence (NICE) guidelines suggest using acarbose as monotherapy when other oral antidiabetic medications are not able to be used, because of its lower glucose-lowering efficacy, higher dropout rate due to intolerance and higher cost in comparison with well-established therapies.

While peripheral insulin resistance is the main aetiology for fasting hyperglycaemia, increased hepatic glucose output and delayed insulin release are responsible for impaired glucose tolerance. Impaired glucose tolerance is more strongly associated with negative cardiovascular outcomes than fasting hyperglycaemia. There are many studies pointing to postprandial glycaemia as an independent risk factor for cardiovascular diseases.

A meta-analysis of seven randomised, double-blind, placebo-controlled studies of acarbose in type 2 diabetes by Hanefeld et al. has shown that acarbose treatment significantly reduced the risk of myocardial infarction (HR 0.36; 95% CI 0.16–0.80; p=0.0120) and any cardiovascular event (HR 0.65; 95% CI 0.48–0.88; p=0.0061). There were also improvements in glycaemic control, triglyceride levels, body weight and systolic blood pressure. These factors are all associated with increased risk of cardiovascular events in type 2 diabetes. This meta-analysis is also controversial as much of the data were unpublished data from the manufacturer's database. A Cochrane systematic review and meta-analysis identified reductions in HbA_1c but no effect on morbidity or mortality (Van de laar et al., 2005). These controversies around acarbose are not mentioned in a more recent review by Hanefeld, who was also one of the STOP-NIDDM investigators (Hanefeld, 2007).

Other supporting laboratory evidence for mechanisms of possible cardiovascular benefit have come from studies in animals and humans. A randomised-controlled study in mice with placebo, sucrose and sucrose-acarbose showed exaggerated cardiac damage after ischaemia/reperfusion injury with repetitive postprandial hyperglycaemia that could be reduced with acarbose treatment. Reactive oxygen species and not altered neutrophil infiltration have been implicated in the enhanced myocardial injury. Postprandial hyperglycaemia has been shown to be associated with enhanced lipid peroxidation, platelet activation, and endothelial dysfunction in early type 2 diabetes, which could be attenuated with acarbose.

 3.2 Absorption of acarbose

Extremely low bioavailability. Less than 2% of an oral dose of acarbose is absorbed as active drug. Peak plasma concentrations of the active drug is achieved 1 hour after dosing. Drug accumulation does not occur with multiple doses.

3.3 Metabolism of acarbose

Acarbose is only metabolized within the gastrointestinal tract by intestinal bacteria and also digestive enzymes to a lesser extent. 4-methylpyrogallol derivatives (sulfate, methyl, and glucuronide conjugates) are the major metabolites. One metabolite (formed by cleavage of a glucose molecule from acarbose) also has alpha-glucosidase inhibitory activity.

3.4 Route of elimination

The fraction of acarbose that is absorbed as intact drug is almost completely excreted by the kidneys. A fraction of the metabolites (approximately 34% of the dose) is absorbed and subsequently excreted in the urine. The active metabolite is excreted into the urine and accounts for less than 2% of the total administered dose. When given intravenously, 89% of the dose is excreted into the urine as the active drug. When given orally, less than 2% of the oral dose is recovered into the urine as active (parent compound and active metabolite) drug.

3.5 Precaution/side effects

Acarbose is contraindicated in patients with known hypersensitivity to the drug and in patients with diabetic ketoacidosis or cirrhosis. Acarbose is also contraindicated in patients with inflammatory bowel disease, colonic ulceration, partial intestinal obstruction or in patients predisposed to intestinal obstruction. In addition, acarbose is contraindicated in patients who have chronic intestinal diseases associated with marked disorders of digestion or absorption and in patients who have conditions that may deteriorate as a result of increased gas formation in the intestine.

The side effects of acarbose usually do not need medical attention because they may go away during the course of treatment as the body adjusts to it.

Some of these side effects include;

·        Abdominal or stomach pain

·        Yellow eyes or skin

·        Diarrhea

·        Passing of gas etc.

CHAPTER FOUR

4.0 Mechanism of action of miglitol as an inhibitor of alpha glucosidase activity

Miglitol is an oral anti-diabetic drug that acts by inhibiting the ability of the patient to breakdown complex carbohydrates into glucose. It is primarily used in diabetes mellitus type 2 for establishing greater glycemic control by preventing the digestion of carbohydrates (such as disaccharides, oligosaccharides, and polysaccharides) into monosaccharides which can be absorbed by the body. Miglitol is a desoxynojirimycin derivative that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. As a consequence of plasma glucose reduction, miglitol reduce levels of glycosylated hemoglobin in patients with Type II (non-insulin-dependent) diabetes mellitus. Systemic non enzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time. Because its mechanism of action is different, the effect of miglitol to enhance glycemic control is additive to that of sulfonylureas when used in combination. In addition, miglitol diminishes the insulinotropic and weight-increasing effects of sulfonylureas. In contrast to sulfonylureas, miglitol does not enhance insulin secretion. The anti hyperglycemic action of miglitol results from a reversible inhibition of membrane-bound intestinal a-glucoside hydrolase enzymes. Membrane-bound intestinal a-glucosidase hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in delayed glucose absorption and lowering of postprandial hyperglycemia. Miglitol inhibits glycoside hydrolase enzymes called alpha-glucosidase. Since miglitol works by preventing digestion of carbohydrates, it lowers the degree of postprandial hyperglycemia. For use as an adjunct to diet to improve glycemic control in patients with non-insulin-dependent diabetes mellitus (NIDDM) whose hyperglycemia cannot be managed with diet alone, It must be taken at the start of main meals to have maximal effect. Its effect will depend on the amount of non-monosaccharide carbohydrates in a person’s diet.

Figure 4: Structure of Miglitol

Miglitol has minor inhibitory activity against lactase and consequently, at the recommended doses, would not be expected to induce lactose intolerance. Recent study on rats by shrivastava et al showed that miglitol has antioxidant effect and hypocholesterolemic effect (Shrivastava et al., 2013).

4.1.1 Absorption of miglitol

Absorption of miglitol is saturable at high doses with 25 mg being completely

absorbed while a 100-mg dose is only 50-70% absorbed. No evidence exists to show

that systemic absorption of miglitol adds to its therapeutic effect.

4.1.2   Metabolism of miglitol

Miglitol is not metabolized in human beings.

4.1.3   Route of elimination

It is eliminated through renal excretion in the kidney  as an unchanged drug  and half life from plasma is 2hours.

4.1.4  Precaution/ side effects

An overdose may result in transient increases in flatulence, diarrhea, and abdominal discomfort. Because of the lack of extra-intestinal effects seen with miglitol, no serious systemic reactions are expected in the event of an overdose.

4.2 Mechanism of action of voglibose as an inhibitor of alpha glucosidase   activity

Voglibose is an alpha-glucosidase inhibitor used for lowering post-prandial blood glucose levels in patients with diabetes mellitus. Voglibose is known for its ability to increase glucagon-like peptide-1 (GLP-1) secretion in humans. Recent study demonstrated new mechanisms by which voglibose increases plasma active GLP-1 levels in diabetic ob/ob mice. As expected, the stimulatory effects of voglibose on GLP-1 secretion resulted in increased active GLP-1 levels in plasma in a 1-day dosing study. Unexpectedly, chronic but not 1-day treatment with voglibose decreased plasma dipeptidyl peptidase-4 (DPP-4) activity by reducing its circulating protein levels. It  has also been revealed that chronic dosing of voglibose increased Neurod1 and Glucagon gene expression, and GLP-1 content in the lower gut. Active GLP-1 levels in plasma achieved by chronic treatment with voglibose were higher than those achieved by 1-day treatment. The use of acarbose, another alpha-glucosidase inhibitor with different selectivity, as a comparator, shows that inhibition of alpha-glucosidase induces a decrease in plasma DPP-4 activity in ob/ob mice. But compared to acarbose, voglibose  demonstrates a more favorable effect on DPP-4 activity, GLP-1 secretion and gut GLP-1 content, when glucose levels were equally improved, leading to higher plasma active GLP-1 levels. These findings provide new insights into the treatment of diabetes mellitus.

 Figure 5:  Structure of  voglibose

4.2.1 Absorption of voglibose

It is poorly and slowly absorbed by the human body.

4.2.2 Metabolism of voglibose
Voglibose is not metabolized in humans or any animal species. This can be seen as there is no metabolite detected in plasma, urine or feaces, indicating a lack of either systemic or presystemic metabolism.
4.2.3 Precaution/ side effects
An overdose of Voglibose may result in transient increase in flatulence, diarrhea and abdominal discomfort. The lack of extra intestinal effects seen indicates that no serious systemic reactions are expected in the event of an overdose. 

                                                           CHAPTER FIVE

Conclusion

Oral antidiabetic drugs are becoming increasingly important as rates of type 2 diabetes, uncontrolled by dietary intervention alone, increase around the world. Therapeutic agents that target the early stages of type 2 diabetes, such as the α-glucosidase enzyme inhibitor acarbose, which reduces postprandial hyperglycaemia and hyperinsulinaemia, now have a more prominent role to play in diabetes management in view of increasing evidence that the postprandial state is an important contributing factor to the development of atherosclerosis. Postprandial hyperglycaemia plays a major role in the ongoing metabolic decline in type 2 diabetes, the progression from IGT to type 2 diabetes, and in the development and progression of the vascular complications of established type 2 diabetes. The control of postprandial hyperglycaemia is therefore an important goal in the management of established diabetes and in the defence against diabetes in high-risk individuals with impaired glucose control. By delaying the absorption of carbohydrates, the α-glucosidase inhibitors reduce postprandial hyperglycaemia and improve overall glycaemic control without loss of efficacy over time. Unlike many other antidiabetic agents, the therapeutic activity of the α-glucosidase inhibitors is not accompanied by a risk for hypoglycaemia or weight gain. The inhibition of α-glucosidase activity is an effective therapy for type 2 diabetes and an important option for addition to treatment regimens comprising other antidiabetic agents. This landmark trial also showed significantly reduces the risk for onset of hypertension, myocardial infarction, and any cardiovascular event.

Recommendation

The treatment of diabetes mellitus has been met with the use of various drug therapy. The use of alpha glucosidase inhibitors however is advised as they have no known life threatening effects or weight gain.

Also, the drugs are not necessarily taken as pills but as smart foods or food supplement, and so people who find difficulty in swallowing pills can easily take them.

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