DIABETES AND ITS COMPLICATIONS AND SGLT-2 INHIBITORS: A NOVEL THERAPY FOR TYPE 2 DIABETES MELLITUS

 

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About Authors:
Shivkant M. Kide*, Rahul M. Kide, Lokesh T. Thakare, Komal V. Ambulkar
Department of Pharmacology,
Institute of Pharmaceutical Education and Research,
Borgaon (Meghe), Wardha-442 001,(M.H.), India.
shivpharma08@gmail.com

ABSTRACT:
The incidence of type 2 diabetes mellitus is increasing worldwide. The pharmacotherapy for type 2 diabetes until the last decade only consisted of biguanides, sulphonylureas, and insulin. The existing therapeutic classes of antidiabetic drugs are not adequately effective in maintaining long-term glycemic control in most patients, even when used in combination. One emerging novel therapeutic class of antidiabetic drugs is sodium glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 accounts for 90% of the glucose reabsorption in the kidney. The SGLT2 inhibitors increase urinary excretion of glucose and lower plasma glucose levels in an insulin-independent manner. Forxiga (Dapagliflozin) the most prominent molecule in this class is currently approved by USFDA. Other members of this class (eg, sergliflozin, remogliflozin) are also effective. This class of novel agents can effectively control blood sugar level without producing weight gain or hypoglycemia.

REFERENCE ID: PHARMATUTOR-ART-2183

PharmaTutor (ISSN: 2347 - 7881)

Volume 2, Issue 6

Received On: 07/04/2014; Accepted On: 16/04/2014; Published On: 01/06/2014

How to cite this article: SM Kide, RM Kide, LT Thakare, KV Ambulkar; Diabetes and its Complications and SGLT-2 Inhibitors: A Novel Therapy for Type 2 Diabetes Mellitus; PharmaTutor; 2014; 2(6); 75-94

INTRODUCTION:
Diabetes mellitus is a metabolic disorder of multiple etiologies characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or a combination of both. According to estimates from the International Diabetes Federation, the global incidence of diabetes mellitus in 2010 was ~6.6% and it was predicted to increase to ~7.8% by 2030, representing an increase of 153 million patients.[1] It is the most common non-communicable disease worldwide and the fourth to fifth leading cause of death in developed countries.[2] Diabetes also contributes to 5% of the total mortality.[3]

Type 2 diabetes has become a major health concern all over in Asia. Developing countries such as India have had the maximum increases in the last few years. The current prevalence of type 2 diabetes is 2.4% in the rural population and 11% in the urban population of India. It has been estimated that by the year 2025, India will have the largest number of diabetic subjects in the world.[4]

Diabetes mellitus is a heterogeneous group of disorders characterized by high blood glucose levels.[5] Several distinct forms of diabetes exist which are caused by a complex interaction of genetics, environmental factors and life-style choices. Some forms are characterized by absolute insulin deficiency or a genetic defect leading to defective insulin secretion while other forms share insulin resistance as their underlying etiology.

The greatest increase in prevalence is expected to occur in Asia and Africa. The increase in incidence of diabetes in developing countries follows the trend of urbanization and lifestyle changes.[6] Many causes have been postulated for the rise in the number of cases, including urbanization, sedentary lifestyles, poor nutrition & obesity.[7]

The metabolic abnormality can be improved by various means to ameliorate the deficiency of insulin effects. There are characteristics symptoms of diabetes such as polydipsia, polyuria and weight loss often occur. In severe cases, ketoacidosis or hyperglycemic hyperosmolar states may occur and lead to disturbances of consciousness, coma and even death unless treated appropriately.

Diabetes is a metabolic disorder, with long duration of diabetic metabolism, diabetes specific complications, chiefly involving small vessels (retinopathy, nephropathy and neuropathy), may ensure and lead to serious outcomes such as visual disturbance, renal failure and gangrene.Diabetes accelerates and exacerbates the occurrence of arteriosclerosis, increasing the risks for myocardial infarction, cerebral infraction and occlusive artery disease of the lower extremities. These complications constitute the major causes of morbidity and mortality in diabetic patients. So, diabetes is one of the most debilitating common illnesses and requires lifelong management.[8]

Type 2 diabetes mellitus is a complex trait because both genetic and environment factors play a role in the disease etiology. Type 2 diabetes mellitus is the most common form of diabetes, accounting for > 90% of all cases in the developed world.[9]

The etiology of type 2 diabetes mellitus is intricate and multifaceted, but virtually all patients contend with both relative insulin deficiency and insulin resistance to varying degrees. People with type 2 diabetes are not dependent on exogenous insulin, but may require it for the control of blood glucose levels if this is not achieved with diet alone or with oral hypoglycemic agents. The resulting hyperglycemia can facilitate ß-cell failure in the pancreas and worsen insulin resistance, thus triggering a cycle of impaired metabolism and glucotoxicity.[10] High caloric intake and physical inactivity are major contributors to obesity which within the appropriate genetic background, can cause insulin resistance, hyperglycemia & glucotoxicity mediated by pancreatic ß-cell failure. Hyperglycemia contributes to and exacerbates insulin deficiency by increasing apoptosis of ß-cells and diminishing ß-cell mass, thus reducing gene transcription, synthesis and secretion of insulin.[11]

It is now well established that hyperglycemia and glucotoxicity contribute to disease progression in patients with type 2 DM and therefore, hyperglycemia is a risk factor for the development of long-term complications, including microvascular disease as well as macrovascular disease.[12]

The current scenario of diabetes in India
India, the world’s second most populous country, now has more people with type 2 DM (more than 50 million) than any other nation. With India having the highest number of diabetic patients in the world, the sugar disease is posing an enormous health problem in the country. Calling India the diabetes capital of the world. According to a WHO fact sheet on diabetes, 2004 recorded an estimated 3.4 million deaths due to consequences of high blood sugar. WHO also estimates that 80 % of diabetes deaths occur in low and middle-income countries & projects that such deaths will double between 2005 and 2030.

A glance at statistics from Global Data proves one point: that the two countries having the highest diabetes prevalence (India and China) score quite low when it comes to the expenditure on disease.

Diabetes also imposes large economic burdens in the form of lost productivity and foregone economic growth. It has been estimated that the global burden of type 2 diabetes mellitus for 2010 would be 285 million people (2010) which is projected to increase to 438 million in 2030; a 65 % increase Similarly, for India this increase is estimated to be 58%, from 51 million people in 2010 to 87 million in 2030.

The impacts of type 2 DM are considerable: as a lifelong disease, it increases morbidity and mortality and decreases the quality of life. At the same time, the disease and its complications cause a heavy economic burden for diabetic patients themselves, their families and society. A better understanding about the cause of a predisposition of Indians to get type 2 DM is necessary for future planning of healthcare, policy and delivery in order to ensure that the burdens of disease are addressed.[13]

Insulin resistance and type 2 diabetes mellitus
Insulin resistance is a characteristic feature of most patients with type 2 diabetes mellitus and is almost a universal finding in type 2 diabetic obese patients. In obese subjects, insulin levels typically increase to maintain normal glucose tolerance. Basal and total 24-h rates of insulin secretion are three to four times higher in obese insulin-resistant subjects than in lean controls.[14] The hyperinsulinemia associated with insulin resistance results from a combination of an increase in insulin secretion and a reduction in insulin clearance rates.

The insulin resistance of obesity and type 2-diabetes is characterized by defects at many levels with decreases in receptor concentration and kinase activity, the concentration and phosphorylation of IRS-1 and IRS-2, PI-3-K activity, glucose transporters translocation and the activity of intracellular enzyme.[15] Insulin increases glucose transport in fat and muscle cells by stimulating the translocation of the transporter GLUT4 from intracellular sites to the plasma membrane. GLUT4 is found in vesicles that continuously cycle from intracellular stores to the plasma membrane. Insulin increases glucose transport by increasing the rate of GLUT4 vesicle exocytosis and by slightly decreasing the rate of internalization.[16]

Insulin causes remodeling of cortical actin filaments just below the plasma membrane and induces membrane ruffling. The docking and fusion of the GLUT4 vesicle at the plasma membrane may also be subject to regulation by insulin. Circulating free fatty acids (FFAs) derived from adipocytes are elevated in many insulin-resistant states and have been suggested to contribute to the insulin resistance of diabetes and obesity by inhibiting glucose uptake, glycogen synthesis and glucose oxidation and by increasing hepatic glucose output. Elevated FFAs are also associated with a reduction in insulin-stimulated IRS-1 phosphorylation and IRS-1-associated PI-3-K activity. The link between increased circulating FFAs and insulin resistance might involve accumulation of triglycerides and fatty acid-derived metabolites (diacylglycerol, fatty acyl-CoA and ceramides) in muscle and liver.

In addition to its role as a storage depot for lipid, the fat cell produces and secretes a number of hormones, collectively called adipokines, which may profoundly influence metabolism and energy expenditure. Expression of tumor necrosis factor a (TNF-a) is increased in the fat of obese rodents and humans and has been shown to produce serine phosphorylation of IRS-1, resulting in reduced insulin receptor kinase activity and insulin resistance.[17]

ß- Cell dysfunction in type 2 diabetes mellitus
In type 2 diabetes, more moderate abnormalities of secretion that cause glucose intolerance are present only if insulin resistance is also present. The genetic basis of ß-cell dysfunction in this form of diabetes is more complex involving both multiple interacting genes and environmental factors which determine whether diabetes will develop and at what age. Despite a genetic predisposition, diabetes may never manifest and hyperglycemia, when it occurs usually does so later in life (after 50 years of age).The compensatory hypersecretion of insulin in insulin-resistant states is due to an expansion of ß-cell mass and alteration in the expression of key enzymes of ß-cell glucose metabolism and is believed to be a consequence of increased levels of this glycolytic enzyme hexokinase. In normal pancreatic ß-cells, glucokinase mediates the conversion of glucose to glucose 6-phosphate and determines the threshold at which glucose stimulates insulin secretion.[18]

Insulin resistance is associated with increased ß-cell hexokinase activity, leading to secretion of insulin at lower glucose concentration. It has been suggested that increased free fatty acids in serum could precipitate ß-cell failure. Short-term exposure of pancreatic islets to free fatty acids increases insulin secretion but long-term exposure inhibits glucose-induced insulin secretion and biosynthesis and may lead to ß-cell deaths by apoptosis. These effects may be mediated by increased expressions of proteins which uncouple glucose metabolism from oxidative phosphorylation, a key link between ß-cell glucose metabolism and insulin secretion.[19]

Genetic aspect of type 2 diabetes mellitus
Diabetic islets show reduced insulin gene transcription. This might be due to at least in part, to reduced insulin action in that tissue and indicate that activation of insulin gene transcription is an important effect of insulin-mediated signaling. Genetic variation in the gene encoding Calpain-10, a ubiquitously expressed cysteine protease, has also been associated with type 2 diabetes, increasing risk as much as three-fold through affects on both the normal function of the ß-cell and insulin action in muscle and fat.[20]

Current diagnostic criteria of diabetes mellitus
Many persons with type 2 diabetes already show the presence of the long-term complications associated with diabetes at the time of diagnosis. It is now widely accepted that if diabetes is detected early and adequate steps are taken, it may be possible to significantly delay the onset and progression of these complications. When a patient is symptomatic and fasting plasma glucose (FPG) is unequivocally elevated, diagnosis of diabetes does not present any difficulty. When a patient is without clinical symptoms diagnosis of diabetes is more difficult. Revised criteria for diagnosing DM have been issued by a consensus panel of experts from the National Diabetes Data Group and the WHO. The revised criteria reflect new epidemiological and metabolic evidence and are based on the following premises:
1. The spectrum of fasting plasma glucose (FPG) & the response to an oral glucose load varies in normal individuals.
2. Diabetes mellitus defined as the level of glycemia at which diabetes-specific complications are noted and not on the level of glucose tolerance from a population-based viewpoint.

Glucose tolerance is classified into three categories based on the fasting plasma glucose:
1. FPG <5.56 mmol/ l (<100 mg/dl) is considered normal,
2. FPG >5.56 mmol/l (>100 mg/dl) but <7.0 mmol/l (<126 mg/dl) is defined as impaired fasting glucose (IFG) and
3. FPG >7.0 mmol/l (>126 mg/dl) warrants the diagnosis of diabetes mellitus.

IFG is a new diagnostic category defined by the expert committee on the diagnosis and classification of diabetes mellitus (American Diabetes Association). It is analogous to IGT, which is defined as plasma glucose levels between 7.8 and 11.1 mmol/l (140 and 200 mg/dl) 2 hrs after a 75- gram oral glucose load.

Individuals with IFG or IGT are at substantial risk for developing type 2 diabetes mellitus and cardiovascular disease in the future, though they may not meet the criteria for diabetes mellitus. Thus the criteria for diagnosis of diabetes mellitus are as follows:
• Symptoms of diabetes plus random blood glucose concentrations >11.1 mmol/l (>200 mg/dl).
• Fasting plasma glucose >7.0 mmol/l (>126 mg/dl) OR
• Two-hour plasma glucose >11.1 mmol/l (>200 mg/dl) during an oral glucose tolerance test. The revised criteria for the diagnosis of DM emphasize FPG as the most reliable and convenient test for diagnosing DM in asymptomatic individuals. 

Oral glucose tolerance testing although still a valid mechanism for diagnosis of DM is not recommended as part of routine screening. Some investigators have advocated acetylated hemoglobin (HbA1c) as a diagnostic test for DM. Though there is strong correlation between elevations in plasma glucose and HbA1c, the relationship between FPG and HbA1c in individuals with normal glucose tolerance or mild glucose intolerance is less clear and the test is not universally standardized or available.[21]

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