A REVIEW OF NATEGLINIDE IN THE MANAGEMENT OF TYPE 2 DIABETES

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ABOUT AUTHORS:
Mistry Ripal*, Haresh T. Mulani
Department of Pharmaceutics
Indubhai Patel College of Pharmacy and Research Centre,
Dharmaj, Gujarat
*rx.ripalmistry@gmail.com

ABSTRACT:
Diabetes mellitus, or simply diabetes, is a chronic disease that occurs when the pancreas is no longer able to make insulin, or when the body cannot make good use of the insulin it produces. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels. The success of oral hypoglycemic drug therapy is usually based on are storation of normal blood glucose levels. Traditionally, the term oral hypoglycemic was used interchangeably with sulfonylureas, but more recently the development of several new drugs has broadened this designation to include all oral medications for diabetes. Nateglinide, a D-phenylalanine derivative, is a novel insulinotropic drug which has recently been launched as a therapeutic agent for Type II diabetes. Clinical studies have shown that nateglinide induces a rapid onset of insulin release synergistic with meal administration which effectively restores the early phase of insulin secretion. Since the loss of early insulin secretion is thought to play an important role in the development of glucose in tolerance the ability of nateglinide to promote early insulin release is potentially of considerable therapeutic benefit.

REFERENCE ID: PHARMATUTOR-ART-2212

PharmaTutor (ISSN: 2347 - 7881)

Volume 2, Issue 8

Received On: 11/05/2014; Accepted On: 26/05/2014; Published On: 01/08/2014

How to cite this article: R Mistry, HT Mulani; A Review of Nateglinide in the Management of Type 2 Diabetes; PharmaTutor; 2014; 2(8); 8-15

INTRODUCTION:
Vast amounts of literature have been written about the current and growing epidemic of diabetes mellitus (DM) and its associated complications. The cost of diabetes to the United States healthcare system is staggering, amounting to $100 billion in direct and indirect expenditures annually. Currently 15 million Americans have diabetes, one third of whom have yet to be diagnosed.1 Now worldwide 375 million people are suffer from diabetes mellitus (DM) and India has the second highest number of people with diabetes in the world which is expected to increase to 101.2 million by the year 2030. Type 2 diabetes accounts for approximately 85 to 90 percent of all the diabetics in the country.2 The recent rise in obesity in the United States accounts for much of the observed and anticipated rise in cases of diabetes mellitus in this country. Although insulin treatment has greatly increased the life expectancy of the diabetic patient, diabetes remains the third leading cause of death by disease, the second leading cause of blindness,and the second leading cause of renal failure. Diabetes mellitus is a heterogeneous group of disorders characterized by abnormalities in carbohydrate, protein and lipid metabolism. The central disturbance in diabetes mellitus is an abnormality in insulin production or action or both, although other factors can be involved. Hyperglycemia is a common end point for alltypes of diabetes mellitus and is the parameter that is measured to evaluate and manage the efficacy of diabetes therapy.3,4

1. Disease Profile:
Type 2 diabetes mellitus is a progressive disease with aninsidious onset.5 The high incidence and prevalence of this condition, the chronic nature and the high costs associated with the disease and its complications make type 2 diabetes mellitus an ideal candidate for disease management.

According to the American Diabetes Association (ADA) the criteria for the diagnosis of diabetes mellitus are:
· the presence of the classic symptoms of the disease (polyuria, polydypsia and unexplained weight loss) plus a plasma glucose level of ≥11.1 mmol/L (sampled at any time of the day without regard to time since the last meal), or
· a fasting (no caloric intake for ≥8 hours) plasma glucose (FPG)level of ≥7 mmol/L, or
· a 2-hour post load plasma glucose level of ≥11.1 mmol/L[corresponds to a glycosylated hemoglobin (HbA1c) of ≈6.9%]during an oral glucose tolerance test.

The World Health Organization recommends that both an FPG level and a 2-hour post load plasma glucose level are taken, with the tests confirmed on different days.1In many cases, type 2 diabetes mellitus begins as a symptom less disease. Acute symptoms are only manifest when the plasma glucose level is well above its normal range; however, as it progresses,the disease is characterized by the appearance of microvascular and macrovascular complications. Indeed, macrovascular complications can start even before type 2 diabetes mellitus is diagnosed.

1.1  Anatomy of Pancrease :7
The pancreas is located deep in the abdomen, 12-15 cm long, sandwiched between the stomach and the spine. It lies partially behind the stomach. The other part is nestled in the curve of the duodenum (small intestine). The pancreas is formed of a broad, right extremity, the head, a main part, the body, and a narrow, left extremity, the tail. The ductal system consists of 20 to 30 small lobular ducts, which coalesce to form the main pancreatic duct.

The main pancreatic duct enters the duodenal wall with the biliary duct at the papilla of Vater in the majority of humans (90%), the rest having the accessory duct and the papilla as the main routes for pancreatic secretion.

Figure 1:Anatomy of Pancrease

1.2  Glucose Homeostasis :8
Carbohydrates, particularly glucose, are an important source of fuel for living organisms. Glucose is a major energy source for all cells, and some tissues (e.g., brain)need a continuous delivery of glucose. Maintenance of serum glucose concentrations within a normal physiological range, critical to the maintenance of normal fuel use, is primarily accomplished by two pancreatic hormones, insulin and glucagon. Derangements of glucagon or insulin regulation can result in hyperglycemia or hypoglycemia, respectively.

Glucose penetrates most tissues slowly unless insulin is present to facilitate its uptake; however, central nervous system (CNS) cells, capillary endothelial cells,gastrointestinal epithelial cells, pancreatic cells, and renal medullary cells are freely permeable to glucose.The endocrine portion of the pancreas, called the islets of Langerhans, consists of cord like groups of cells arranged along pancreatic capillary channels. Two major types of secretory cells exist within the islets: α-cells, which produce glucagon; and β-cells, which produce insulin. Other cell types are also present in the islets, including the δ-cells, which secrete somatostatin and PP cells, which produce pancreatic polypeptide. These pancreatic cells monitor changes in the availability of small calorigenic molecules, namely glucose, and to a lesser extent amino acids, ketone bodies and fatty acids. Pancreaticβ-cells appropriately alter their rates of insulin secretion in response to fluctuations in the levels of these calorigenic molecules, with glucose playing the dominant role in regulation of insulin secretion. Pancreatic α-cells secrete glucagon in response to increases in amino acid and fatty acid levels; however, glucose inhibits glucagon secretion. If blood glucose levels fall (e.g., during hypoglycemia or fasting), glucagon secretion is augmented, providing a counter regulatory hormonal response that stimulates gluconeogenesis in the liver and other tissues to avoid hypoglycemia.

Blood glucose concentrations are strictly maintained within homeostatic limits by a variety of biochemical and physiological control mechanisms. Circulating glucose levels are determined by the balance among absorption, storage, production, and use(metabolic rate). Glucagon and insulin are the two most important hormones that maintain glucose homeostasis when blood concentrations are perturbed.

1.3  Type of Diabetes mellitus :8,9,10
Diabetes mellitus has been traditionally classified into insulin-dependent diabetes mellitus (IDDM), also known as type I (formerly called juvenile-onset diabetes mellitus) and non–insulin-dependent diabetes mellitus (NIDDM), also known as type II (formerly referred to as adult-onset diabetes mellitus).

Type 1 diabetes (Insulin-Dependent Diabetes Mellitus)
This form of diabetes, which accounts for only 5–10% of those with diabetes, called by the terms Insulin Dependent Diabetes or Juvenile-onset diabetes, results from a autoimmune destruction of the cells of the pancreas. The factor or factors that trigger this autoimmune response are unknown. The progression of the autoimmune response is characterized by lymphocytic infiltration and destruction of the pancreatic cells resulting in insulin deficiency. In this form of diabetes, the rate of b-cell destruction is quite variable, being rapid in some individuals (mainly infants and children) and slow in others (mainly adults). Some patients, particularly children and adolescents, may present with ketoacidosis as the first manifestation of the disease.

Type II diabetes (Non-Insulin-Dependent Diabetes Mellitus)
This form of diabetes, which accounts for; 90–95% of those with diabetes, called as Non–Insulin-Dependent Diabetes, type 2 diabetes, or adult onset diabetes, encompasses individuals who have insulin resistance and usually have relative (rather than absolute) insulin deficiency. In contrast, type II is not an autoimmune process and may or may not be insulin dependent; that is, a diabetic state that is most effectively managed by insulin therapy. In this type of DM pancrease doesn’t produce enough insulin or defective responsiveness of body tissues to insulin is believed to involve. Most patients with this form of diabetes are obese, and obesity itself causes some degree of insulin resistance. Patients who are not obese by traditional weight criteria may have an increased percentage of body fat distributed predominantly in the abdominal region.

Table 1: Features Of Type I And Type Ii Diabetes Mellitus

Characteristic

Type I

Type II

Onset (age)

Usually ≤ 30

Usually ≥ 40

Type of onset

Abrupt

Gradual

Nutritional status

Often thin

Often obese

Clinical symptoms

Polydipsia,polyuria, polyphagia

Often asymptomatic

Ketosis

Present

Usually absent

Endogenous insulin

Absent

Variable

Insulin therapy

Required

Sometimes

Because the incidence of diabetes is high in families of persons with NIDDM, a  strong  genetic  predisposition  is  suspected. However, NIDDM is most likely a polygenic disease, involving multiple genetic predispositions to the development  of  the diabetic state. The three major metabolic abnormalities that contribute to hyperglycemia in NIDDM are defective glucose-induced insulin secretion,  increased  hepatic glucose output, and inability of insulin to stimulate glucose  uptake in peripheral target tissues.

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