CHAPTER ONE

INTRODUCTION

• BACKGROUND OF STUDY

 Diabetes mellitus is a group of metabolic disorders in which a person has high plasma glucose, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. The high plasma glucose produces the classical symptoms of polyuria, polydipsia and polyphagia (Rother, 2007). Type 2 diabetes mellitus, formerly non-insulin dependent diabetes mellitus or adult onset diabetes, is a metabolic disorder that is characterized by hyperglycemia in the context of insulin resistance and relative insulin deficiency (Vinayet al., 2008). It has been regarded as one of the most common metabolic diseases with the rate of 6.4 % in people aged 20-79 years and one of the leading causes of death all over the world (Burtiset al., 2008; Vinayet al., 2008; Rosen, 2012). Nearly 80% of the type 2 diabetes mellitus patients come from developing countries (Dhindsaet al., 2009). Many factors, such as genetics, aging and life style, have been involved in the development of type 2 diabetic mellitus, diagnosis of type 2 diabetic mellitus are found to be obese (Ramarao and Kaul, 2009). Over 90% of people with diabetes mellitus are type 2 diabetics and it is reported to be associated with certain endocrine disorders. There have been increasing anti-diabetic drugs such as sulfonylureas, biguanides and dipeptidyl peptidase-4 have been used to control type 2 diabetes mellitus (Murali and Saravanan, 2012; Neeratiet al., 2014). However, most of these anti-diabetic drugs have limited efficacy and many undesirable side effects such as drug resistance, weight gain, dropsy and high rates of secondary failure (Tahraniet al., 2010; Murali and Saravanan, 2012). Therefore, the development of low toxicity, effective and economic anti-diabetic drugs is still needed and has far-reaching significance. Metformin, a class of insulin sensitizers, is commonly used for the treatment of type 2 diabetes. While lowering the blood glucose level, metformin can cause reduction of fat mass and inhabitation of tumor cell proliferation (Kargulewiczet al., 2016; Huoet al., 2017).Diabinese is equally used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (Murali and Saravanan, 2012).

Metformin hydrochloride, a biguanide, is the most popular oral glucose-lowering medication in most countries, widely viewed as ‘foundation therapy’ for individuals with newly diagnosed type 2 diabetes mellitus. This reputation has resulted from its effective glucose-lowering abilities, low cost, weight neutrality, overall good safety profile (especially the lack of hypoglycaemia as an adverse effect), and modest evidence for cardioprotection (Inzucchiet al., 2015). A derivative of guanidine, which was initially, extracted from the plant Galegaofficinalis or French lilac, metformin was first synthesised in 1922 and introduced as a medication in humans in 1957, after the studies of Jean Sterne (Sterne, 2007). Its popularity increased after eventual approval in the USA in 1994, although it was used extensively in Europe and other regions of the world prior to that (Pryor and Cabreiro, 2015). The drug’s efficacy has been demonstrated in monotherapy as well as in combination with other glucose lowering medications for type 2 diabetes mellitus. Based on these important characteristics, there continues to be extensive interest in this compound, even many years after its incorporation into the diabetes pharmacopeia. Interestingly, and despite this popularity, there still remains controversy about the drug’s precise mechanism of action, although most data point to a reduction in hepatic glucose production being predominately involved although, recent data suggests that some of the drug’s effect may involve the stimulation of intestinal release of Incretin hormones (Rena et al., 2017).

Diabinese (chlorpropamide) is an oral blood-glucose-lowering drug of the sulfonylurea class(Inzucchiet al., 2015).It lowers the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which diabinese lowers blood glucose during long-term administration has not been clearly established(Inzucchiet al., 2015). Extra-pancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs.

1.2       JUSTIFICATIONAt rest, women have greater storage of free Fatty acids than men, but during exercise and conditions of sustained increased demand, women were shown to exert higher oxidation of lipids in relation to carbohydrates. Males instead rely relatively more on glucose and protein metabolism (Mauvais-Jarvis, 2015). During times of food deprivation, females reduce energy expenditure with consequent loss of fat stores contrary to males.