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1.1. General Background:
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the β-cells of the pancreas with consequent insulin deficiency to abnormalities that result in resistance to insulin action. The basis of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes is deficient action of insulin on target tissues. Deficient insulin action results from inadequate insulin secretion and/or diminished tissue responses to insulin at one or more points in the complex pathways of hormone action. Impairment of insulin secretion and defects in insulin action frequently coexist in the same patient, and it is often unclear which abnormality, if either alone, is the primary cause of the hyperglycemia.(ADA, 2009) Diabetes mellitus is the commonest endocrine disorder encountered in clinical practice. It may be defined as a syndrome characterized by hyperglycemia due to an absolute or relative lack of insulin and/ or insulin resistance.(clinical biochemistry, second edition, Churchill livingstone)
Diabetes is not one disease, but rather a heterogenous group of syndrome characterized by an elevation of fasting blood glucose caused by relative or avsolute deficiency in insulin. (Lippincott’s biochemistry 3rd edition) Diabetes mellitus (type1, or insulin-dependent diabetes mellitus; IDDM) is characterized by decreased glucose tolerance as a result of decreased secretion of insulin as a result of progressive destruction of pancreatic β-islet cells.(Harper’s illustrated biochemistry, 27th edition) 1.2. Statement of problem: Diabetes is of two types, type 1 accounting for 5% prevalence and type 2 for 95% prevalence among diabetics. This calls for improved treatment of hyperglycaemia and other risk factors associated with metabolic syndrome. Since it is possible to dramatically lower the risk of both micro and macrovascular complications. Persistent elevations in blood sugar increase the risk for the long-term vascular complications of diabetes such as coronary disease, heart attack, stroke, heart failure, kidney failure, blindness, erectile dysfunction, neuropathy (loss of sensation, especially in the feet), gangrene and gastro paresis (slowed emptying of the stomach). Poor blood glucose control also increases the risk of short-term complications of surgery such as poor wound healing (Sultanpur C M, Deepa K, et al. 2010). Assigning a type of diabetes to an individual often depends on the circumstances present at the time of diagnosis, and many diabetic individuals do not easily fit into a single class. For example, a person with gestational diabetes mellitus (GDM) may continue to be hyperglycemic after delivery and may be determined to have, in fact, type 2 diabetes. Alternatively, a person who acquires diabetes because of large doses of exogenous steroids may become
normoglycemic once the glucocorticoids are discontinued, but then may develop diabetes many years later after recurrent episodes of pancreatitis. Another example would be a person treated with thiazides who develops diabetes years later. Because thiazides in themselves seldom cause severe hyperglycemia, such individuals probably have type 2 diabetes that is exacerbated by the drug. Thus, for the clinician and patient, it is less important to label the particular type of diabetes than it is to understand the pathogenesis of the hyperglycemia and to treat it effectively, (ADA, Diabetes Care; vol.29, 2006). 1.3. Rationale of study: About 2 million people in our country are today affected with diabetes mellitus. It is generally due to genetic or by metabolic defect. Diabetes mellitus is the leading cause of mortality of people across the globe causing various secondary disorders such as CHD, renal dysfunction, neuropathy, and various ocular disorders such as retinitis pigmentosa. Diabetes mellitus is associated with several metabolic alternations. Most important
them are hyperglycemia,
hypertrygyceridemia and dyslipidemia. Hyperglycemia: elevation of blood glucose concentration is the hallmark of uncontrolled diabetes. Hyperglycemia is primarily due to the reduced glucose uptake by tissues and its increased production via gluconeogenesis and glcogenolysis. When the blood glucose level goes beyond renal threshold, glucose is excreted into urine (glycosuria).
of ketone bodies fatty acids results in often leads to which • Hypertrygyceridemia: Conversion of fatty acids to triacylglycerols and the secretion of VLDL and chylomicrons are comparatively higher in diabetics. Dyslipidemia in Diabetes mellitus is seen as the result of inherited disorders of lipoproteins metabolism and transport. • Type II a: This is also known as hyperbetalipoproteinemia and is caused by a defect in LDL receptors. Consequently. It is observed in 4 . The enzyme defect causes increase in plasma chylomicrons and TG levels. According to Frederickson’s classification of dyslipidemia it is of following types: • Type I: This is due to familial lipoprotein lipase deficiency. It is genetic defect where there is defect in LDL-receptors.• Ketoacidosis: Increased Mobilisation of overproduction ketoacidosis. • Hypercholesterolemia: It is also frequently seen in diabetics as the Acetyl CoA pool is increased and more molecules are channeled to cholesterol. • Hyperlipidemia: Hyperlipidemia is the elevation of on or more of the lipoprotein fractions constitute hyperlipidemia is also called as dyslipidemia. the plasma level of VLDL. chylomicrons and triacylglycerols are increased. Further. the activity of the enzyme lipoprotein lipase is low in diabetic patients. enzyme lipoprotein lipase deficiency or overproduction of endogenous triacylglycerols with rise in VLDL.
hypothyroidism. 5 . ocular dystrophy etc. • Type II b: Both LDL and VLDL increase along increase with elevation in plasma cholesterol and triacylglycerol. nephrotic syndrome etc. It is usually associated with obesity. alcoholism.Diabetes mellitus. it is characterized by hypercholesterolemia. • Type III: This is commonly known as broad beta disease and is characterized by the appearance of broad beta band corresponding to IDL on electrophoresis. diabetes mellitus and excessive alcohol intake. • Type V: Both chylomicrons and VLDL are increased. Thus Hyperlipidemia is categorized as a risk factor for diabetes mellitus which leads to other neuropathy. It is due to overproduction of apo B. diabetes mellitus etc. It is mostly due to secondary condition such as obesity. • Type IV: This is due to overproduction of endogenous triacylglycerols with rise in VLDL. secondary disorders like CHD.
General objective: To study lipid profile in diabetes mellitus type 2 patients.4. To estimate serum LDL-C in type 2 diabetic patients. 1. OBJECTIVE OF THE STUDY 1.2. Specific objective: 6 .4. To estimate serum Triglyceride in type 2 diabetic patients.1. To estimate serum cholesterol in type 2 diabetic patients.1.4. To estimate serum HDL-C in type 2 diabetic patients.
CHAPTER II LITERATURE REVIEW
2.1. Definition: Diabetes Mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the β-cells of the pancreas with consequent insulin deficiency to abnormalities that result in resistance to insulin action. The basis of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes is deficient action of insulin on target tissues. Deficient insulin action results from inadequate insulin secretion and/or diminished tissue responses to
insulin at one or more points in the complex pathways of hormone action. (American Diabetes Association, 2010)
Classification of diabetes mellitus:
Type 1 diabetes (Beta-cell destruction, usually leading to absolute insulin deficiency): Type 1 diabetes is a chronic (lifelong) disease that occurs when the pancreas does not produce enough insulin to properly control blood sugar levels. Type 1 diabetes can occur at any age, but it is most often diagnosed in children, adolescents, or young adults. Insulin is a hormone produced by special cells, called beta cells, in the pancreas, an organ located in the area behind your stomach. Insulin is needed to move blood sugar (glucose) into cells, where it is stored and later used for energy. In type 1 diabetes, these cells produce little or no insulin. (Medline plus, 2010). Although the cause of type 1 diabetes is still not fully understood it is believed to be of immunological origin. There is a growing body of evidence that diet may play a role in the development of type 1 diabetes, through influencing gut flora, intestinal permeability, and immune function in the gut; wheat in particular has been shown to have a connection to the development of type 1 diabetes, although the relationship is poorly understood. Type 1 can be distinguished from type 2 diabetes via a C-peptide assay, which measures endogenous insulin production. (Wikipedia, 2010) Normally, the body's immune system fights off foreign invaders like viruses or bacteria. But for unknown reasons, in people with type 1 diabetes, the immune system attacks various cells in the body. This
results in a complete deficiency of the insulin hormone. (WebMD, 2010) Immune-mediated diabetes: This form of diabetes, which accounts for only 5–10% of those with diabetes, previously, encompassed by the terms insulin dependent diabetes, type I diabetes, or juvenile-onset diabetes, results from a cellular-mediated autoimmune destruction of the βcells of the pancreas. Markers of the immune destruction of the βcells include islet cell autoantibodies, Autoantibodies decarboxylase to insulin, and autoantibodies autoantibodies to to glutamic the acid (GAD65), tyrosine
phosphatases IA-2 and IA-2. One and usually more of these autoantibodies are present in 85–90% of individuals when fasting hyperglycemia is initially detected. Also, the disease has strong HLA associations, with linkage to the DQA and DQB genes, and it is influenced by the DRB genes. These HLA-DR/DQ alleles can be either predisposing or protective. In this form of diabetes, the rate of betacell 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. Others have modest fasting hyperglycemia that can rapidly change to severe hyperglycemia and/or ketoacidosis in the presence of infection or other stress. Still others, particularly adults, may retain residual _-cell function sufficient to prevent ketoacidosis for many years; such individuals eventually become dependent on insulin for survival and are at risk for ketoacidosis. At this latter stage of the disease, there is little or no
(ADA. the presence of obesity is not incompatible with the diagnosis. vitiligo. but it can occur in any age. but have no evidence of autoimmunity. (ADA. autoimmune hepatitis. Although only a minority of patients with type 1 diabetes fall into this category. Immunemediated diabetes commonly occurs in childhood and adolescence. Individuals with this form of diabetes suffer from episodic ketoacidosis and exhibit varying degrees of insulin deficiency between episodes. lacks immunological evidence for Betacell autoimmunity. These patients are also prone toother autoimmune disorders such as Graves’ disease. Some of these patients have permanent insulinopenia and are prone to ketoacidosis. even in the 8th and 9th decades of life. Although patients are rarely obese when they present with this type of diabetes. This form of diabetes is strongly inherited. 2005) Type 2 diabetes (ranging from predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance): 10 . myasthenia gravis.of those who do.insulin secretion. 2005) Idiopathic diabetes: Some forms of type 1 diabetes have no known etiologies. and is not HLA associated. An absolute requirement for insulin replacement therapy in affected patients may come and go. most are of African or Asian ancestry. as manifested by low or undetectable levels of plasma C-peptide. and pernicious anemia. Hashimoto’s thyroiditis. Autoimmune destruction of _-cells has multiple genetic predispositions and is also related to environmental factors that are still poorly defined. Addison’s disease. celiac sprue.
People who are overweight are more likely to have insulin resistance. 2010) This form of diabetes. which accounts for ∼90–95% of those with diabetes. previously referred to as non-insulin-dependent diabetes. there is very little tendency toward ketoacidosis though it is not unheard of. amputation. In type 2 diabetes.Diabetes mellitus type 2 – formerly non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes – is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. poor diet. When glucose builds up in the blood instead of going into cells. 2010). Insulin is necessary for the body to be able to use glucose for energy. type 2 diabetes can also develop in those who are thin. especially the elderly. and excess body weight (especially around the waist) significantly increase your risk for type 2 diabetes. One effect that can occur is nonketonic hyperglycemia. (Wikipedia. which is the basic fuel for the cells in the body. However. (ADA. Type 2 diabetes usually occurs gradually. Long-term complications from high blood sugar can include increased risk of heart attacks. Insulin takes the sugar from the blood into the cells. and kidney failure. either the body does not produce enough insulin or the cells ignore the insulin. or adult-onset diabetes. When you eat food. Unlike type 1 diabetes. Low activity level. strokes. Family history and genetics play a large role in type 2 diabetes. it can lead to diabetes complications. Most people with the disease are overweight at the time of diagnosis. because fat interferes with the body's ability to use insulin. (Medlineplus. the body breaks down all of the sugars and starches into glucose. type II diabetes. encompasses individuals who have insulin resistance and usually have relative (rather than 11 . 2010). Diabetes is often initially managed by increasing exercise and dietary modification.
Whereas patients with this form of diabetes may have insulin levels that appear normal or elevated. and patients do not have any of the other causes of diabetes listed above or below.absolute) insulin deficiency At least initially. and lack of physical activity. and obesity itself causes some degree of insulin resistance. There are probably many different causes of this form of diabetes. when seen. and often throughout their lifetime. obesity. Thus. such patients are at increased risk of developing macrovascular and microvascular complications. It is often 12 . autoimmune destruction of β-cells does not occur. Patients who are not obese by traditional weight criteria may have an increased percentage of body fat distributed predominantly in the abdominal region. Although the specific etiologies are not known. Nevertheless. and its frequency varies in different racial/ethnic subgroups. Ketoacidosis seldom occurs spontaneously in this type of diabetes. Insulin resistance may improve with weight reduction and/or pharmacological treatment of hyperglycemia but is seldom restored to normal The risk of developing this form of diabetes increases with age. it usually arises in association with the stress of another illness such as infection. It occurs more frequently in women with prior GDM and in individuals with hypertension or dyslipidemia. Most patients with this form of diabetes are obese. the higher blood glucose levels in these diabetic patients would be expected to result in even higher insulin values had their βcell function been normal. these individuals do not need insulin treatment to survive. This form of diabetes frequently goes undiagnosed for many years because the hyperglycemia develops gradually and at earlier stages is often not severe enough for the patient to notice any of the classic symptoms of diabetes. insulin secretion is defective in these patients and insufficient to compensate for insulin resistance.
stimulates insulin secretion by the β-cell. These forms of diabetes are frequently characterized by onset of hyperglycemia at an early age (generally before age 25 years). They are referred to as maturity-onset diabetes of the young (MODY) and are characterized by impaired insulin secretion with minimal or no defects in insulin action. The most common form is associated with mutations on chromosome 12 in a hepatic transcription factor referred to as hepatocyte nuclear factor (HNF)-1α.(ADA. the genetics of this form of diabetes are complex and not clearly defined. Abnormalities at six genetic loci on different chromosomes have been identified to date. in turn. However. more so than is the autoimmune form of type 1 diabetes. 2005) Other specific types of Diabetes Genetic defects of the β-cell: Several forms of diabetes are associated with monogenetic defects in β-cell function.associated with a strong genetic predisposition. Thus. A second form is associated with mutations in the glucokinase gene on chromosome 7p and results in a defective glucokinase molecule. glucokinase serves as the “glucose 13 . Glucokinase converts glucose to glucose-6phosphate. They are inherited in an autosomal dominant pattern. the metabolism of which.
Similarly. leading to an A-to-G transition. Because of defects in the glucokinase gene. Genetic abnormalities that result in the inability to convert proinsulin to insulin have been identified in a few families.sensor” for the β-cell. encephalopathy. diabetes is not part of this syndrome. The resultant glucose intolerance is mild. The metabolic abnormalities associated with mutations of the insulin receptor may range from hyperinsulinemia and modest hyperglycemia to severe diabetes. however. Some individuals with these mutations may have acanthosis 14 . and strokelike syndrome). increased plasma levels of glucose are necessary to elicit normal levels of insulin secretion.(ADA. The less common forms result from mutations in other transcription factors. and such traits are inherited in an autosomal dominant pattern. lactic acidosis. and NeuroD1. Point mutations in mitochondrial DNA have been found to be associated with diabetes mellitus and deafness the most common mutation occurs at position 3243 in the tRNA leucine gene. HNF-1β. An identical lesion occurs in the MELAS syndrome (mitochondrial myopathy. the production of mutant insulin molecules with resultant impaired receptor binding has also been identified in a few families and is associated with an autosomal inheritance and only mildly impaired or even normal glucose metabolism. insulin promoter factor (IPF)-1. suggesting different phenotypic expressions of this genetic lesion. 2005) Genetic defects in insulin action: There are unusual causes of diabetes that result from genetically determined abnormalities of insulin action. including HNF-4α.
Pancreatic fibrosis and calcium stones in the exocrine ducts have been found at autopsy. The former has characteristic facial features and is usually fatal in infancy. (ADA. and pancreatic carcinoma. In the past. pancreatectomy. Women may be virilized and have enlarged. 2005) Diseases of the exocrine pancreas: Any process that diffusely injures the pancreas can cause diabetes. while the latter is associated with abnormalities of teeth and nails and pineal gland hyperplasia. Alterations in the structure and function of the insulin receptor cannot be demonstrated in patients with insulin-resistant lipoatrophic diabetes.nigricans. 2005) 15 . trauma. cystic fibrosis and hemochromatosis will also damage β-cells and impair insulin secretion. If extensive enough. adrenocarcinomas that involve only a small portion of the pancreas have been associated with diabetes. Fibrocalculous pancreatopathy may be accompanied by abdominal pain radiating to the back and pancreatic calcifications identified on X-ray examination. Leprechaunism and the Rabson-Mendenhall syndrome are two pediatric syndromes that have mutations in the insulin receptor gene with subsequent alterations in insulin receptor function and extreme insulin resistance. With the exception of that caused by cancer. infection. cystic ovaries. damage to the pancreas must be extensive for diabetes to occur. (ADA. Therefore. Acquired processes include pancreatitis. it is assumed that the lesion(s) must reside in the postreceptor signal transduction pathways. this syndrome was termed type A insulin resistance. This implies a mechanism other than simple reduction in β-cell mass.
Patients receiving α-interferon have been reported to develop diabetes associated with islet cell antibodies and. (ADA. by inhibiting insulin secretion.or chemical-induced diabetes: Many drugs can impair insulin secretion.g.g.. in certain instances. severe insulin deficiency. This generally occurs in individuals with preexisting defects in insulin secretion. Somatostatinomaand aldosteronoma-induced hypokalemia can cause diabetes. at least in part. Such drug reactions fortunately are rare. Examples include nicotinic acid and glucocorticoids. 2005) 16 . In such cases. growth hormone. These drugs may not cause diabetes by themselves. the classification is unclear because the sequence or relative importance of β-cell dysfunction and insulin resistance is unknown. acromegaly. (ADA. glucagonoma. Excess amounts of these hormones (e. but they may precipitate diabetes in individuals with insulin resistance. pheochromocytoma. There are also many drugs and hormones that can impair insulin action. Certain toxins such as Vacor (a rat poison) and intravenous pentamidine can permanently destroy pancreatic β-cells. Cushing’s syndrome.Endocrinopathies: Several hormones (e.. epinephrine) antagonize insulin action. Hyperglycemia generally resolves after successful removal of the tumor. and hyperglycemia typically resolves when the hormone excess is resolved. respectively) can cause diabetes. glucagon. cortisol. 2009) Drug.
In the past. patients with anti-insulin receptor antibodies often have acanthosis nigricans. adenovirus. thereby blocking the binding of insulin to its receptor in target tissues. However. and approximately one-third will develop diabetes. 2005) 17 . and others are likely to occur. Diabetes occurs in patients with congenital rubella. In addition. (ADA. and mumps have been implicated in inducing certain cases of the disease. As in other states of extreme insulin resistance. these antibodies can act as an insulin agonist after binding to the receptor and can thereby cause hypoglycemia. Anti-insulin receptor antibodies are occasionally found in patients with systemic lupus erythematosus and other autoimmune diseases. Patients usually have high titers of the GAD autoantibodies. Anti-insulin receptor antibodies can cause diabetes by binding to the insulin receptor. (ADA. this syndrome was termed type B insulin resistance. although most of these patients have HLA and immune markers characteristic of type 1 diabetes. in some cases. there are two known conditions.Infections: Certain viruses have been associated with β-cell destruction. coxsackievirus B. The stiff-man syndrome is an autoimmune disorder of the central nervous system characterized by stiffness of the axial muscles with painful spasms. 2005) Uncommon forms of immune-mediated diabetes: In this category. cytomegalovirus.
These include the chromosomal abnormalities of Down’s syndrome.Other genetic syndromes sometimes associated with diabetes: Many genetic syndromes are accompanied by an increased incidence of diabetes mellitus.S. It does not exclude the possibility that unrecognized glucose intolerance may have antedated or begun concomitantly with the pregnancy.(ADA. resulting in ∼135. Gestational 18 . Wolfram’s syndrome is an autosomal recessive disorder characterized by insulin-deficient diabetes and the absence of β-cells at autopsy. Diagnostic tests detect inappropriately high levels of glucose in blood samples. Gestational diabetes generally has few symptoms and it is most commonly diagnosed by screening during pregnancy. hypogonadism. 2009) Gestational diabetes mellitus (GDM): GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. GDM) is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy. The definition applies regardless of whether insulin or only diet modification is used for treatment or whether the condition persists after pregnancy.(ADA.000 cases annually. GDM represents nearly 90% of all pregnancies complicated by diabetes. 2005) Gestational diabetes (or gestational diabetes mellitus. Additional manifestations include diabetes insipidus. The prevalence may range from 1 to 14% of pregnancies. optic atrophy. and Turner’s syndrome. Klinefelter’s syndrome.. and neural deafness. GDM complicates ∼4% of all pregnancies in the U. depending on the population studied.
1 mmol/l). Casual is defined as any time of day 19 . The baby’s blood sugar is too low—called hypoglycemia. The baby’s skin turns yellowish and the whites of the eyes may change color—called jaundice. Some potential risks include (National institute of health. 2010) In some cases. (Wikipedia. A large baby may need to be delivered by a surgical procedure called cesarean section. The cause is believed to be due to deficiency in Vitamin D. instead of naturally through the vagina. 2008) The baby’s body is larger than normal—called macrosomia.diabetes affects 3-10% of pregnancies. This problem can causes muscle twitching or cramping. Starting to breastfeed right away can help get more glucose to the baby. gestational diabetes can affect the pregnancy and baby. though. Criteria for the diagnosis of Diabetes mellitus: (ADA. treated by giving the baby extra minerals. The baby may also need to get glucose through a tube into his or her blood. The baby may have low mineral levels in the blood. depending on the population studied. This condition is easily treated and is not serious if treated. The baby may have trouble breathing and need oxygen or other help—called Respiratory Distress Syndrome. 2009) Symptoms of diabetes plus casual plasma glucose concentration ≥200 mg/dl (11. but can be Table 2.
using a glucose load containing the equivalent of 75 gm anhydrous glucose dissolved in water. polydipsia. Dyslipidemia: Dyslipidemia is one of the major risk factors for cardiovascular disease in diabetes mellitus. FPG ≥126 mg/dl (7. The lipid changes associated with diabetes mellitus are attributed to increased free fatty acid flux secondary to insulin resistance. most people with diabetes mellitus are candidates for statin therapy. Although drug therapy for dyslipidemia must be individualized. The availability of multiple lipid-lowering drugs and supplements provide new opportunities for patients to achieve target lipid levels.0 mmol/l). and unexplained weight loss. However. The test should be performed as described by WHO. The prevalence of hypercholesterolemia is not increased in patients with diabetes mellitus. The classic symptoms of diabetes include polyuria. 3. 2-h post load glucose ≥200 mg/dl (11. low HDL cholesterol concentration and increased concentration of small dense LDL-cholesterol particles. 2. without regard to time since last meal. and often need treatment with multiple agents to achieve therapeutic goals.1. and lowering of cholesterol with statins reduces diabetic patients’ relative cardiovascular risk. 20 . The characteristic features of diabetic dyslipidemia are high plasma triglyceride concentration. Fasting is defined as no caloric intake for at least 8 h. but mortality from coronary heart disease increases exponentially as a function of serum cholesterol levels.1 mmol/l) during an OGTT. the variety of therapeutic options poses a challenge in the prioritization of drug therapy.
(The above information was reviewed from the article published by Arshag D Mooradian which was published in English manuscript that was identified through the search done on google. and decreased levels of high-density lipoprotein (HDL). including lipoprotein overproduction and deficiency. The term used to make the search was “dyslipidemia in diabetes”) Dyslipidemias are disorders of lipoprotein metabolism. are the most characteristic lipoprotein abnormalities in type 2 diabetes.(Syvanne M et al 1997. Belteridge DJ 1999) Most patients with type 2 diabetes have concentrations of LDL 21 . Garg A 1998. Belteridge DJ 1999 ) Elevated concentrations of triglyceride-rich lipoproteins. (The above two paragraph were taken from the Essence Series. essential information in brief. Syvanne M et al 1997. which is invariably linked to the presence of insulin resistance and central obesity.(Taskinen MR 1990. leading to effective treatment strategies. Knowledge of pathophysiology of dyslipidemia has grown dramatically in the last few years.) Patients with type 2 diabetes have an increased frequency of dyslipidemia. They may manifest as one or more of thefollowing: elevated total cholesterol. Ischemic cardiovascular and cerebrovascular events are leading causes of morbidity and mortality. which was identified through the search made in google. especially very-low-density lipoprotein (VLDL). Dyslipidemia is closely associated with atherosclerosis and is a major causal factor in the development of ischemic diseases. measured as HDL cholesterol. low-density lipoprotein cholesterol (LDL). a cipla initiative. and triglyceride levels or as decreased high-density lipoprotein cholesterol (HDL) level.
all of which are strongly associated with insulin resistance.(Zilversit DB 1979) Indeed. patients with type 2 diabetes may be regarded as permanently-postprandial. Syvanne M et al 1997. and modifications through glycation and oxidation which increase their atherogenicity. may be a more appropriate therapeutic target in type 2 diabetes. This review elaborates upon the lipoprotein abnormalities in type 2 diabetes and the underlying mechanisms. including the preponderance of smaller and denser particles. in type 2 diabetes there are important qualitative changes in LDL. (Belteridge DJ 1999) however. is an independent risk factor for CHD.cholesterol which are similar to those of nondiabetic subjects. De Man FH et al 1996. rather than LDL cholesterol. Patsh Jr. In view of the interrelationship of the lipoprotein abnormalities and their atherogenic potential. Lipids and lipoproteins: 22 . et al 1992) In view of their lipid profile. characterized by a long residence time of triglyceride-rich remnants in the circulation and subsequent decrease in HDL levels. Belteridge DJ 1999) Recently. Mero N et al 1996 ) have revived interest in the concept that atherosclerosis may be a postprandial phenomenon. (Ebenbichler CF et al 1995. Garg A 1998. evidence from clinical studies suggests that postprandial lipemia.( Taskinen MR 1990. it is suggested that both fasting and postprandial levels of triglyceride-rich lipoproteins (collectively termed non-HDL cholesterol). which was formulated by Zilversmit more than 20 years ago. studies investigating derangements of postprandial lipid metabolism in type 2 diabetes and their atherogenic potential.(Ebenbichler CF et al 1995.
providing energy storage and metabolic fuels. Endogenous synthesis of cholesterol in the liver is controlled by the rate limiting step involving the microsomal enzyme 3-hydroxy-3methylglutaryl-CoA (HMG-CoA) reductase. (Biochemistry for clinical medicine. The absorption of triglyceride is essentially complete whereas that of cholesterol varies between 30-50%.) Lipids are transported in plasma as components of lipoprotein complexes. aiding in digestion. (TIETZ Textbook of clinical biochemistry and molecular diagnostics. Chemically. 27th edition. acting as functional and structural components in cell membranes.Lipids are ubiquitous in the body tissue and have important role in virtually ll aspects of life-serving as hormones or hormone precursors. The term lipid applies to compound that are soluble in organic solvent and nearly insoluble in water. 2001) Cholesterol is widely distributed in all cell of the body but particularly in nervous tissue. and forming insulation to allow nerve conduction or to prevent heat loss. Lipoproteins are spherical complex particles made up of 23 . It is a major constituent of the plasma membrane and of plasma lipoproteins. It can be obtained from the diet or synthesized de novo. lipids are either compound that yields fatty acids on hydrolysis or complex alcohols that combine with fatty acids to form esters. (Harper’s illustrated biochemistry. fourth edition) Lipids are a heterogeneous group of organic bimolecules soluble in non-polar solvents such as ether and benzene.
The lipoprotein consist of the protein part known as apolipoprotien or apoprotein. Plasma lipids consist of triglycerols (16%). Four major groups of plasma lipoprotein have been identified that are important physiologically and in clinical diagnoisis. 24 . They are (1) chylomicrons.hundreds of lipids and protein molecules. Lipids are transported in the plasma as lipoproteins. (3) low density lipoprotein (LDL) and (4) high density lipoprotein (HDL). and cholesteryl ester (36%) and a much smaller fraction of unesterified long chain fatty acids (4%). cholesterol (14%). (2) very low density lipoproteins (VLDL). constituiting nearly 70%os some HDL and as little as 1% of chylomicrons. phospholipids (30%). Proteins called apolipoproteins occupy the surface of lipoproteins. These serve as an additional interface between lipid and aqueous environments and play an important role in the regulation of lipid transport and lipoprotein metabolism.
C-I. ipids. cholester ol Triacylgl B-100. C-II. chylom icrons 21 50 79 50 25 . C-I. C-III. E Triacylgl B-48. cholester ol cholester B-100 ol Phosphol A-I. CIII Triacylgl B-100. Lipopro tein chylomi cron Source Diam eter 901000 Density (g/ml) Less than 0. B48. A-IV.006 1. A-II.951. ycerol A-IV.019 1. C-III.0191. cholester C-II. C-II. Composition of the lipoprotein in plasma of humans.0061. ol D. E Intesti ne chylomi cron remnan ts VLDL IDL chylom 45icron 150 6-8 9294 Liver (intesti ne) VLDL 3090 2535 2025 4-10 0. Cycerol I. VLDL. E ycerol.210 7-10 11 9093 89 LDL HDL VLDL Liver. E ycerol.0631.95 Less than 1. intesti ne. A-II.Table 2.063 1. phosphol ipids.006 compositio n Prot Lipi ein d 1-2 9899 Main apolipopr lipid otein compone nts Triacylgl A-I.
Shortly after entering the circulation . The newly formed particle. The fatty acids taken up by muscle cells as an energy source or into adipose cell for storage. The lipid content of nascent chylomicrons consists mainly of TG (90% by mass). activities the LPL attached to the luminal surface of endothelial cells. These particles are then transported by exocytosis into the extracellular space and introduced into circulation through the intestinal villi. Exogenous pathway: Nascent chylomicrons are assembled from dietary TG and cholesterol in the enterocytes and packaged in secretory vesicles in the golgi apparatus. which rapidly hydrolyzes the TG to free fatty acids. Simultaneously. these particles acquire the C apolipoprotein and apo E from circulating surface of chylomicrons. some of the phospholipids and the apo A apolipoproteins and transferred from the chylomicron particle onto HDL. 26 .Lipoprotein metabolism: The pathways of lipoprotein metabolism are complex. whereas the protein components include apo B-48 and the A lipoprotein (2% by mass). They include exogenous and endogenous pathways based on whether they carry lipids of dietary or hepatic origin and other pathways such as the intracellular LDL receptor pathway and HDL reverse cholesterol transport pathway.
contains 80% to 90% of the TG content of the original chylomicron. Figure1: Exogenous and endogenous pathway 27 . the cholesterol from these remnants can down regulate reductase. be incorpoted into newly synthesized HMG-CoA lipoprotein. rate enzyme cholesterol biosynthesis.the chylomicron remnant. Because of the presence of apo B-48 and apo E on its surface. the or be stored limiting as cholesteryl of ester. the chylomicron remnant can be recognized by specific hepatic remnant receptors and internalized by endocytosis. Furthermore. the components of particle are then hydrolyzed in the lysosomes. The cholesterol released can form bile acids.
apo E. Additional C lipoproteins are transferred after secretion from circulating HDL. when dietary cholesterol acquired from the receptor mediated uptake of chylomicron remnantsis insufficient. however. and small amount of C apolipoproteins on its surface. compared with the 5 to 10 minutes of chylomicron triglyceride. 28 . hepato cytes also synthesize their own cholesterol by increasing the activity of HMG-CoA reductase. that the rate of hydrolysis of VLDL TG is significantly lower than that of chylomicron triglyceride. and introduced into circulation through the fenestrae of the hepatic sinusoidal endothelium in the form of nascent VLDL. As in the case of chylomicron metabolism.Endogenous pathway: Hepatocytes have the ability to synthesize TG from carbohydrates and fatty acids. apo C-II present on the surface of VLDL activates LPL on endothelial cells. the average residence time of VLDL triglyceride is 15-60 minutes. transported by exocytosis into the extracellular space. The endogenously made TG and cholesterol are packaged in secretory vesicles in the golgi apparatus. which leads to the hydrolysis of VLDL TG and the release of free fatty acids. It is important to note. The TG rich particle (55% by mass) contains apo B-100. In addition. This difference may be attributed to the fact that VLDL particles are smaller and bind to fewer LPL molecules than chylomicron.
Large IDL particles. which returns to the cell surface for reuse. Low density lipoprotein receptor pathway: The mechanism by which LDL is removed from circulation is well understood. apo B-100 is degrade to small peptides and 29 . VLDL particles are thus converted to VLDL remnants. whereas LDL migrate to the lysosome. IDL undergoes a further hydrolysis in which most of the remaining triglyceride are removed and all apolipoproteins except B-100 are transferred to other lipoproteins. about 50% of IDL is removed by hepatocytes. the C apolipoproteins are transferred back to HDL. LDL dissociates from the receptor. Once the LDL is delivered to the lysosome. Surface materials from IDL. some of which are taken up by the liver and rest converted to smaller. bind the hepatic remnant receptors and are removed from circulation. free cholesterol. This process ends with ultimate formation of LDL. Cholesteryl esters are transferred from HDL to LDL.During the hydrolysis of VLDL triglyceride. denser particles called IDL. which also have several molecules os apo E. including some phospholipids. which then fuse to form an endosome. and apolipoproteins. Specific receptors present in coated pits on plasma membrane recognize and bind apo B-100 of LDL. The LDL particles are internalized in coated vesicles. because of the acidic medium of the endosome. In humans. The net result of the coupled lipolysis and the cholesteryl esters exchange reaction is the replacement of much of the triglyseride core of the original VLDL with cholesteryl esters. or from HDL de novo in the circulation. are transferred to HDL.
Cholesterol esters are also hydrolysed. Reverse Cholesterol Transport: Reverse cholesterol transport refers to the process by which cholesterol is removed from the tissues and returned to the liver. The non-receptor mediated uptake becomes important as plasma LDL comncentration increase. Cells have the ability to regulate their cholesterol content. steroid hormones in tissue that make them. Two thirds of LDL is normally removed by LDL receptors and remainder by the scavenger cell system. as in familial hypercholesterolemia. Scavenger receptor are unregulated as well and recognize LDL that has been modified in various way. LDL is also taken up by extrahepatic tissue through scavenger receptor or non-receptor mediated pinocytosis. (TIETZ Textbook of clinical biochemistry and molecular biology. Macrophages that become engorged with cholesteryl esters are called foam cells and are considered the earliest components of the atherosclerotic lesion. and the transfer of cholesteryl esters between lipoproteins. HDL is the key lipoprotein involved in reverse cholesterol transport.amino acids.the physiology of the lipoprotein metabolic cascades 30 . with the cholesterol ten available for the synthesis of cell membranes. about 3 days. LDL has a relatively long residence in circulation. fourth edition) Physiology of lipid metabolism: In order to enable understanding of the lipoprotein abnormalities in type 2 diabetes. They are found in macrophages and other cells. Non-receptor mediated uptake is not saturable amd not regulated. and bile acids in hepatocytes. Compared with VLDL and chylomicrons.
Lipoprotein metabolism can be divided into two major pathways. the apolipoprotein (apo) B-lipoprotein and HDL pathways. which hydrolyzes the triglyceride core of the chylomicrons and releases fatty acids for energy production in muscle and for storage in adipose tissue (Figure 1). The triglyceride-rich apo B-48-containing chylomicrons transport dietary lipids from the intestine to the liver and peripheral tissues. 31 .(Brewer HB Jr. 1995.is summarized below. lipoprotein lipase (LPL). The catabolism of the triglyceride-rich chylomicrons is initiated by the endothelial enzyme. 1999) The apo B-lipoprotein pathway consists of a cascade of lipoproteins containing either the apo B-48 or the apo B-100 isoform of the B apolipoprotein secreted from the intestine or liver. respectively.
hepatic lipase (HL). similarly to chylomicrons. which have a high affinity for apoE. dense (lipid-poor and protein-enriched) LDL that are modified (eg. (Kreiger M. Hydrolysis of core TG by hepatic lipase (HL) produces small. and impaired endothelial lipoprotein lipase (LPL) activity lead to raised plasma concentrations of TG-rich lipoproteins (LP). VLDL remnants and IDLcontaining apo E are removed by hepatic LDL receptors and LDLreceptor-related protein receptors. Increased endogenous very-lowlipoprotein (VLDL) production. High TG-rich lipoprotein concentrations increase the transfer of TG to low-density lipoprotein (LDL) and high-density lipoprotein (HDL). 1994) In a parallel cascade. IDL. Schematic overview of lipoprotein elevated metabolic postprandial pathways in type 2 diabetes. and simultaneous transfer of cholesteryl esters (CE) from LDL and HDL to TG-rich lipoproteins.Figure density 2. triglyceride (TG) concentrations. fatty acids. Similarly. undergoes hydrolysis by LPL and is remodeled to intermediate-density lipoprotein (IDL) and partly further to LDL (Figure 1). small. mediated by cholesteryl ester transfer protein (CETP). which. the liver assembles triglyceride-rich VLDLcontaining apo B-100.(Krieger M 1994. The latter step involves another enzyme. FA. but it also may become modified or oxidized and 32 . dense HDL particles are produced that have a higher catabolic rate and may be dysfunctional with regard to reverse cholesterol transport. (Syvanne M et al 1997) The chylomicron remnants are taken up by the liver by the LDLreceptor-related protein and LDL receptors. by oxidation or glycation). intermediate-density lipoprotein. Goldstein JL 1985) LDL contains only apo B-100 and is metabolized by two pathways: it may be taken up into the liver by an LDL-receptor-mediated mechanism.
(Taskinen MR 1990. HDL is synthesized as nascent HDL particles from both the liver and intestine as well as by transfer of lipids and apolipoproteins during the metabolism of triglyceride-rich chylomicrons and VLDL. insulin resistance and visceral obesity have a major impact on the regulatory processes of both the apo Blipoprotein and the HDL pathways.(Action S. Bruce C 1995) RCT is initiated by the removal of nonesterified or free cholesterol from cells mediated by the ATPbinding cassette transporter ABCA1 (formerly ABC1). Many steps in the lipoprotein metabolic cascades are insulin-sensitive. A major function of HDL is the transport of excess cellular cholesterol from peripheral cells to the liver. Xu s Hobbs HH. Rigotti A. free cholesterol on nascent HDL is converted to cholesteryl ester (CE) by lecithin cholesterol acyltransferase.(Glosmet JA 1968.(Glosmet JA 1968.(Oram JF 2000) In plasma. Syvanne 33 .removed by the scavenger receptor-A or CD36 scavenger receptors on macrophages. In the HDL pathway. Krieger M 1996) Lipoprotein metabolism in type 2 diabetes: the impact of insulin resistance: In type 2 diabetes. Bruce C 1995) The CE synthesized on HDL can be transferred to apo B-containing lipoproteins by the cholesteryl ester transfer protein (CETP) in exchange for triglycerides (Figure 1). a process called reverse cholesterol transport (RCT). Fielding CJ 1995.and LDL-receptor-related protein receptors) or by selective removal of CE from the particle (mediated by the scavenger receptor BI). Landschulz KT.(Bruce C 1995) Hepatocytes remove CE from HDL and apo B-containing lipoproteins either by direct uptake of the whole lipoprotein particle (mediated by LDL.
(Bagdade JD et al 1990) The enhanced transfer of triglycerides to LDL renders them better substrates for HL. Small. an important step in the development of atherosclerosis (Mamo JC et al 1998. dense LDL particles and triglyceride-rich lipoproteins readily enter the artery wall and show substantial intimal retention. The prolonged circulating time of high triglyceride-rich lipoprotein particles allows longer exposure to CETP. Thus. Postprandially.(Malmstrom R et al 1997) LPL activity is lower in type 2 diabetics than in nondiabetic subjects and increases with improved glycemic control. independent of the FFA flux. Tabas I 1999). hepatic VLDL production is not normally suppressed. HL hydrolyzes triglycerides from the core of LDL and turns them into smaller and denser LDL particles. This increased flux of FFA to the liver is a major stimulus for overproduction of VLDL. the raised concentration of triglyceride-rich lipoproteins in type 2 diabetes is due to hepatic overproduction of VLDL and impaired clearance of apo B-containing remnant particles (Figure-1). which facilitates transfer of cholesterol from LDL and HDL to VLDL and chylomicrons in exchange for triglycerides. resulting in competition for LPL with exogenous triglycerides carried on chylomicrons. 34 .et al 1997) Apo B-lipoprotein pathway in diabetes: The insulin-resistant state impairs the normal suppression of free fatty acid (FFA) release from the abundantly present adipose tissue. The same holds true for modification of HDL.
(Tan KC et al 1999) It should be noted.Retained lipoprotein particles may then undergo enzymatic or oxidative modifications. Belteridge DJ 1999) Epidemiological studies have shown a relation between small-sized LDL particles and the risk of myocardial infarction in nondiabetic populations. which has an increased metabolic rate and helps to explain the low HDL concentration. Steiner G 1998) Indeed. however. Lamarche B et al 1998) In type 2 diabetes. which is a surrogate marker for cardiovascular risk.(Tabas I 1999)These qualitative changes may increase the atherogenicity of LDL particles in type 2 diabetes.(Syvanne M et al 1995.(Stampfer MJ et al 1996. An inverse relationship exists between hypertriglyceridemia and the number of small. small LDL particles from patients were associated with reduced endothelium-dependent arterial dilation. 35 . dense HDL. 1996) It has been suggested that other abnormalities in the RCT cascade may contribute to the development of CHD in type 2 diabetes. analogous to LDL.( Scheffer PG et al 1998. dense LDL particles. modified HDL in type 2 diabetes has been associated with CHD because its compositional changes may lead to impaired RCT. dense LDL particles in atherogenesis in type 2 diabetes are still awaited. that prospective studies evaluating the role of small. Both increased and decreased CETP activity have been described in type 2 diabetes. In type 2 diabetes. Also. (Syvanne M et al 1997. triglyceride-enriched HDL is readily modified into small.(Lahdenpera S 1993) HDL pathway in type 2 diabetes: The above-described changes in apo B-lipoprotein metabolism in type 2 diabetes strongly affect the HDL pathway and consequently its antiatherogenic potential. lowering triglyceride levels in type 2 diabetes using fibrates was shown to increase LDL particle size.
(Levis GF et al 1991) 36 . and the fasting level of triglyceride-rich lipoproteins is positively correlated with the area under the curve for plasma triglyceride levels after the meal (Figure 2). population studies indicate that with regard to the development of atherosclerosis. a return to the basal state occurs within 2–3 h. the rise in triglyceride-rich lipoprotein concentrations is greater in type 2 diabetic patients than in nondiabetic subjects.(Jones RJ 1996. the duration of the postprandial state depends on the composition of the meal: after a meal consisting mainly of carbohydrates. Postprandial lipid abnormalities in type 2 diabetes In healthy subjects.(Schrezenmeir J 1993) Since most individuals eat intermittently throughout daylight hours. and after a fat-rich meal the return to baseline may take as long as 8–10 hours. after a mixed meal it takes 3–5 h. type 2 diabetic patients may be regarded as postprandial throughout 24 h. they are postprandial for about 18 h of each 24-h day. Quntao EC 2000) Although as yet this controversy has not been conclusively settled. plasma HDL rather than CETP levels maybe of more importance.(Kreiberg KA 1998) In view of their abnormal lipoprotein profile. Following a fatenriched meal.
Postprandial changes in triglyceride levels in patients with type 2 diabetes mellitus: relation to fasting triglyceride level. postprandial lipid disturbances have been associated with alterations in coagulation mechanisms that predispose them to arterial thrombosis. 37 . collectively result in prolonged exposure of arteries to potentially atherogenic triglyceride-enriched particles. still has to be demonstrated in outcome studies. which are linked to insulin resistance. however.(Selvieria A 1996. (Levis GF et al 1991) This postprandial lipemia is due to an impaired suppression of hepatic VLDL synthesis after meals and the competition of chylomicrons and their remnants with endogenous VLDL particles for common removal pathways through LPL (Figure 1). Atherogenecity of diabetic dyslipidemia: the case of non-HDL particles: There have been frequent attempts to determine which of the dyslipidemic alterations in type 2 diabetes is the most atherogenic.(Vogel RA 1997. These mechanisms.(Mero N et al 2000) The true atherogenic potential of postprandial dyslipidemia in type 2 diabetes. an association was found between postprandial levels of triglyceride-rich remnants and the severity of coronary artery disease in type 2 diabetic patients. Also.Figure 3. Shige H 1999) In addition. Georgopoulus A et al 1998) Recent studies have demonstrated impaired endothelium-dependent vasodilation following a fatty meal both in healthy subjects and in type 2 diabetic patients. and to assign an independent risk status to changes in the individual lipoproteins.
several prospective studies in type 2 diabetics have convincingly shown a strong association between the different lipoprotein abnormalities and CHD in these patients. and the Long-term Intervention with Pravastatin in Ischemic Disease trial. In view of the close association between the lipoprotein abnormalities in type 2 diabetes. the importance of LDL as a risk factor for CHD in diabetic patients has been demonstrated in subgroup analyses of the major secondary prevention trials. patients with type 2 diabetes do not have marked elevations of LDL cholesterol. N Engl J Med 1999) In all these trials intensive LDL-lowering therapy reduced recurrent CHD events in type 2 diabetic patients. Leato S et al 1993. decreased HDL cholesterol was identified as 38 .(Laakso M et al 1993) In the UKPDS.(Sacks FM et al 1996. beside LDL cholesterol. although no prospective trials have been conducted on the effects of lipid-lowering agents on subsequent CHD specifically in diabetic populations. mere estimates of LDL cholesterol levels may underestimate the total atherogenic risk potential associated with the total apo B-containing lipoprotein fractions and low (modified) HDL. Thus. low HDL. the Cholesterol and Recurrent Events trial. And. triglyceride levels were positively associated with increased risk for CHD in populations with type 2 diabetes. such as the Scandinavian Simvastatin Survival Study.(JAMA 1993) As stated before. and high levels of total and VLDL triglycerides and VLDL cholesterol were all found to be powerful risk indicators for CHD events. however. HDL2 cholesterol. current clinical guidelines have identified LDL as the major atherogenic lipoprotein and the primary target of lipid-lowering therapy.(Foutbonne A et al 1989.Based on a large body of evidence. Laakso M et al 1993 ) In a 7-year prospective study in type 2 diabetics.
and department of biochemistry. Gyawali P.5%) individuals. and small. Kathmandu. department of biochemistry. IOM. Shrestha R. low (modified) HDL cholesterol. therapeutic interventions in patients with type 2 diabetes should be aimed at lowering fasting and postprandial levels of triglyceride-rich lipoproteins. TUTH. low HDL-C in 41% individuals an higher TG in about 50% individuals. Millus H. 48% and 39 . even more so. Stratton IM. Majhi S. In view of their atherogenic properties. 54% diabetic individuals had LDL-C. it appears that in type 2 diabetes all major lipoprotein abnormalities. The study done by Regmi P.9%)individuals. (Garg A 1998.(Turner RC. decreased HDL C was found in 54(37. BP Koirala Institute of Health Sciences. constitute the atherogenic phenotype independent of LDL cholesterol levels. Similarly 16%. Matthews DR.5%) individuals and increased LDL C was found in 69(47. Neil HA. greater than 50% individuals had increased TG.an indicator of CHD. (Garg A 1998) Table I lists the lipoprotein abnormalities in type 2 diabetes and their proposed atherogenic potential. Study by Curtis et al in african-american type 2 diabetic individuals found higher LDL in 58% individuals. among the 144 type 2 diabetic individual and 56 healthy controls showed that hypercholesttrolemia was found in 51(35. also termed non-HDL particles. Mehta D K. including elevated triglyceride-rich lipoproteins. They also found decreased HDL-C in 73% individuals. all these derangements are present in the fasting and. in the postprandial state. which needs to be confirmed in prospective studies.4%) individuals. Sigdel M. The study of Sehran et al in pakistan. dense (modified) LDL particles. Dharan. Manly SE. similarly hypertriglyceridemia was found in 90(62. Vogel RA 1997) In patients with type 2 diabetes. 1998) Thus.
A chronic. especially in type 2 diabetes mellitus (DM).34% individuals respectively had one. including renal dysfunction and CVD. hypertension and dyslipidemia. systemic inflammatory state has been proposed to underline this increased risk for atherosclerotic disease. (Julie Lin et al. Bays et al. 2006). Data from the two national surveys reported here support the common clinical observation that patients with higher BMI are at higher risk for having diabetes mellitus. but the relation between these biomarkers and mild or moderate renal dysfunction has Not been well characterized. Type 2 DM is now Recognized as an inflammatory condition associated with insulin resistance and abnormal endothelial vascular reactivity. type 2 DM is an increasingly prevalent etiology of micro vascular and macro vascular disease. They also confirm the converse – the majority of patients with these metabolic diseases are either overweight or obese (H. Studies have generally suggested a positive association between dyslipidemia and Inflammation and end-stage renal disease or advanced chronic kidney failure. investigations have not focused on the relation between glomerular filtration rate and dyslipidemia or inflammatory biomarkers in individuals with type 2 diabetes. Defining the relationship between body weight and metabolic diseases is critical toward better understanding of the underlying pathophysiological processes leading to these diseases. two and more than two abnormal parameters. 2007). 40 . As the leading cause of kidney disease and an important cause of cardiovascular disease (CVD) in the Western world. Identification of such serologic markers may reveal new approaches to the prevention of progressive renal insufficiency and CVD in this population. however. E.
confirming the importance of promoting better control in lipid management for these youth. (Xilin Yang et al. dyslipidemia. Adolescents with type 1 DM had the lowest tHcy values which were reflective of the limited extant research with this population. Greater effort is needed to stimulate medication adjustments in patients with insufficiently controlled hypertension and combined risk factors.Hypertension and Hyperlipidemia management in type 2 diabetes patients has improved in the past decade but further improvement is possible. or diabetes had their therapy modified and. 2008) Two measurements of fasting triglyceride levels obtained 5 years apart can assist in identifying apparently healthy young men at increased risk for diabetes. (Jacoba P Greving et al. Among patients with type 2 diabetes. 2008) As an additional measure of the quality of care. Lipid profiles and dietary energy did not differ significantly among the 3 groups. Many patients with poorly controlled hypertension. Hemoglobin A1C was related to total cholesterol and triglycerides in those with type 1 DM. measuring therapy modifications in response to poor control in a large population is feasible. Future research should continue to explore the validity of tHcy and lipids as predictors of CV risks for youth with type 1 and type 2 DM. 2006). 2007). ( Rafael Bitzur et al. 41 . independent of traditional risk factors and of associated changes in BMI and lifestyle parameters. whereby both low and high levels of LDL cholesterol were associated with elevated risk of cancer. the association between LDL cholesterol and cancer was V Shaped. thus. (Wei-Hsun Chao et al.
9% vs.3% overall. The cornerstone of treatment for diabetic dyslipidemia is therapeutic lifestyle change. Having two or more doctor visits annually is associated with goal attainment for dyslipidemia. 63. (Ishwarlal Jialala et al. and preponderance of small dense LDL particles. Therapy with 3-hydroxy-3-methylglutaryl (HMG) Coreductase inhibitor (statins) in both the Heart Protection Study (HPS) and the Collaborative Atorvastatin Diabetes Study (CARDS) has shown that there is clear reduction in cardiovascular events in type 2 diabetes. Dyslipidemia prevalence is 60. (Nicolas Rodondi et al.6% vs. (Margaret McDonald et al. with LDL cholesterol generally being similar to that of no diabetic patients.4%). 2009) 42 .2% of older adults for and all 50.1%).0%) and a significantly lower rate of control when treated pharmacologically (42. recent clinical trials have demonstrated the benefits of statin therapy.9%). In addition to these measures. Diabetes affects 21.seemed to receive clinically “appropriate care” with this new quality measure. 2006) Women have a significantly higher prevalence of hypertension than men (76. and diabetes (50. problematic Goal attainment conditions treated three hypertension dyslipidemia (64. low Levels of HDL-C.9%).9% of prevalent among — cases those are treated is (48.8%). 2009) Dyslipidemia commonly associated with type II diabetes includes elevated triglycerides. 59.1% vs. 57. and women are significantly more likely to be aware of their condition than men (71. pharmacologically.
Study duration: Study was conducted for the duration of 3 month From July 2010 to September 2010.CHAPTER III RESEARCH METHODOLOGY Study design: Cross sectional. Lekhnath Marg. Study method: Quantitative Study population: People with diabetes mellitus type 2 Study subjects: 43 . descriptive Study site: Study was conducted in Manmohan Memorial Community Hospital. Kathmandu. Thamel.
verbal consent of patients was taken. 44 . Instrumentation: Laboratory investigation Inclusion Criteria: Patient with Diabetes mellitus . Patients who refused to give consent for blood examination. Patient not suffering from any mental illness and malignant diseases. Patient not suffering from coronary heart disease. Standard study design was applied. The patient who refused to give consent was not included in the study.Patient attending Out Patient Department (OPD) and wards of Hospital Sample size: 40 type 2 diabetic patients and 40 non-diabetic patients. Exclusion Criteria : Patient who were unconscious. Reliability and Validity: Appropriate sample size was selected. Ethical consideration: Approval from institution was taken before carrying out study. Before drawing blood.
Low-density lipoprotein cholesterol (LDL-C) and very-low density lipoprotein cholesterol (VLDL-C) were calculated by Fridewald’s formula. Nepal. CHAPTER IV MATERIALS AND METHOD This study was conducted in the department of pathology. ThamelKathmandu. Highdensity lipoprotein cholesterol (HDL-C) was measured by precipitation followed by enzymatic methods. a National Cholesterol Education Programme-Adult Treatment Panel III (NCEP-ATPIII) guideline was referred. LDL-C as 150mg/dl 45 . Clinical laboratory services. Serum glucose was measured by enzymatic glucose oxidase-peroxidase method. Manmohan Memorial Hospital. For serum lipids. hypercholesterolemia is defined as TC>200mg/dl. Total 40 type 2 diabetic individuals and 40 nondiabetic individuals were included in the study. Serum total cholesterol (TC) level was measured by enzymatic methods. Study variables: Biochemical indicators Serum TG Serum LDL-C Serum HDL-C Serum total cholesterol. Serum was separated within 30 min of blood collection. According to NCEP-ATPIII guideline. hypertriglyceridemia as >150mg/dl. Blood sample was collected from 10-12 hr fasting subjects.
Statistical analysis was done using SPSS (version 16.and LDL-C as >150mg/dl. Dyslipidemia is defined by presence of one or more than one abnormal serum lipid concentration. Chylomicrons and VLDL transport mainly triglyceride(TG). Estimation of serum HDL-C and LDL-C: (Peg/Chod-PAP method) PRINCIPLE: Lipoproteins are the proteins which mainly transport fats in the blood stream. LDL carries cholesterol to peripheral tissues where it can be deposited and increase the risk of coronary heart disease (CHD).0). low density lipoprotein (LDL). PROCEDURE: 46 . low LDL level is atherogenic. of total thus and LDL HDL has protective effect. They can be grouped into chylomicrons. and high density lipoprotein (HDL). The measurement cholesterol provide valuable information for the risk of CHD. HDL transport cholesterol from peripheral tissue to liver for excretion. Hence. though VLDL also transport cholesterol. very low density lipoprotein (VLDL).
0 1.1 ml This was mixed well and was incubated at room temperature for 5 minutes.0 1.0 Blank (ml) Standard (ml) Test (ml) 47 .05 0.05 0. and then it was centrifuged at 2500-3000 rpm to obtain clear supernatant.Wavelength/filter: 505 nm/green Temperature: 37*C Light path: 1 cm Precipitation of VLDL and LDL: Precipitating reagent Sample 0.1 ml 0. Cholesterol assay: Three clean dry test tubes were taken and labeled and then pipetted with reagent as follows: Addition sequence Working reagent D/W HDL standard Supernatant 0.05 1.
x 25 x 2. LDL = total cholesterol-TG/5-HDL (Freidwald’s formula) Estimation of serum triglyceride: PRINCIPLE: 48 . Where 2 is the dilution factor due to depolarizing step.This was mixed well and was incubated at 37*C and OD was measured. Calculations: HDL (mg/dl) = Absorbance of test/absorbance of std.
Lipoprotein lipase hydrolyses TG to glycerol and fatty acid. PROCEDURE: Three test tubes were taken and labeled as blank (B).0 0. x 200 Normal range: serum/plasma (suspicious) = 150mg/dl (Elevated) = 300 mg/dl 49 . The H2O2 further reacts with phenolic compound and 4-amino-antipyrine by the catalytic action of peroxidase to produce a red colored quinine imino complex.01 1. The glycerol formed with ATP in the presence of glycerol kinase forms glycerol-3-phosphate oxidase to form H2O2. Calculation: Concentration of test = OD of test/OD of std. standard (S) and test (T) respectively. The presence of TG in serum is directly proportional to the concentrations of substances in serum.0 0.01 Blank (ml) Standard (ml) Test (ml) These was mixed well and incubated at 37*C and absorbance was measured. Addition sequence Working reagent D/W TG Serum 1.01 1.0 0.
Biochemical parameters Diabetic subjects Mean(SD) mg/dl Healthy controls Mean(SD) mg/dl Total cholesterol(TC) 182.35(44.328) 52.248) Triglyceride(TG) 214.942) 154.15(5.32(119.085) According to my study the following result was found: 50 . Baseline values of glucose and lipid is presented with their SD.816) LDL-C 92. Table 3: Baseline character of diabetic subjects and controls.68(22.40(45.763) 88.840) 170.98(8.08(19.760) HDL-C 46.20(49.CHAPTER V RESULT The study include 40 type 2 diabetic individuals and 40 healthy controls who were the patients attending Manmohan Memorial Community Hospital.
Among 40 diabetic patients 30 individuals had any two abnormalities.5%) individuals. Figure 4: Relation between diabetic and non-diabetic individuals in regard to lipid profile.5%) individuals.5%.e. Hypercholesterolemia was found in 13 diabetic patient among 40 i. 62.e. Hypertriglyceridemia was found in 25 diabetic patient i.1. 32. 4. 5.5%. 27 individuals had three abnormalities and 7 individuals had all four abnormalities. It was 51 . Decreased HDL-C was found in 7 (17. 3. 2. The above bar diagram represents the relation between the type 2 diabetic patient and healthy control on basis of lipid profile. Increased LDL-C was found in 19 (47.
found that there was no any significant corelation between diabetic and healthy control on basis of Cholesterol. but it was found a marked significant on triglyceride. the diabetic patient had much more higher TG level compared to the healthy control. CHAPTER VI 52 . HDL-C and LDL-C.
5%.4% had hypercholesterolemia and 47. 3. These findings are similar to my study. in Kathmandu. In the study of Regmi et. hypertriglycerademia. al. There are several factors that are responsible for diabetic dylipidemia: 1.DISCUSSION The objective of my study was to evaluate dyslipidemia in type 2 diabetic individuals.9% had increased LDL-C. 53 . Insulin effects on liver apoprotein production. But compared to our study they found decreased HDL-C in 37. One effect of hepatic lipase deficiency is to decrease the clearance of remnant lipoproteins. Hepatic lipase is an enzyme synthesized by hepatocytes that hydrolyses phospholipids and triglycerides on HDL remnant lipoproteins. 2. LpL is the major enzyme responsible for convertion of lipoprotein triglyceride into free fatty acids. Some studies suggest that this enzyme is reduced byinsulin deficiency.5% diabetic individual had hypertriglycedemia. 4. The study reveals the prevalence of hypercholesterolemia. 35. Regulation of lipoprotein lipase (LpL). abnormally high LDL-C. Peripheral actions of insulin on muscle and adipose tissue. and low HDL-C levels which are well-known risk factors for cardiovascular disease. The reason for decrease in HDL found in patient with diabetes maybe due to increased concentration of plasma VLDL drive the exchange of triglyceride from VLDL for the cholesteryl esters found in HDL. Action of cholesterol ester transfer protein(CETP). 62.
The main factor responsible for hypertriglyceridemia in our population could be diets that are rich in carbohydrates and the standard life style among the rich people. CHAPTER VII 54 . Diet with high fat and calorie intake and lack of physical activity could be the major factor contributing dyslipidemia among our population. >50% individuals had increased TG. frying and refrying in the same oil which causes trans fatty acid formation which contributes to increase of dyslipidemia in our population. In my study dyslipidemia was found in almost all the diabetic patient with one or more than one abnormal lipid concentration. these findings are also similar to my findings but they found decreased HDL-C in73% which is higher compared to my study. Besides it also involves the over-cooking of food. 54% individuals had elevated LDL-C.In another study carried by Sehran et al in pakistan.
CONCLUSION Dyslipidemia in diabetes is a major problem and the individuals who are diabetic with dyslipidemia are at higher risk for cardiovascular disease. Diabetic individuals must frequently monitor their lipid profile as they are higher risks associated with dyslipidemia. CHAPTER VIII 55 . My study concludes me to a point that most of the type 2 diabetic patients are more likely to have hypertriglyceridemia which was found in most of my cases taken. Cholesterol or LDL and decreased HDL. As per my study I came to the conclusion that in the most cases of type 2 diabetic patients they come across the risk for cardiovascular disease which is reflected by the increased TG.
RECOMMENDATION The present study would provide information that lipid profile seems destined to continue to be the most valuable parameter for assessing the complication of diabetes. This study was conducted with low sample size. However the present study due to various constraints and time limitation is preliminary so some recommendations are listed below. the categorization of the patient would be more beneficial. so for further best result. 56 . This study do not categorize the patient with duration of diabetes mellitus. it show the necessities of large sample size so that more accurate result would be produce.
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WORK PLAN 66 .
objectives and drafting of proposal and defense Visit to Manmohan Memorial Community HospitalMMCH and data collection Data entry and analysis Finalizing the report Thesis defense and dissemination 67 .Activities July week) 1-2 (in August 3-4 1-2 3-4 September October 1-2 3-4 1-2 3-4 Selection of study area.
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