Morbidity And Mortality Associated With Diabetes Biology Essay

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India tops the list with the largest number of diabetic subjects in the world. According to the International diabetes Federation, the number of diabetics in india was around 40.9 million in 2006 and is expected to rise to 69.9 million by 2025.2

Type 2 DM patients are at risk of an ischemic cardiac event as patients without diabetes who have a history of myocardial infarction. Diabetes is considered a "coronary heart disease risk equivalent" and require aggressive reduction of risk factors.3

Incidence of retinopathy and nephropathy are comparatively lower in Indians compared to the incidence of coronary artery disease which is much higher in Indian diabetics as compared to other ethnic group.2

Coronary artery disease is a major cause of mortality and morbidity in type 2 diabetes patients.4 The lipid profile in patients with type 2 diabetes is characterized by elevated triglycerides, low levels of high-density lipoprotein (LDL) cholesterol particles and is believed to be a key factor in promoting atherosclerosis in these patients.4 Dyslipidemia in type 2 diabetes is due to increasing hepatic secretion of very low-density lipoprotein particles and by impaired the clearance of lipoprotein particles because of insulin resistance . Lifestyle interventions and pharmacologic therapies (lipid-lowering medications and anti-diabetic agents) are to be initiated in order to achieve recommended reduction of LDL to less than 100 mg/dl, regardless of baseline lipid levels.6

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Early recognition of dyslipidemia in type 2 diabetes mellitus patients will help reduce the cardiovascular risk. This study is an attempt to know the frequency of occurrence of dyslipidemia in type 2 diabetes mellitus patients along with recognition of specific ethnic pattern of dyslipidemia.

AIM

This study aims at knowing the frequency of dyslipidemia in patients with type 2 diabetes mellitus.

OBJECTIVE

1. To know the frequency of occurrence of dyslipidemia in type 2 diabetes mellitus patients.

2. To study the correlation between various fractions of lipids like total cholesterol, triglycerides, HDL, LDL, VLDL and the ratio of LDL is to HDL with type 2 diabetes mellitus.

3. To study dyslipidemia in patients with type 2 diabetes mellitus based on their sex.

4. To study dyslipidemia in patients depending on their glycemic control.

Review of Literature

Type 2 Diabetes Mellitus

It is a group of disorders characterised by variable degree of insulin resistance, impaired insulin secretion, increased glucose productivity, and abnormal fat metabolism.7

Epidemiology

According to the report of World Health Organization (WHO), India tops the world with the largest number of diabetic subjects. This is attributed to the rapid epidemiological transition, which is accompanied by urbanization that is occurring in India.8, 14

The burden of diabetes is to a large extent the consequence of macrovascular (coronary artery disease, peripheral vascular disease, and atherosclerosis) and microvascular (like retinopathy, neuropathy, and nephropathy) complications of the disease.9 Approximately 80% of deaths in diabetic patients are attributable to cardiovascular disease (CVD), which in turn is highly correlated with diabetic dyslipidemia. Among diabetics, Asian Indians have higher risk of heart attacks than whites, but blacks have only half the risk, which in turn is attributed to more favourable dyslipidemia.10

Morbidity and Mortality associated with Diabetes

Global Morbidity and Mortality associated with Diabetes

• Close to four million deaths in the age group of 20-79 years in 2010

(International Diabetes Federation (IDF) Report 2009)

• Accounting for 6.8% of global all-cause mortality in this age group in 2010

(IDF 2009). IDF 2006 reported >50 million diabetes people in South East Asia.

• 7.97 million DALYs were lost because of diabetes (Jönsson 1998)

Diabetes Morbidity and Mortality in India

• Responsible for 109 thousand deaths in 2004 (Venkataraman et al. 2009)

• 1.157 million years of life lost in 2004 (Venkataraman et al. 2009)

• 2.263 million disability adjusted life years (DALYs) in India during 2004

(ICMR 2006)9

"Asian Indian Phenotype"

Indian people are found to have unique features characterised by increased insulin resistance, greater abdominal adiposity, lower adiponectin and higher C-reactive protein levels which has lead to the term "Asian Indian Phenotype". This particular phenotype makes Indians more prone to diabetes and premature coronary artery disease.2

The occurrence of microvascular complications of diabetes are comparatively lower in Indians than the occurence of premature coronary artery disease which is much higher in Indians compared to other ethnic groups.2, 11

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Mohan et al. 2008 found that the incidence of:

(1) T2DM in the urban south Indian population was 20.2 per 1,000 person years,

(2) Pre-T2DM was 13.1 per 1,000 person years,

(3) T2DM among subjects with impaired glucose tolerance (IGT) at baseline was higher compared to those with normal glucose tolerance (NGT).9

This research team recommended that Indian Diabetes Risk Score (IDRS) was best predictive tool of estimating incidence of T2DM in Asian Indians.9

Type 2 Diabetes Mellitus is a chronic disease which increases morbidity and mortality along with economic burden for patients , their families and society.9, 15 A better understanding is required to shed more light into the predisposition of Indians to diabetes and coronary artery disease .9

As we are well aware that lipid abnormalities are major risk factors for premature coronary artery disease12, 13, studies on the risk factors and Indian ethnic predisposition are urgently needed.

Diagnosis of Type 2 Diabetes Mellitus

In 1997, the first Expert Committee on the Diagnosis and Classification of Diabetes Mellitus revised the diagnostic criteria, using the observed association between Fasting Plasma Glucose (FPG) levels and presence of retinopathy as a key factor with which to identify threshold glucose level. Based on three cross sectional studies that assessed retinopathy with fundus photography or direct ophthalmoscopy and measured glycemia as FPG, 2 hour plasma glucose and glycosylated haemoglobin (HbA1c), the Committee came to a new diagnostic cut point16. The criteria are as follows:

Fasting Blood Glucose

Fasting is defined as no caloric intake for 8 hours. Fasting plasma glucose more than or equal to 126 mg/dl (7.0mmol/L) is taken as one of the criteria for diagnosis.16,17

2-hour Plasma Glucose

The test should be performed as described by the World Health Organisation, using a glucose load containing equivalent of 75gm anhydrous glucose dissolved in water.2-h Plasma glucose more than or equal to 200mg/dl (11.1mmol/l) during an oral glucose tolerance test (OGTT) is taken as a criterion.16,17

Glycosylated Haemoglobin

A report by an International Expert Committee on the role of HbA1c in the diagnosis of diabetes recommended that HbA1c can be used to diagnose diabetes and that the diagnosis can be made if the HbA1c level is 6.5%. Diagnosis should be confirmed with a repeat HbA1c test, unless clinical symptoms and plasma glucose levels >11.1mmol/l (200 mg/dl) are present in which case further testing is not required. Levels of HbA1c just below 6.5% may indicate the presence of intermediate hyperglycaemia. The precise lower cut-off point for this has yet to be defined, although the ADA has suggested 5.7 - 6.4% as the high risk range. While recognizing the continuum of risk that may be captured by the HbA1c assay, the International Expert Committee recommended that persons with an HbA1c level between 6.0 and 6.5% were at particularly high risk and might be considered for diabetes prevention interventions. HbA1c reflects average plasma glucose over the previous eight to 12 weeks. It can be performed at any time of the day and does not require any special preparation such as fasting. These properties have made it the preferred test for assessing glycaemic control in people with diabetes .18

Pathophysiology

Synthesis, Secretion and Action of Insulin

Beta cells of the pancreatic islets produces insulin hormone as precursor polypeptide preproinsulin which is cleaved to proinsulin. Cleavage of proinsulin generates the C peptide, A and B chains of insulin, which are connected by disulfide bonds. They are stored as secretory granules in the beta cells.64

During early hours most of the glucose in the blood is supplied by the liver which is utilised by the brain without any role of insulin in the glucose uptake. Rapid rise in blood glucose levels after a meal stimulates insulin secretion which helps in glucose uptake, metabolism and storage by muscle and adipocytes. Insulin lowers serum free-fatty-acid, inhibits hepatic glucose production and glucagon secretion. Cellular transporters of glucose consist of sodium-linked glucose transporters that are largely restricted to the intestine and kidney where glucose transport occurs actively. The other group consists of five transmembrane proteins, GLUT-1, 2, 3, 4, and 5 which facilitates passive diffusion of glucose. 7,19

GLUT2 glucose transporter facilitates glucose entry whereby it is phosphorylated by glucokinase; further metabolism via glycolysis generates ATP, which inhibits the activity of an ATP-sensitive K+ channel. Inhibition of this K+ channel induces beta cell membrane depolarization, which opens voltage-dependent calcium channels and stimulates insulin secretion. Incretins are released from gastrointestinal tract following food ingestion and amplify glucose-stimulated insulin secretion and suppress glucagon secretion. 87

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GLUT-4 transport are present in muscles which differs from other glucose transporters in that majority of it are sequestered intracellularly in the absence of insulin or other stimuli such as exercise. 19

Activation of other insulin receptor signalling pathways induces glycogen synthesis, protein synthesis, lipogenesis, and regulation of various genes in insulin-responsive cells. 19,65

Metabolic Abnormalities

Decreased ability of insulin to act effectively on target tissues is a feature of type 2 DM and results from a combination of genetic susceptibility and obesity. Supernormal levels of circulating insulin will normalize the plasma glucose but it impairs glucose utilization by insulin-sensitive tissues and increases hepatic glucose output

Insulin receptor levels and tyrosine kinase activity in skeletal muscle are reduced which play the predominant role in insulin resistance by reducing translocation of GLUT4 to the plasma membrane. Hyperinsulinemia accelerates diabetes-related conditions such as atherosclerosis.

The obesity in type 2 DM is central or visceral in location .The adipocyte mass leads to increased levels of circulating free fatty acids and other fat cell products.7

Islet amyloid polypeptide or amylin forms the amyloid fibrillar deposit in individuals with long-standing type 2 DM . Improvement in glycemic control is often associated with improved islet function20,21

Lipid storage or steatosis in the liver may lead to non-alcoholic fatty liver disease and abnormal liver function tests. This is also responsible for the dyslipidemia found in type 2 DM [elevated triglycerides, reduced high-density lipoprotein (HDL), and increased small dense low-density lipoprotein (LDL) particle.7,65

Insulin Resistance Syndromes - it is a group of metabolic derangements that includes insulin resistance, hypertension, dyslipidemia (low HDL and elevated triglycerides), central or visceral obesity, type 2 diabetes or IGT/IFG, and accelerated cardiovascular disease. 71,87

Genomic factors for Insulin Resistance

Decreased beta-cell responsiveness, leading to impaired insulin processing and decreased insulin secretion (TCF7L2)

Lowered early glucose-stimulated insulin release (MTNR1B, FADS1, DGKB,GCK)

Altered metabolism of unsaturated fatty acids (FSADS1)

Dysregulation of fat metabolism (PPARG)

Inhibition of serum glucose release (KCNJ11)

Increased adiposity and insulin resistance (FTO and IGF2BP2)

Control of the development of pancreatic structures, including beta-islet cells (HHEX)

Transport of zinc into the beta-islet cells, which influences the production and secretion of insulin (SLC30A8)

Survival and function of beta-islet cells66

Advanced Glycation End Products (AGES) are a group of compounds produced by non enzymatic sequential glycation and oxidation of sugars with free amino groups on proteins, peptides or amino acids. N- carboxymethyllysine, pentosidine, methylglyoxal, glycated haemoglobin are some of the well characterised compounds that are used as AGE markers. AGESs modifies intracellular proteins, extracellular proteins and induces the production of reactive oxygen species (ROS) , transcription factors, nuclear factors , cytokines and growth factors. In diabetic retinopathy AGEs moieties produce structural changes like thickening of basement membrane, enhanced vascular permeability, and loss of pericytes leading to micro aneurysm. Induction of ROS and growth factors will promote neovascularisation. Mechanisms like overactive polyol pathways , ROS , over expression of receptors of AGEs , ischemia / hypoxia , growth factors, increased protein kinase c , nuclear factors, endothelial NO deficiency, cytokines result in segmental demyelination and axonal atrophy leading on to diabetic neuropathy , trans differentiation of tubular epithelial cells to myofibroblast and proteinuria induced tubulointerstitial damage result in nephropathy. AGEs accumulation on collagen, albumin, apolipoprotein and its cross linking of macromolecules result in stiffness. Reduction of thrombomodulin, changes from anti coagulant to pro coagulant states, activated macrophages, decreased LDL clearance due to glycation lead on to plaque formation and "Accelerated Atherosclerosis".22

LIPID AND LIPOPROTEIN METABOLISM

Lipoproteins are complexes of lipids and proteins that are essential for the transport of cholesterol, triglycerides, and fat-soluble vitamins. They are much smaller than red blood cells and visible only by electron microscopy. The major lipids of lipoproteins are cholesterol, triglycerides and phospholipids.56

Triglycerides and esterified form of cholesterol (cholesteryl esters) are non polar lipids that are insoluble in aqueous environment (hydrophobic) and constitute the core of lipoproteins. Phospholipids and free cholesterol (unesterified), which are soluble in lipids and aqueous environment, cover the surface of the particles; where they act as the interface between the plasma and core components.56,46 There is also a family of proteins called as apolipoproteins, which occupy the surface of the lipoproteins to serve as an additional interface between lipids and aqueous environment. These proteins play crucial role in the regulation of lipid transport and lipoprotein metabolism.55

The plasma lipoproteins are divided into five major classes based on their relative densities chylomicrons, very low density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). HDL is the smallest and most dense lipoprotein, whereas chylomicrons and VLDL are the largest and least dense lipoprotein particles.46,56

APOLIPOPROTEINS

The surface proteins of the lipoproteins are apolipoproteins. The apolipoproteins are required for the assembly and structure of lipoproteins. Apolipoproteins also serve to activate enzymes important in lipoprotein metabolism and to mediate the binding of lipoproteins to cell-surface receptors.55

ApoA-I, which is synthesized in the liver and intestine, is found on virtually all HDL particles. ApoA-II is the second most abundant HDL apolipoprotein and is found on approximately two-thirds of all HDL particles. ApoA-I and ApoA-II are synthesized in the small intestine and liver. There is also ApoA-IV, which is a minor component of HDL and chylomicrons. It is synthesized in the intestine. ApoA-I also activates the enzyme, lecithin cholesterol acyl transferase (LCAT). The levels of ApoA-I are inversely related to the risk of coronary heart disease (CHD).56,57

ApoB is the major structural protein of chylomicrons, VLDL, IDL, and LDL; one molecule of apoB, either apoB-48 (chylomicrons) or apoB-100 (VLDL, IDL, or LDL), is present on each lipoprotein particle. ApoB-100 is synthesized in the liver, and the intestine makes apoB-48, which is derived from the same gene by mRNA editing. 50