RR interval(sec) with FBS

STUDY OF RELATIONSHIP BETWEEN GLYCEMIC STATUS AND QTc INTERVAL IN ELECTROCARDIOGRAM AMONG TYPE II DIABETES

MELLITUS PATIENTS

Dissertation submitted to

THE TAMILNADU Dr. M.G.R. MEDICAL UNIVERSITY CHENNAI – 600 032

In partial fulfillment of the requirement for the degree of Doctor of Medicine in Physiology (Branch V)

M.D. (PHYSIOLOGY) MAY – 2019

DEPARTMENT OF PHYSIOLOGY TIRUNELVELI MEDICAL COLLEGE

CERTIFICATE

This is to certify that the dissertation entitled, “STUDY OF RELATIONSHIP BETWEEN GLYCEMIC STATUS AND QTc INTERVAL IN ELECTROCARDIOGRAM AMONG TYPE II DIABETES MELLITUS PATIENTS” done by Dr.H.KAVINGAR KANNAN postgraduate in PHYSIOLOGY (2016-2019), is a bonafide research work carried out under our direct supervision and guidance and is submitted to The Tamilnadu Dr. M.G.R.

Medical University, Chennai, for M.D. Degree Examination in Physiology (Branch V), to be held in May 2019.

Dr. A.Jeya Jancy Selvi Ratnam DGO,MD Head Of the Department

Department of Physiology Tirunelveli medical college

Tirunelveli - 11.

Dr. S.M . Kannan M.S,M.Ch.., Tirunelveli medical collegeDean

Tirunelveli – 11.

ENDORSEMENT BY THE GUIDE

This is to certify that the dissertation entitled, “STUDY OF RELATIONSHIP BETWEEN GLYCEMIC STATUS AND QTc INTERVAL IN ELECTROCARDIOGRAM AMONG TYPE II DIABETES MELLITUS PATIENTS’’ is a bonafide research work carried out by Dr.H.KAVINGAR KANNAN, in the Department of Physiology, Tirunelveli Medical College Hospital, Tirunelveli – 11 under my direct guidance and supervision in partial fulfillment of the requirement for the award of the degree of MD in PHYSIOLOGY (Branch – V) in May 2019.

GUIDE

Dr. A. Jeya Jancy Selvi Ratnam DGO,MD, Head Of the Department,

Department of Physiology, Tirunelveli Medical College,

Tirunelveli – 11.

DECLARATION

I solemnly declare that the dissertation entitled “STUDY OF RELATIONSHIP BETWEEN GLYCEMIC STATUS AND QTc INTERVAL IN ECG AMONG TYPE 2 DIABETES MELLITUS PATIENTS ’’ is done by me at Tirunelveli Medical College Hospital, Tirunelveli.

The dissertation is submitted to The Tamilnadu Dr. M.G.R. Medical University towards the partial fulfillment of the requirement for the award of M.D.

Degree (Branch V) in Physiology.

Place : Tirunelveli Dr.H.KAVINGAR KANNAN,

Date : Postgraduate Student,

M.D. (Physiology),

Department of Physiology, Tirunelveli Medical College,

Tirunelveli-627011

ACKNOWLEDGEMENT

First, I thank myGod, the Almighty for providing me this opportunity to do a study and complete it successfully.

 I sincerely express my heartful gratitude to our beloved Dean, Prof. Dr.S.M.Kannan M.S, M.Ch (urology) and to our respected Vice Principal Prof. Dr.C.Revathy M.D., Tirunelveli Medical College, Tirunelveli for their encouragement during the study period.

 I express my sincere gratitude to my guide Dr. A. Jeya Jancy Selvi Ratnam DGO,MD, Head of the Department of Physiology, Tirunelveli Medical College for she has not only my guide but also who constantly extends her tremendous support and valuable guidance during these three years period.

 I thank the Head of the Department of Medicine and Biochemistry, Tirunelveli Medical College for providing the subjects and laboratory respectively for the successful completion of the study. I thank all the lab technicians, Central Lab, Tirunelveli medical college hospital for their support throughout my study.

 I thank the librarian, Mrs. M. Mala Shanmugapriya and all other staff of central library

 I thank Dr.S.Karthikeyan MD (SPM), Associate professor ,Department of community medicine, Government Medical college ,Palakkad for their loving support during the collection of reference articles.

 I am highly obliged to all Associate Professors and all Assistant Professors and Tutors, in our department for their encouragement, and comments during the research period.

 My special thanks are to my seniors Dr.I.J.V.Pradeep Vaiz,T and Dr.Sherry Jenilin who always giving moral support me and postgraduate colleagues Dr.S.Muruganantham,Dr.S.Seeniammal,Dr.V.Logeshwari Dr.A.Suba, and Dr.Shahul Hammed and my dear friend Dr.Gurusamy for they gave me their helping hands when needed throughout the study.

 Last, but an important note of thanks to all participants of this study without whom this could not be accomplished.

CERTIFICATE – II

This is certify that this dissertation work title “STUDY OF RELATIONSHIP BETWEEN GLYCEMIC STATUS AND QTc INTERVAL IN ECG AMONG TYPE 2 DIABETES MELLITUS PATIENTS” of the candidate Dr.H.KAVINGAR KANNAN with registration Number 201615302 for the award of M.D. Degree in the branch of PHYSIOLOGY (V). I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains from introduction to conclusion page and result shows5 percentageof plagiarism in the dissertation.

Guide & Supervisor sign with Seal.

CONTENTS

Sl. No. TITLE PAGE No.

1 INTRODUCTION 1

2 AIM AND OBJECTIVES 4

3 MATERIALS AND METHODS 5

4 REVIEW OF LITERATURE 12

5 STATISTICAL ANALYSIS 58

6 DISCUSSION 75

7 CONCLUSION 79

8 BIBLIOGRAPHY

9 ANNEXURES

LIST OF ABBREVIATIONS

AV - Atrioventricular

BMI - Body mass index

CABG - Coronary Artery Bypass Graft

CAD - Coronary artery disease

CCS - Coronary Calcium scoring

CHD - Coronary heart disease

CI - Confidence interval

CVD - Cardiovascular diseases

DES - Drug Eluting Stents

DIAD - Detection of Ischemia in Asymptomatic Diabetes

DM - Diabetes Mellitus DPP - Dipeptidyl peptidases

ECG -Electrocardiogram

FRS - Framingham risk score

GCK - Glucokinase

GIP - Glucose dependent insulinotropic polypeptide

GLP-1 - Glucagon like peptide-1

GLUT-4 - Glucose transporter protein

HDL - High Density Lipoproteins

HNF1A - Hepatocyte nuclear factor 1α HNF1B - Hepatocyte nuclear factor 1β HNF4A - Hepatocyte nuclear factor 4α

HOPE - Heart Outcomes Prevention Evaluation

hsCRP - High sensitivity C-Reactive protein

IL - Interleukin

IMA - Internal Mammary Artery

LDL - Low Density Lipoproteins

MI – Myocardial Ischemia

MODY - Maturity-onset diabetes of the young MP - Myocardial perfusion

NCB - Non communicablle diseases

NEURODI - Neurogenic differentiation factor 1 OGTT - Oral glucose tolerance test

OR - Odds ratio

PDX1 - Pancreatic and duodenal homeobox 1 PP - Pancreatic peptide

PPAR- γ - Peroxisome proliferator-activated receptor γ

SA node - Sinoatrial node

SBP -Systolic blood pressure

SPECT - Single Photo Emissin Computed Tomography

TG -Triglyceride

UKPDS - United Kingdom ProspectiveDiabetes Study

INTRODUCTION

Across the world, Diabetes Mellitus (DM) prevalence has risen dramatically from 30 million cases to 285 million cases, over the past two decades. The International Diabetes Federation, on analyzing the recent trends, predicts that the diabetes prevalence will peak to 438 million cases by 2030. In DM, occurrence of both Type 1 and type 2 is increasing throughout the world. Yet, due to raised obesity incidence and physical inactivity which is a result of countries becoming more industrialised, the type 2 DM prevalence has been rising more rapidly. These high prevalence trends of DM are mostly seen in Asian countries with India being one among them.

Worldwide prevalence of Diabete Mellitus

Global estimation is 382 million individuals with diabetes. Regional estimates of the number of the individuals with diabetes 20-79 years of age are shown (2013) M - Millions

Based on multiple epidemiological studies, compared to the non-diabetics of same sex and age, risk of developing cardiovascular disease is doubled in diabetics. The mortality due to cardiovascular diseases in type 2 DM is also increased. The doubled cardiovascular risk among diabetics remains even if the conventional risk factors for cardiovascular disease like hypertension, dyslipidemia, smoking, lack of physical activity are within normal limits. This suggests the presence of multiple other mechanism for the raised risk. Among the cardiovascular abnormalities, Ventricular instability which is manifested in QT abnormalities, is an important mechanism seen at higher rate in diabetics. The time needed for ventricular repolarization in an electrocardiogram is denoted by QT interval. By adjusting for heart rate this interval is termed as, the corrected QT interval(QTc). QTc is corrected in accordance with heart rate. The corrected QT (QTc) prolongation is nothing but the increased length of the QT interval indicating presence of a precursor of torsade de pointes, which is life-threatening ventricular dysrhythmia and ventricular fibrillation¹. Morbidity and mortality is raised in people with QTc prolongation.

The QTc interval is proven to be affected by cardiac ischemia yet the influence of hyperglycemia on this QT interval is not yet fully established. QTc has been found to be longer in DM cases than in healthy controls.

A number of studies suggests that assessment of the QTc interval is a much appreciated cost-effective way of grouping patients on their order of cardiovascular risk enabling provision of aggressive treatment to improve outcome .This QTc prolongation is acknowledged to enable the prediction of occurrence of cardiac death among type 2 DM.

Hence the aim of this study is to assess the relationship between glycemic status and QTc interval in ECG among type 2 DM patients. Here the relationship between QTc and the duration of Dm ,HbA1c,blood pressure and body mass index (BMI)has also been analysed.

AIM AND OBJECTIVES

AIM

The aim of the study is to assess the relationship between the glycemic status and QTc interval in ECG among patients with Type II DM

OBJECTIVES

 To correlate QTc interval and Fasting Blood sugar

 To correlate QTc interval and Postprandial Blood sugar

 To correlate QTc interval and blood pressure

 To correlate QTc interval with HbA1c

 To correlate QTc interval with FBS,PPBS ,BP and HbA1c

MATERIALS AND METHODS

STUDY DESIGN: This was a cross-sectional type of study.

STUDY CENTRE AND PERIOD: This study was carried out in Tirunelveli Medical College Hospital from October 2017 to August 2018

SAMPLE SIZE: The sample size was 100 ETHICAL CONSIDERATIONS:

Institutional ethical committee clearance was obtained prior to the commencement of the study. The patients who were attending the diabetic OPD were recruited for this study. All the subjects were clearly explained about the study in their own language. Informed consent was obtained from those who were willing to participate in this study.

INCLUSION CRITERIA:

 Patients with Type II DM on regular follow up in diabetic op of TVMCH, Tirunelveli

 Both sexes

 No age limit

EXCLUSION CRITERIA:

Patients with any of the following illness are excluded from this study such as

 SHT( Systemic Hypertension)

 CHD (Congenital Heart Disease)

 CAD (Coronary Artery Disease)

 IHD (Ischaemic heart Disease)

 MI (Myocardial Infarction)

 Unstable angina

 Anaemia

 Any acute illness conditions

 CRF Chronic Renal Failure

 Drugs:

Intake of beta blockers, beta agonists, CCB and digitalis

 Smokers and Chronic alcoholics also excluded from this study Were excluded from this study

METHODOLOGY:

After getting informed consent, the information about personal details, family history, medical history was noted in a separate proforma sheet.

Their anthropometric measurements like height, weight were taken to assess BMI.

Measurement of Height:

With participants in bare feet, using a non stretchable measuring tape which was secured to the wall, height was measured in centimeters to the top of the head (nearest 0.5cm)

Measurement of weight:

Using a professional body weight scale, weight was measured in kilograms, with only light clothing and after asking them to empty all belongings.

Measurement of BMI:

BMI was calculated using Quetlet’s formula: weight (kg)/ height (m²).

BMI(kg/m2) Classification

18.5-22.9 Normal

23.0-24.9 Overweight

>25 Obese

ECG :

ECG was recorded for study group patients in supine position,. A standard resting 12-lead surface ECG record at a paper speed of 25 mm/s and a gain of 10 mm/mV by using BPL CARDIART 6208 VIEW 3 channel ECG machine

Measurement of Blood pressure:

Blood pressure was determined using standard mercury sphygmomanometer after 5 minutes of rest. BP >140/90 mm Hg were considered as hypertensive.

Blood investigations:

After an overnight fastingblood samples were collected from antecubital vein using 5ml disposable syringeunder strict aseptic precautions for fasting blood sugar

and one and half an hour after breakfast another sample taken for postprandial blood sugar.Fasting and Postprandial blood sugar were estimated using Fully Automated Clinical Chemistry Analyzer XL-640 (ERBA) Liquixx glucose Trinder ‘s method.

HbA1C was estimated using Erba Mannheim XLSyspack by which uses particle enhanced immunoturbidmetrictest.Results were interpreted as

PARAMETERS NORMAL VALUES (mg/dl)

ABNORMAL (mg/dl)

FBS <126 >126

PPBS <150 >150

RBS <200 >200

FULLY AUTOMATED CLINICAL CHEMISTRY ANALYZER XL-640

REVIEW OF LITERATURE

 GLUCOSE

 GLUCOSE HOMEOSTASIS

 ANATOMY AND EMBRYOLOGY OF PANCREAS

 INSULIN BIOSYNTHESISAND REGULATION

 NORMAL β CELL FUNCTION AND β CELL DYSFUNCTION IN TYPE 2 DM

 SECRETION OF INSULIN IN TYPE 2 DM

 REGULATION OF INSULIN RELEASE

 INSULIN ACTION AND ITS SIGNALLING PATHWAYS

 DIABETES MELLITUS- PATHOPHYSIOLOGY

 CLASSIFICATION OF DIABETES MELLITUS

 EPIDEMIOLOGY OF DIABETES MELLITUS

 PATHOGENESIS OF TYPE 2 DIABETES MELLITUS

 COMPLICATIONS OF DIABETES MELLITUS

 CARDIAC CHANGES IN TYPE 2 DIABETES MELLITUS

 PHYSIOLOGY OF ELECTROCARDIOGRAPHY (ECG), WAVES AND INTERVALS

 CAUSES OF QTc PROLONGATION

GLUCOSE

Glucose is a simple sugar with the molecular formula C6H12O6. It is the most abundant monosaccharide a subcategory of carbohydrates. In energy metabolism glucose is the most important source of energy in all organisms. Glucose circulates in the blood animals as blood sugar. The naturally occurring form of glucose is D- glucose. L-Glucose is produced synthetically.

Molecular structure of D- glucose

Hormones involving glucose metabolism:

 Insulin

 Glucagon

 Thyroid hormones

 Growth hormones

Except Insulin all other hormones are increasing the blood sugar level.

GLUCOSE HOMEOSTASIS:

Three interlinked processes are known to tightly regulate normal glucose homeostasis, which are

1.Glucose production in the liver

2.Glucose uptake and utilization by peripheral tissues, chiefly skeletal muscle 3.Actions of insulin and counter-regulatory hormones, including glucagon, on glucose uptake and metabolism.

Insulin and glucagon are found to be having opposing regulatory effects on glucose metabolism. In fasting states, there is low levels of insulin along with high glucagon levels which produces hypoglycaemia by facilitating hepatic gluconeogenesis and glycogenolysis. So, the hepatic glucose output levels primarily determines the fasting plasma glucose blood levels. Followed by a meal which is a large glucose load, there is a raise in insulin levels and fall in glucagon levels. The insulin is found to promote glucose uptake and utilization in peripheral tissues. The skeletal muscle is the major insulin-responsive site for postprandial glucose utilization, and is critical for preventing hyperglycemia and maintaining glucose homeostasis².

PANCREAS

Pancreas is a Greek word meaning “all flesh”. This organ has an unique feature of having both an exocrine and endocrine part .

EMBRYOLOGY

The endocrine and exocrine part of pancreas is formed by islets and acinar cells respectively. Embryologically, it originates as ventral and dorsal pancreatic buds by emerging from ventral and dorsal regions of foregut endoderm on 32 and 26 days respectively. By 36^th day, fusion of these buds occur³. Most of the parts of pancreas develop from the dorsal bud, with a posterior part of head of pancreas developing from ventral bud. At around 12^th week, islets having independent blood supply, are noted in human embryo. They become functionally active by 16^thweek⁴. Islets are of two types, namely ‘A cell rich’ and ‘F cell rich’. Dorsal and ventral pancreatic bud gives rise to ‘A cell rich’ and ‘F cell rich’islets respectively⁵.

ENDOCRINE PANCREAS

Islets of Langerhans having a multitude of cells aids in the endocrine function of pancreas. A German physician named, Paul Langerhans in the year 1869 discovered the islet cells which are tightly bound collection of cells found admist the exocrine tissue of pancreas. Islets has four cell types: α cells, β cells, δ cells and PP (pancreatic peptide) cells also known as γ cells. Among them, major portion is formed by the β cells, which secrete insulin, amylin and other peptides⁶

CELLS OF PANCREAS

The β cells produce insulin in response to stimulatory factors like presence of hormones glucagon, gastric inhibitory peptide epinephrine, raised blood glucose levels and aminoacid levels. These cells have a polyhedral shape comprising of

secretory granules⁷. The α cells, δ cells and γ cells secrete glucagon, somatostatin and pancreatic polypeptide respectively. Most of mammals are found to have a thin layer of α, δ, and PP cells, surrounding the centrally placed β cells⁸. But in humans, in some instances the islets takes the shape of oval and cloverleaf pattern rather than the characteristic concentric cell collection making it less defined⁹.β cells constitute 70-80% of the entire islet mass. In an adult man with an average of 70kg body weight pancreas are found to have about 3,00,000 -1.5million islets.

INSULIN BIOSYNTHESIS

Canadian physician Frederick Banting and American medical student Charles .Best discovered hormone insulin in pancreatic extract of dogs in 1921¹⁰. In 1922 a diabetic teenager called Leonard Thompson was the first person to receive an insulin injection. Banting and Macleod received the Nobel prize in Medicine in 1923. In protest Banting shared half his award money with Best.

The β cells of pancreas are the major and the only site of expression of insulin gene and insulin biosynthesis, with possible exception of the fetal liver and yolk sac in mammals¹¹.Theproduction, storage and regulated secretion of insulin are the prime functions of β cell; Enabling a readily available pool of insulin to aid in meeting any sudden increase in glucose load. Insulin biosynthesis in human body helps in replenishing the released insulin quantity. Insulin being a peptide hormone, is synthesized the rough endoplasmic reticulum as preprohormone, which is then converted to prohormone with the help of an enzyme called signal peptidase in the rough endoplasmic reticulum itself. In order to maintain the preproinsulin composition very minimal, the proteolysis is mostly made cotranslationally¹².

INSULIN -BIOSYNTHESIS

STRUCTURE OF HUMAN INSULIN

REGULATION OF INSULIN BIOSYNTHESIS

a)The biphasic glucose – stimulated release of insulin from pancreatic islets b)The glucose –insulin dose response curve for islets of Langerhans

The proinsulin’s synthesis rate is under the control of multiple factors like nutrients, hormones and neurotransmitters¹³. Among them, the most significant factor is glucose. In order to trigger the biosynthesis and secretion of insulin, the threshold concentration of glucose is found to be between 2-4mM and 4-6mM respectively¹⁴. The peak concentration of proinsulin synthesis occurs when the blood glucose becomes 10-12mM. The β cell stimulation by glucose and the proinsulin biosynthesis prominent raise are not immediate, they have a lag period of 20 minutes. In an hour (60 minutes), the synthesis rate is increased to 10- 20folds. The other insulin biosynthesis stimulatory hormones are growth hormone¹⁵, glucagon like peptide-1and glucagon. Insulin biosynthesis stimulated by hormones like glucagon and glucagon like peptide stimulate through cAMP dependent pathway. In obesity, there is increase in rate of proinsulin biosynthesis and βcell mass with islet cell hyperplasia. Unlike the proinsulin biosynthesis which depends on Mg2+, insulin release in reponse to glucose stimulation depends on extracellularCa²⁺(calcium)¹⁶. Insulin release is potentiated markedly by long chain fatty acids. The proinsulin biosynthesis occurs majorly in rough endoplasmic reticulum. Inthe βcells, trans-Golgi region, which is identified by clathrin coated cytosolic surfaces¹⁷, is the site where the earliest form of secretory granule is synthesised. As maturation process occurs, the involvement of clathrin in purging

of unwanted proteins from the secretory granules is discovered. The clathrin coated immature secretory granule is the place of synthesis of insulin and C-peptide from proinsulin¹⁸.

NORMAL β CELL FUNCTION:

The pancreatic β cell aids in cellular fuels storage and metabolism via their insulin secretion. This is brought about by a feedback loop: glycemia causes β cell to secrete insulin; proinsulin biosynthesis occurs; then conversion of proinsulin to insulin takes place; and the secreted insulin in turn lowers plasma glucose by increasing glucose uptake into target cells like skeletal muscle. The secretion of insulin is in a pulsatile form with 11-14 minutes as periodicity which is needed to allow regulation of fully regulate hepatic glucose production¹⁹. Insulin release also occurs in multiple large bouts followed by each meals, enabling a noticeable raise in nutrient clearance efficiency. Insulin secretion occurs in an oscillatory pattern, which is known by the term entrainment²⁰. Absence of entrainment occurrence is found to lead toan early defect in insulin secretion which occurs much prior to abnormalities in traditional tests. The secretion of C-peptide and insulin are equimolar in ratio even with minimal hepatic degradation undergone by C-peptide.

This enables the usage of C-peptide as a tool for estimating the true rate of insulin

β cell dysfunction in type 2 DM

The proportionof type 2 diabetes mellitus cases among the general population is increasing each day. There is prediction that type 2 DM incidence will reach 300 million cases by 2025, given by WHO²².The associated risk factors include obesity, aging, a high fat diet, inactivity or genetic basis which will lead to insulin resistance along with βcell dysfunction. This dysfunction occurs much earlier, making hyperglycemia as predated²³.Thereis a substantial change in βcell function compared to the insulin resistance where there is only minute change as the abnormality progresses from impaired glucose tolerance to DM. This β cell dysfunction is reversible easily to a great extent, even after the onset of overt diabetes by intense glycemic control²⁴.

SECRETION OF INSULIN IN TYPE 2 DM

The pairing of obesity and insulin resistance is a common occurrence now a days.

Hyperinsulinemia is regular finding among them yet the degree of it is very much low for the plasma glucose levels. Anyhow, in these patients even if they are under dietary restriction with or without an oral hypoglycaemic drug, the β cell is reserved to an adequate extent which helps to maintain a normal glucose level. In the background of insulin resistance, there is established occurrence of β cell function defects both of which converge to form type 2 DM²⁵.In a study made with

animal model having hyperinsulinemia, obesity and insulin resistance, inadequate expansion of βcell mass was a significant causative factor for the occurrence of diabetes mellitus; this result is also supported by autopsy findings made in humans.

The introduction of intravenous glucose in these patients show an absence of insulin and C-peptide responses in the first phase and response are also reduced in the second phase. Hence a marked flattening is seen in the glucose-insulin secretion dose-response curve²⁶. However, even after strict glycemic control this abnormal first phase response is found to be persisting which supports the presence of an intrinsic defect in β cell in patients with type 2 DM. Furthermore studies made established consistent elevated levels of proinsulin in association with increases in the molar ratio of proinsulin to insulin; indicating that theβ cells of type 2 DM patients release immature secretory granules in excess into the circulation. There is relationship found between the degree of glycemic control and the amount of proinsulin secreted in these patients which does not vary with the duration of diabetes.

Hence in type 2 DM cases the hyperinsulinemia reported represents hyperproinsulinemia rather than true hyperinsulinemia. The basal insulin secretion levels which is estimated over a period of 24 hourin patients with type 2 DM is found to be higher. In the Postprandial period, due to reduction in insulin’s

reduction in the amount of insulin secreted. β cell secretory activity is re- established once the diabetic control is improved²⁷.

REGULATION OF INSULIN RELEASE

Theβ cells of the pancreatic islets are the site where insulin gene expression takes place. The rough endoplasmic reticulum synthesise insulin and delivers it to the golgi apparatus where a series of multiple proteolytic cleavage occurs to generate mature insulin and C-peptide, a cleavage peptide. Both of which are secreted in response to a physiologic stimulation. Thus, C-peptide levels serve as a eterminant for β-cell function. In type 1 diabetes, their levels decreases with loss of β-cell mass and increases with insulin resistance–associated hyperinsulinemia. Glucose is the most important stimulus for insulin synthesis and release. A raise in glucose level noted in the immediate phase of insulin causing the increased glucose to enter the beta cells through the GLUT-2 insulin independent glucose transporter. By glucose metabolism process, intracellular ATP levels increases which inhibits the ATP –sensitive K+ channel activity causing membrane depolarization and influx of extracellular calcium. The oral food intake produces the release of many incretin hormones which causes the following changes: raised insulin secretion by beta cells, fall in glucagon secretion along with gastric emptying delay. The incretins commonly secreted are GIP (glucose dependent insulinotropic polypeptide) and

GLP-1(glucagon like peptide-1)²⁸. These circulating incretins are degraded by dipeptidyl peptidases(DPP),mainly DPP-4. The above mentioned incretin effect is significantly blunted or reduced in patients with type 2 diabetes mellitus. Hence in the treatment of type 2 DM, two new drugs such as GLP-1 receptor agonists and DPP-4 inhibitors.

INSULIN ACTION AND ITS SIGNALLING PATHWAYS

The Insulin acts with the help of insulin receptor. The binding stimulates activity of receptor kinase, further inducing several insulin receptor substrate proteins phosphorylation by activation of downstream cascades including PI3 and MAP kinase pathways. In the end the AKT pathway is activated, enabling the movement of the GLUT-4 glucose transporter protein to the plasma membranes. Hence the main outcome of this process is increased glucose transport. These pathways are negatively regulated by variety of phosphates mainly protein tyrosine phosphates 1 B and PTEN²⁹.

The primary metabolic function of insulin is to improve glucose transport into the target cells which are primarily skeletal muscle and adipocytes. Once cell glucose uptake occurs, it is stored as either glycogenin skeletal muscle or lipid in adipose tissue or oxidised to generate ATP. Lipid catabolism by adipocytes is inhibited,

protein synthesisare promoted by the insulin released, which also has cell mitogenic effects.

DIABETES MELLITUS- PATHOPHYSIOLOGY

Definition of diabetes mellitus

Diabetes mellitus is a heterogeneous group of metabolic disorder characterized by elevated blood glucose and associated with disturbances in carbohydrate, fat and protein metabolism resulting from defect in secretion of insulin and action of insulin or both³⁰.

Criteria for Diagnosing Diabetes Mellitus:

Normal levels of serum blood glucose isin a range of 70 to 120 mg/dl. According to WHO, diagnostic criteria for diabetes include:

1.A fasting plasma glucose ≥ 120 mg/dl 2.A random plasma glucose ≥200 mg/dl

3.2 hour plasma glucose ≥200 mg/dl during an oral glucose tolerance test with a loading dose of 75 gm and

4.A Glycated hemoglobin (Hb A1C ) level ≥ 6.5%

Impaired glucose tolerance ( Prediabetes ) is defined as 1.A fasting plasma glucose between 100 and 125 mg/dl

2.2 hour plasma glucose between 140 and 199 mg/dl following a 75 mg of glucose OGTT( oral glucose tolerance test) and /or

3.A glycated hemoglobin (Hb A1c ) level between 5.7% and 6.4%.

Transient hyperglycemia is found to occur in acute stress conditions like severe infections, burns or trauma, which may be due to catecholamines and cortisol secretions that has the opposite action of insulin³¹. Diabetes mellitus is a metabolic disorder characterized by the presence of

chronic hyperglycemia and associated with the impairment in the metabolism of carbohydrates,lipids and proteins. Egyptian manuscript which was about 3000 years old was the first literature to document diabetes³².In general, diabetes is classified into two broad classes-

Type-1 Diabetes- by an immune mediated or idiopathic

Type-2 Diabetes- by a combination of peripheral resistance to insulin action and an inadequate secretory response by beta cells of pancreas.

Among the two, occurrence of Type 2 diabetes mellitus usually is a consequence of interaction between genetic, environmental and behavioral risk factors and is also associated with gestational environment variations, certain drugs, genetic defects and infections.

CLASSIFICATION OF DIABETES MELLITUS³³

1. Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency)

Immune-mediated Idiopathic

2. Type 2 diabetes (combination of insulin resistance and β-cell dysfunction)

3. Genetic defects of β-cell function

Maturity-onset diabetes of the young (MODY), caused by mutations in:

Hepatocyte nuclear factor 4α (HNF4A) in MODY1 Glucokinase (GCK) in MODY2

Hepatocyte nuclear factor 1α (HNF1A) in MODY3

Pancreatic and duodenal homeobox 1 (PDX1) in MODY4 Hepatocyte nuclear factor 1β (HNF1B) in MODY5

Neurogenic differentiation factor 1 (NEUROD1) in MODY6

Neonatal diabetes (activating mutations in KCNJ11 and ABCC8, encoding Kir6.2 and SUR1, respectively)

Maternally inherited diabetes and deafness (MIDD) due to mitochondrial DNA mutations (m.3243A➙G)

Defects in proinsulin conversion Insulin gene mutations

4. Genetic defects in insulin action

Type A insulin resistance

Lipoatrophic diabetes, including mutations in PPARG (Peroxisome proliferator activated receptor gene)

5. Exocrine pancreatic defects

Chronic pancreatitis Pancreatectomy/trauma Neoplasia

Cystic fibrosis

Hemachromatosis

Fibrocalculouspancreatopathy 6. Endocrinopathies

Acromegaly

Cushing syndrome Hyperthyroidism Pheochromocytoma Glucagonoma 7. Infections

Cytomegalovirus Coxsackie B virus Congenital rubella 8. Drugs

Glucocorticoids Thyroid hormone Interferon-α

Protease inhibitors β-adrenergic agonists Thiazides

Nicotinic acid

Phenytoin (Dilantin) Vacor

9. Genetic syndromes associated with diabetes

Down’s syndrome Kleinfelter’s syndrome Turner’s syndrome Prader-Willi syndrome

10. Gestational diabetes mellitus

EPIDEMIOLOGY

There has been a dramatic raise in the prevalence of diabetes throughout the world. It is found that there are 346 million diabetic individuals approximately across the globe of which 90% are having type 2 DM³⁴. There has been an uproar of type 2 DM cases in the recent era among various countries with India and China topping the chart becoming the leading world’s diabetic load contributors³⁵. Diabetic epidemic mostly indicating the increasing simultaneous occurrence of diabetes and obesity may be contributed to the alarming raise in the sedentary life and unhygienic eating habits³⁶.

PATHOGENESIS OF TYPE 2 DIABETES MELLITUS

Genetic factors:

Genetic factors play an important role, which is further strengthened by the fact that > 90% disease concordance in monozygotic twins. Even in the absence of family history, first degree relatives are found to have five to ten fold increase in disease incidence³⁷.

Environmental factors:

More than 80% of the individuals having type 2 diabetes mellitus are obese, with sedentary life style being another risk factor.

Metabolic defects :

The main cardinal features are as follows:

1.Insulin Resistance 2.Beta- cell dysfunction

▶Insulin resistance which is decreased response to insulin by target organs like muscle, fat and liver leads to early development of hyperglycemia which is mostly accompanied by compensatory beta cell hyper function and hyperinsulinemia.

▶inadequate insulin secretion mostly due to insulin resistance and hyperglycemia (beta-cell dysfunction)³⁸.

Insulin resistance:

This is reflected by reduction in skeletal muscle glucose uptake, fall in both hepatic glycolysis and fatty acid oxidation. The main reason for this resistance

is found to be defects in the insulin signaling pathway, which is implicated mainly to reduced tyrosine phosphorylation of insulin receptor and IRS proteins in peripheral tissues, thereby reducing cell surface glucose transporter named GLUT-4.³⁹

Free fatty acids :

A rise in Body mass index(BMI) is found to rise the risk of Diabetes. In obese, the free fatty acid levels in muscle and liver are markedly higher, resulting in increased fatty acid oxidation and leading to toxic intermediates like ceramide and diacylglycerol to be accumulated. These free fatty acids also compete with glucose for substrate oxidation, producing glycolysis feedback inhibition.

Adipokines:

One of the prime source of cytokine is fat. The cytokines formed by them include those that are proglycemic such as resisting and retinol binding protein 4 and antiglycemic such as leptin and adiponectin. The latter by enhancing AMP activated proteinkinase activity aids in improvement of the tissue insulin

sensitivity and thus promoting fatty acid oxidation⁴⁰.

Inflammation:

Excess free fatty acid within the macrophages and beta cell can activate Inflammasomes multiprotein cytoplasmic complexes that generate interleukinIL- 1β .IL-1β then mediates the production of additional proinflammatory cytokines that are released into the circulation and promote insulin resistance.⁴¹

β – CELL DYSFUNCTION :

In diabetes mellitus at early stages compensatory mechanism to counter the insulin resistance by raising the beta cell function occurs in order to maintain euglycemia. Yet, the raised function becomes exhausted making the patient attain a state of relative insulin deficiency. The main features of β-cell function entails excess free fatty acid oxidation and chronic hyperglycemia. Incretin effect is also brought about by low GIP and GLP-1 secretion along with reduced insulin secretion. Approximately in more than 90% diabetics, islets are found to have amyloid deposition, but there is no study existing to state if at all it is a cause for β- cell dysfunction⁴².

COMPLICATIONS OF DIABETES MELLITUS

ACUTE COMPLICATIONS 1. Hypoglycemia

2. Hyperglycemic crises such as

▶Diabetic ketoacidosis

▶Hyperglycemic hyperosmolar state CHRONIC COMPLICATIONS

MICROVASCULAR COMPLICATIONS

1. Diabetic nephropathy 2. Diabetic neuropathy 3. Diabetic retinopathy

MACROVASCULAR COMPLICATIONS

1. Impaired growth and development

2. Associated with other Auto immune disorders 3. Lipodystrophy

Non Alcoholic fatty liver disease

In case of long standing diabetes, multiple serious complication leads to onset of major morbidities. The main step of intiation of morbidity is mainly by occurrence lesions involving both large and medium-sized muscular arteries (macrovascular disease) and capillary dysfunction in target organs (microvascular disease).

In the diabetic population, macrovascular disease causes accelerated atherosclerosis, eventually leading to an increased risk of myocardial infarction, stroke and lower extremity gangrene. The organs most commonly affected in microvascular disease are the retina, kidneys, and peripheral nerves, which on disease progression becomes diabetic retinopathy, nephropathy, and neuropathy respectively.

In the world the overall majority of morbidity and mortality is found to be due to long-term effects of diabetes. In most of the cases, these complications begin approximately 15 to 20 years after the onset of hyperglycemia.

Macrovascular complications like myocardial infarction, renal vascular insufficiency, and cerebrovascular accidents are the major causes of mortality in long-standing diabetes. Diabetics have 2-4 times higher incidence of coronary

complications than nondiabetics. Diabetes is often accompanied by multiple underlying factors that favor the development of adverse cardiovascular events⁴³. CARDIAC CHANGES IN TYPE 2 DIABETES MELLITUS:

Diabetes mellitus(DM)and coronary artery disease(CAD) have common risk factors such as obesity ,physical inactivity ,dyslipidemia ,age and hypertension⁴⁴. Thus DM presence indicates the risk of future CAD⁴⁵.Currently the leading cause of mortality world wide is cardiovascular diseases (CVD),which includes both CAD and cerebrovascular diseases ,this accounts for about 21.9% of total deaths and are projected to rise to 26.3% by 2030⁴⁶ . The risk for developing coronary disease is two to four fold higher in patients with diabetes. Patient with diabetes have CAD which is more severe ,more complex and with higher complication rate than in patients without diabetes⁴⁷.Until onset of myocardial infarction or sudden cardiac death ⁴⁸,CAD remains asymptomatic in diabetic patients .As opposed to to non diabetics ,the incidence of CAD is reported to occur 2-3 decades earlier.

Women with diabetes are more likely to develop CAD than men with diabetes⁴⁹. The key feature of Type 2 Diabetes Mellitus is relative insulin deficiency such that there is insufficient insulin production to overcome the resistance to insulin action ,which inturn is contrast to type 1 Diabetes Mellitus in which there is

rapid loss of insulin production and absolute deficiency resulting in ketoacidosis and death ,if insulinis not replaced.

In India ,now-a-days with incresing urbanistion ,literacy levels , immunisation schemes and financial security, there is a rise in the incidence of non communicablle diseases (NCB) like hypertension, DM, CAD etc.The leading cause of mortality among NCB is cardivascular disease .CVD’s are found to be the rapidly increasing chronic illness rising at the rate of 9.2% annually . Developing nations are expected to borne 85% of global CVD burden, along with the raised CAD mortality compared with the past decade ⁵⁰. Based on the Global Burden of Disease Study ,India is at the risk of bearing the greatest CAD burden among the developing countries. The overall mortality due to CVD is estimated to rise by 103 % in men and 90% in women in the last twenty years.

Researches conducted proved that development of premature artherosclerosis arefound to be higher among Asian-Indian diabetics than their non diabetic counterpart.Prevalence of insulin resistance , hyperinsulinemia and other components of metabolic syndrome are increased among Asian – Indians. In India ,general population is known to have very low High Density Lipoproteins (HDL) – Cholestrol levels ,resulting raise in the ratios of total cholestrol ,High Density Lipoproteins – Cholestrol (HDL) and Low Density Lipoproteins – Cholestrol

South Indians, it was evident that small dense LDL levels were higher in diabetic patients .

The pathologic changes in diabetic patients are much similar to those in non diabetic subjects ,but the difference and remarkable feature is these pathologic changes occur at an early age and are more extensive and severe in diabetics.The histopathological hallmark of diabetic microangiopathy is thickening of capillary basement membrane which is mostly associated with increased vascular permeability which occurs throughout body and there is occurrence of accelerated artherosclerosis which is identified to result from the local response to generalised vascular injury . For example, increased permeability of arterial endothelium, especially when combined with other risk factors like hyperinsulinemia and hypertension , this may lead to increased deposition of atherogenic lipoproteins .

The major macrovascular complication of Diabetes Mellitus is Coronary Artery Disease which is also with a higher mortality rate. Based on gender, the Relative Risk of occurrence of CAD for women with diabetes is higher than non- diabetic and the death due to CVD is thrice higher in male diabetics

DM is major and independent cardiac risk factor for CAD.Diabetics are two times more prone to have a stroke or heart attack and will die 5-10 yrs before the non diabetics.Excess mortality in diabetes is caused by large blood vessel ,

particularly MI and stroke . Macrovascular disease also cause substantial morbidity from MI ,stroke, angina ,cardiac failure and intermittent claudication. In diabetes , CAD has a multifactorial pathogenesis with a number of traditional risk factors like age ,gender, smoking, increased LDL-C and decreased HDL-C,including diabetes itself . In all asymptomatic adults without any clinical history of Coronary heart disease(CHD) , Framingham risk score (FRS) use the above mentioned traditional risk factor for risk assessment.⁵¹Based on the Framingham risk score major CHD events are predicted well in different demographic and ethnic groups .One of the major independent and modifiable risk factor for CAD is Hyperglycemia.⁵²In case of any abnormality hindering glucose metabolism , there is an increase in the risk of CVD.As shown by United Kingdom ProspectiveDiabetes Study (UKPDS) ,for every 1% HbA1C reduction the occurrence of CV events decreases by 14-16%.⁵³ Compared to non-diabetic population , The clustering of risk factors like hypertension , dyslipidemia , obesity and summation of these factors ,causes a steeper rise in the mortality in diabetics population .

Blood Pressure

The progressive and continuous correlation between both systolic and diastolic blood pressure and the risk of coronary vascular disease death in

increase in heart failure and a 17% increase in diabetic related death , in those with even a 10 mm rise in systolic blood pressure (SBP).⁵⁵Also , another study shows Cardio vascular mortality reduces by 18% in those with reduction of SBP by 5.6 mmHg.⁵⁶

Dyslipidemia

In diabetics , dyslipidemia has characteristics features of high triglyceride (TG) concentrations and low HDL-C concentrations. Like BP , LDL-C is also progressive and continuous risk factor for CV in diabetic groups.⁵⁷Basic pathologic changes in diabetic people producing qualitative changes in lipid profile, is an increase in the rate of glycosylation of apolipoprotein B which in turn lead to increased in corporation of LDL-C into macrophages and also these small dense LDL particles facilitate oxidation and accumulation in blood vessels.The relationship between low HDL-C and high TG level also showed similar relationship .Even at a relatively low range of cholestrol values , there is a positive association between LDL-C and CV risk . The risk of cardio vascular events reduces on lowering LDL-C.⁵⁸

Metabolic Syndrome as Risk Factor

Metabolic syndrome’s presence often results in increased risk of CV events and

features like dyslipidemia ,hypertension , abdominal obesity and insulin resistance .An increased risk for both CVD and T2DM in both genders is associated with this syndrome.⁶⁰

Albuminuria

An analysis of data from Heart Outcomes Prevention Evaluation (HOPE) study indicated that for CV events and for heart failure , most important and independant risk factor is albuminuria .An even a higher relative risk for many cardiovascular events have been documented based on studies conducted on macroalbuminuria .

C-Reactive Protein

In artherosclerosis at any stage , inflammation has a main role , which is proved by associations found between inflammatory lipids ,cytokines markers and CAD risk .In Indian Artherosclerosis Research Study conducted among subjects suffered by CAD ,who were further affected by a repeat corornary event in whom the levels of high sensitivity C-Reactive protein (hsCRP) is found higher ,comparing with those who remained as disease free subjects and also in the top quartile of hsCRP showed that about a four fold higher risk is documented when CRP is used as marker for predicting upcoming coronary events .⁶¹ In addition to

this, prediction of premature CAD in young adults is by identifying elevated hsCRP along with dyslipidemia and oxidative stress.⁶²

Clinical Features

The rate of CV mortality is more than four –fold greater in diabetic women and more than two fold greater in diabetic men .Mostly in Asian Indians , there is ocurrence of CAD prematurely , as early at the age of 10-20 yrs compared to other nations .This premature ocurrence seen among Asian Indian cannot be briefed by the routine group of traditional risk factors for CAD -namely , obesity , high cholestrol , smoking and hypertension . Those stable patients with T2DM associated with CAD, do not often present with symptoms of typical angina clinically .In non-diabetics ,more often abesent or atypical (shortness of breath)symptoms are found .Many studies shows that in the presence of myocardial ischemia, angina is reported less frequently in dibetics and the only symptom found may be shortness of breath .This high prevalence of CAD mentioned above has been suggested due to autonomic neuropathy caused by diabetes.The decreased recognition for ischemic pain,impairs the appreciation of myocardial infarction or ischemia during its important golden hour of ischemia ,this leads to delay in appropriate therapy .

Mostly,in diabetis clinical manifestations of autonomic dysfunction and other microvascular complications frequently occur in an inconsistent patterns. The appreciation of angina was severly impaired in diabetic patients ,making the patients to exercise much longer even after the onset of myocardial ischemia even during exercise testing.But the presence of cardiac autonomic neuropathy will not exculde painful MI in diabetic population .So chest pain at any site in diabetics must be recognised as of myocardial origin until proven otherwise . The clinicians must recognise the possibility of silent MI in those with features of unexplained fatigue , confusion , tiredness, edema , hemoptysis,nausea, diaphoresis, cough, dyspnea or arrythmias .

SCREENING AND INVESTIGATIONS

The risk of MI is four to six fold higher in diabetic people.In T2DM approximately 65% of them will die from CV events , mostly from sudden death . The diagnosis of MI is most commonly delyaed or sometimes missed , because the typical features of CV events are often masked in diabetic groups. So in order to reduce the morbidity and mortality among diabetic subjects, multiple effective strategies aiding in earlier detection of clinical CVD is necessary .

Most commonly clinicians use the following advanced techniques like stress electrocardiogram, exercise electrocardiogram,Coronary Calcium scoring (CCS),

myocardial perfusion (MP), single photo emissin computed tomography (SPECT) imaging to identify silent ischemia . Among these investigations , exercise tolerence test with ECG is widely availabe with minimal expense and it is an important investigation in evaluation of CVD. It provides prognostic information in T2DM people where electrocardiography combined with pharmacological stress helps in detecting silent CAD rather than getting complicated with challenge of exercise.⁶³

To improve the yield in screening tests ,the test must be conducted on those who are at higher risk and the method of identifying the higher risk patients who need testing for CV events must be done with more needed insight. It is also discouraged to do routine screening for CAD in asymptomatic diabetic patients. So screening with radionucleotide imaging is useful only in asymptomatic diabetic patients with very high risk of CHD .

In this new era of emerging data , multiple circulating markers like hsCRP , high –sensitivity Troponin T (hsTroponin T) and lipoprotein (Lp a) help in identifying artherosclerosis pathogenesis and may ultimately improve the utility of risk engines in high risk candidates for further testing .⁶⁵

MANAGEMENT OF CORONARY ARTERY DISEASE IN DIABETES

In diabetes , management of CAD must be done carefully taking into consideration the rate of medication along with revascularisation .Diabetic drugs play a critical role in medical management in patients with CAD along with T2DM.

Coronary Artery Bypass Graft (CABG) fared better in terms of major CV event outcomes and reduces 1 year of repeat revascularisation ,in diabetic population . Further upcoming revascularisation evaluation in T2DM patients , the main management of multivessel disease trial found PCI to be much inferior to CABG in case of advanced CAD.⁶⁶The next achievements was the development of drug eluting stents (DES)which highly reduced restenosis rates.

CORONARY ARTERY BYPASS GRAFT OUTCOMES

Internal mammary artery (IMA) offers much raised long term patency and is much preferred in dibetes ,rather than using reversed saphenous veins .Because of risk of sternal wound infection,bilateral IMA should be avoided .There is also increased perioperative risk of stroke with odds ratio (OR)1.4 and 95% confidence interval (CI) 1.2-1.8 .⁶⁷ Thus PCI may be better in these diabetic subjects with multivessel disease.

Screening Asymptomatic Patients with Diabetes for CAD

Nuclear cardiac stress imaging protocol helps in identifying patients with increased likelihood of CAD based on Detection of Ischemia in Asymptomatic Diabetes (DIAD) study .However, the medical therapy has better than usual implementation of protocol and screening arm has low rate of ischemic detection . APPROACH

The foremost step in management includes aggressive control of risk factors of CAD . A high index of suspician must be maintained,as CAD presents with atypical symptoms, because of which threshold for subjecting these patients to stress testing should be low .Coronary Angiography should be advised, if moderate or high risk of ischemia found in the stress test. ECG is a simple and immediately availabile, noninvasive, inexpensive, and highly versatile routinely done investigation to detect many cardiac abnormalities.

ELECTROCARDIOGRAPHY (ECG)

Introduction:

Electrocardiogram (ECG or EKG) is a graphic recording of electric otentials generated by the heart⁶⁸. Metal electrodes attached to chest wall and extremities

electrocardiograph. These ECG leads in general project the instantaneous differencesin potential between the electrodes

Clinical uses of ECG:

It detects multiple cardiac abnormality like Arrhythmias, conduction disturbances, Myocardial ischemia(MI), metabolic disturbances (e.g., hyperkalemia),increased susceptibility to sudden cardiac death (e.g., QT prolongation syndromes).

Electrophysiology:

In cardiac contraction, the initial event is depolarization of the heart. The electric current spreading through the heart are produced by 3major components:

cardiac pacemaker cells, specialized conduction tissue, and the heart muscle itself.

The depolarization (stimulation) and repolarization (recovery) potentials generated by the atrial and ventricular myocardium, are the only signals recorded by the ECG.

Sinoatrial(SA) node or sinus node having a collection of pacemaker cells, is the site of origin of the depolarization stimulus for the normal heartbeat. These cells exhibit automaticity; that is, they fire spontaneously. The spread of

contraction is denoted as the first phase of cardiac electrical. Further down, these impulse stimulates pacemaker and specialized conduction tissues found in the atrioventricular (AV) nodal and His-bundle areas; which by together constitute the AV junction. Two main branches namely the right and left bundles formed by the bundle of His bifurcation, rapidly transmit depolarization wave to the right and left ventricular myocardium through the Purkinje fibers. Further, the left bundle divides into two subdivisions: a left anterior fascicle and a left posterior fascicle with the help of which the depolarization wave spread in the entire ventricular wall, from endocardium to epicardium, leading to trigger of ventricular contraction

NORMAL ECG

In general population ,the QRS-T waveforms corresponds with the different phases of simultaneously obtained ventricular action potentials.

The rapid upstroke (phase 0) --corresponds to the onset of QRS The plateau (phase 2)-- corresponds to the isoelectric ST segment Active repolarization (phase 3) --corresponds to the inscription of the T wave

Impairment in Na⁺ influx (e.g., hyperkalemia and drugs such as flecainide) causes decrease in the slope of phase 0 causes prolongation of QRS duration. Factors that prolong phase 2 (amiodarone, hypocalcemia) increase the QT interval. In contrast, shortening of ventricular repolarization (phase 2), such as by digitalis administration or hypercalcemia, minimizing of the ST segment.

The ECG is recorded on a special graph paper which is divided into 1- mm²gridlike squares. The ECG paper speed is set as 25 mm/s routinely, making the smallest (1 mm) horizontal divisions correspond to 0.04 (40 ms), with heavier lines at intervals of 0.20 s (200 ms). The amplitude of a specific wave or deflection is measured vertically in the graph (1 mV = 10 mm with standard calibration).

There are 4 major intervals in the ECG :R-R, PR, QRS and QT. The heart rate (beats per minute) can be computed readily from the R-R interval by dividing the number of large (0.20 s) time units between consecutive R waves into 300 or the number of small (0.04 s) units into 1500. PR interval measures the time (normally 120–200 ms) between atrial and ventricular depolarization, which notes the physiologic delay due to stimulation of cells in the AV junction area. The QRS

interval (normally 100–110 ms or less) reflects the duration of ventricular depolarization. QT interval includes both ventricular depolarization and repolarization times and varies inversely with the heart rate. A corrected QT interval, QTc, can be obtained using Bazett’s formula which is,

QTc = QT/√(R − R)interval

The normal QTc interval is 0.44 s. Some studies give QTcupper normal limits as 0.43 s in men and 0.45 s in women. Also, a number of different formulas have been developed for calculating the QTc.

Image of long QT interval

CAUSES OF QTC PROLONGATION⁶⁹:

Congenital

Congenital long QT syndromes like

Jervell-lange-neilson syndrome Romano-Ward syndrome

Anti arrythmic drugs Procainamide Disopyramide Amiodarone

Sotalal

Electrolyte disturbances Hypokalemia

Hypomagnesaemia Hypocalcaemia

Others

Myocardial Ischaemia Post cardiac arrest Raised intracranial pressure

Hypothermia Causes of

prolonged QT interval

STATISTICAL ANALYSIS

RESULTS

TABLE 1: AGE DISTRIBUTION OF STUDY GROUP

Age in years Frequency Percent (%)

31-40 7 7.0

41-50 36 36.0

51-60 57 57.0

Total 100 100.0

Table 1 shows the age distribution of the study group. The number of study group in age group was 31-40 years 7(7%), 41-50 years 36(36%), 51-60 years 57(57%) respectively.

TABLE 2: MEAN AGE OF THE STUDY GROUP

N Minimum(yrs) Maximum(yrs) Mean±SD

AGE 100 32 60 50.71±5.5

Table 2 shows mean age of the study group. Maximum age in the study group was 60 years and minimum age with group was 32 years. Mean and SD of the age was 50.71±5.5 in the study.

TABLE 3: GENDER DISTRIBUTION OF THE STUDY GROUP

Gender Frequency Percent (%)

Male 38 38.0

Female 62 62.0

Total 100 100.0

Table 3 shows the gender distribution of the study. The numbers of males in the study group were 38(38%) and females were 62(62%).

0 10 20 30 40 50 60 70

Male Female

38

62

Gender distribution

TABLE 4: DISTRIBUTION OF THE DURATION OF DIABETES IN THE STUDY GROUP

Duration of diabetes Frequency Percent

<6 YEARS 35 35.0

>7 YEARS 65 65.0

Total 100 100.0

Table 4 shows the duration of diabetes of the study group. The number of participants in the study group with duration <6 years were 35(35%) and >35 years were 65(65%).

0 10 20 30 40 50 60 70

<6 years >7 years 35

65

Duration of diabetes

TABLE5:MEAN DURATION OF DIABETES OF THE STUDY GROUP

N Minimum Maximum Mean±SD

Duration of DM 100 4 23 8.50 ± 3.474

Table 5 shows mean duration of the study group. Maximum duration in the group was 4 years and minimum duration with group was 23 years. Mean and SD of the age was 8.50 ± 3.474 in the study group.

TABLE 6: ASSOCIATION OF RR INTERVAL (SEC) WITH FBS OF THE STUDY GROUP

RR interval(sec) N Mean Std. Deviation P VALUE

FBS

<126 67 .79 .08

>127 33 .77 .08 .249

Table 6 shows Association of RR interval (sec) with FBS in the study. In patients with FBS <126 mean RR interval was .79±.08 and with FBS >126 mean RR interval was .77±.08 and the

association was not statistically significant (P>0.05) using Independent ‘t’test.

0.76 0.765 0.77 0.775 0.78 0.785 0.79

<126 >126

0.79

0.77

RR interval(sec) with FBS

TABLE 7: ASSOCIATION OF RR INTERVAL (SEC) WITH PPBS OF THE STUDY GROUP

RR interval(sec) N Mean Std. Deviation P VALUE

PPBS

<140 22 .780 .08

>141 78 .786 .08 .785

Table 7 shows Association of RR interval (sec) with PPBS in the study. In patients with PPBS

<140 mean RR interval was .78±.08 and with PPBS >141 mean RR interval was .78±.08 and the association was not statistically significant (P>0.05) using Independent ‘t’test.

0.776 0.778 0.78 0.782 0.784 0.786

<140 >140

0.78

0.786

RR interval(sec) with PPBS

TABLE 8: ASSOCIATION OF RR INTERVAL (SEC) WITH HBA1C OF THE STUDY GROUP

RR interval(sec) N Mean Std. Deviation P VALUE

HBA1C

<6.4 66 .785 .08

>6.5 34 .786 .08 .994

Table 8 shows Association of RR interval (sec) with HBA1C in the study. In patients with HBA1C <6.4 mean RR interval was .785±.08 and with HBA1C >6.5 mean RR interval was .786±.08 and the association was not statistically significant (P>0.05) using Independent ‘t’test.

0.7844 0.7846 0.7848 0.785 0.7852 0.7854 0.7856 0.7858 0.786

<6.4 >6.5

0.785

0.786

RR interval(sec) with HBA1C