ࡱ> [ DAbjbj 8ΐΐD9    t \;QQQQ000>\@\@\@\@\@\@\[^`j@\,0@\QQU\P%P%P%QQ>\P%>\P%P%2SXQKd{ #*U.*\k\0\XUga$:ga\XgaX0nP%ZdP000@\@\%4000\ga000000000 : RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA ANNEXURE II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION 1.NAME OF THE CANDIDATE AND ADDRESS (in block letters)Dr. RAHIMTAJ BASARIKATTI POST GRADUATE STUDENT, DEPARTMENT OF BIOCHEMISTRY, J.J.M. MEDICAL COLLEGE, DAVANGERE 577004, KARNATAKA.2.NAME OF THE INSTITUTIONJ.J.M. MEDICAL COLLEGE, DAVANGERE- 577004.3.COURSE OF STUDY AND SUBJECTM.D. BIOCHEMISTRY4.DATE OF ADMISSION TO COURSE26-07-2010 5. TITLE OF THE TOPICRELATIONSHIP BETWEEN INSULIN RESISTANCE AND HYPOTHYROIDISM 6.  BRIEF RESUME OF THE INTENDED WORK : 6.1 Need for the study : Hypothyroidism is defined as a deficiency of thyroid activity. It results from reduced secretion either of total thyroxine(T4) and triiodothyronine(T3).Decreased T4 and T3 concentrations lead to hypersecretion of pituitary thyroid stimulating hormone(TSH) and an amplified increase in serum TSH levels. Subclinical hypothyroidism is term used for a condition in which there is elevation in TSH, yet normal circulating levels of thyroid hormones.1 Hypothyroidism affects over 1% of general population and 5%of individual over age of 60 years.2 In Colorado study 9.5% of participants were hypothyroid, most of whom were subclinically hypothyroid vary according to age and sex,4% in 18-24 years old,16-22% in men and women over age of 74 not taking L-thyroxine respectively.3 Clinical and subclinical hypothyroidism are established risk for insulin resistance, hyperlipidemia, hypercoagulability and low grade inflammation4 .Insulin-stimulated glucose transport in monocyte from patients with clinical and subclinical hypothyroidism was found to be decreased due to impaired translocation of GLUT4 glucose transports on the plasma membrane. T3 and insulin have synergistic role in glucose homeostasis since these hormones possess similar action sites in the regulation of glucose metabolism both at cellular and molecular levels. Decreased T3 could lead to impaired insulin stimulated glucose disposal. Even subtle decrease in the levels of thyroid hormones within the physiological range have shown to correlate inversely with HOMA index(homeostasis model assessment).Insulin resistance is observed in both fasting and post glucose state. These findings are consistent with the recent studies reporting an increased cardiovascular risk in these conditions.5 Insulin resistance is due to defect in the ability of insulin to increase glucose utilization in peripheral tissue, mainly muscles.6 Insulin resistance leads to an increased production of hepatic cholesterol.4Patients with mild thyroid failure and even subjects with high normal serum TSH value have evidence of comparable atherogenic factors and high serum cholesterol.5 The body mass index(BMI) of subjects both in clinical and Subclinical hypothyroidism were significantly more than in euthyroid controls.4 According to studies correlation between TSH and insulin as well as TSH and HOMA-IR in female population suffering from both clinical and subclinical hypothyroidism is found. TSH and HOMA-IR showed significant correlation with total cholesterol in clinical hypothyroidism. Development of insulin resistance leads to many of metabolic abnormalities.4 This study is undertaken to evaluate relationship between fasting glucose, fasting insulin, insulin resistance, BMI and total cholesterol levels in hypothyroidism. 6. 2 Review of literature : Studies have shown that patients with subclinical hypothyroidism having insulin resistance is comparable with clinical hypothyroidism. This findings could justify increased risk for insulin resistance associated disorders cardiovascular disorders as observed in these patients.5 Studies have shown that despite increase in plasma insulin level in hypothyroidism net glucose uptake in forearm muscles and adipose tissue was increased after meals suggesting the presence of insulin resistance.6 Studies have shown that elevated TSH levels were associated with deleterious effects on serum lipids in large population based sample of older women.7 Studies have shown that subclinical hypothyroidism in about one sixth of metabolic syndrome patients8 Studies have shown that subclinical hypothyroidism is highly prevalent among elderly women and is associated with a greater frequency of aortic atherosclerosis and myocardial infarction.9 Studies have shown that glucose metabolism in human is dependent on thyroid status. Hypothyroidism induced post-absorptive decrease in both glucose disposal and endogenous glucose appearance impaired the ability of insulin to stimulate glucose disposal related to insulineamia10 6.3 Objectives of the study : To study the levels of serum T3,T4,TSH and to evaluate the relationship between fasting glucose ,fasting insulin, insulin resistance(HOMA-IR), BMI and total cholesterol levels in clinical and subclinical hypothyroidism patients.  MATERIALS AND METHODS 7.1.Materials and methods Source of data The study will be carried out for a period of one year in Bapuji Hospital and Chigateri General Hospital Davangere(Both hospitals are attached to J.J.M.medical college) The study will be carried out in clinically proven cases of hypothyroidism after taking informed consent. 30 clinical hypothyroidism, 30 subclinical hypothyroidism patients and 30 age and sex matched euthyroid healthy individuals as controls will be selected based on inclusion and exclusion criteria. Inclusion Criteria Cases-newly diagnosed, clinically proved cases of hypothyroidism in the age group of 18-70 years. Patients with signs and symptoms of goiter and myxedema. Clinical hypothyroidism patients with (increased serum TSH and decreased T3 and T4 levels) Subclinical hypothyroidism patients with((increased serum TSH and normal T3 and T4 levels) Controls-will include healthy euthyroid age and sex matched individuals without any major illness and not on any medications. Exclusion Criteria Diabetes, hypertension. Patients on thyroxine treatment, hypolipidemics, anti epileptic drugs, women on oral contraceptives. Pregnant women, previous thyroid surgeries, and other systemic illness like liver disorders and kidney disorders. 7.2 Method of data collection: Under all aseptic precautions about 4ml of venous blood will be collected in a sterile bulb after overnight fasting of 12 hours. 2ml will be collected in EDTA vial(for plasma) 2 ml will be collected in plain vial (for serum),it will be subjected for centrifugation , serum and plasma will be separated and T3,T4,TSH, insulin, and cholesterol will be estimated from serum and fasting glucose from plasma . (a)Estimation of serum T3,T4,andTSH by immunoenzymometric assay(chemiluminescence immunoassay).11 Principle: In this procedure, the immobilization takes place during the assay at the surface of a microplate well through the interaction of streptavidin coated on the well and exogenously added biotinylated monoclonal antibody coupled to anylate of interest. Upon mixing monoclonal biotinylated antibody, the enzyme-labeled antibody and a serum containing the native antigen, reaction results between the native antigen and the antibodies, without competition or steric hindrance, to form a soluble sandwich complex. Simultaneously, the complex is deposited to the well through the high affinity reaction of streptavidin and biotinylated antibody. After equilibrium is attained, the antibody-bound fraction is separated from unbound antigen by washing or aspiration. The enzyme activity, determined by the reaction with substrate that generates light in the antibody-bound fraction is directly proportional to the native antigen concentration. (b) Estimation of serum fasting insulin by solid phase two-site enzyme immunoassay12 Principle: In this procedure, the immobilization takes place during the assay at the surface of a microplate well through the interaction of streptavidin coated on the well and exogenously added biotinylated monoclonal insulin antibody. Upon mixing monoclonal biotinylated antibody, the enzyme-labeled antibody and a serum containing the native antigen, reaction results between the native antigen and the antibodies, without competition or steric hindrance, to form a soluble sandwich complex. Simultaneously, the complex is deposited to the well through the high affinity reaction of streptavidin and biotinylated antibody. After equilibrium is attained, the antibody-bound fraction is separated from unbound antigen by washing or aspiration. The enzyme activity determined by the reaction with substrate that generates light, in the antibody-bound fraction is directly proportional to the native antigen concentration. (c) Estimation of fasting plasma glucose by Glucose oxidase-peroxidase method12 Principle: Glucose oxidase enzyme oxidizes glucose to gluconic acid and hydrogen peroxide. The colorimetric indicator, quinonemine is generated from 4-aminoantipyrine and phenol by hydrogen peroxide under catalytic action of peroxidase. Intensity of colour generated is directly proportional to glucose concentration. (d) Calculation of insulin resistance by HOMA & HOMA2 model13 Formula: HOMA-IR = [ fasting plasma glucose(mmol/l) x fasting insulin(mU/l) ] / 22.5 HOMA2 is the updated computer model of HOMA which is available from  HYPERLINK "http://www.ocdem.ox.ac.uk" www.ocdem.ox.ac.uk. (e) Estimation of total cholesterol by cholesterol oxidase/phenol aminoantipyrine method 14 Principle: Cholesterol esterase hydrolyses cholesterol esters to free cholesterol and fatty acids. Then cholesterol is oxidized by cholesterol oxidase forming cholesterol-4-ene-3-one and hydrogen peroxide. In presence of enzyme peroxidase, hydrogen peroxide causes oxidative coupling of phenol and antipyrine to form red colored quinoneimine dye which is measured at 520nm. (f) Calculation of body mass index(BMI)15 Formula: BMI=weight in kgs/(height in meter)2 STATISTICAL ANALYSIS : Statistical analysis: One way ANOVA will be used for multiple groups comparison and student t test for group wise comparison. Correlation analysis will be done to assess any relationship between insulin resistance, serum cholesterol, and BMI with hypothyroidism . 7.3 Does the study require any investigations or interventions to be conducted on patients or other human or animals? if so, please describe briefly Yes Estimation of serum T3, T4,TSH, fasting glucose, fasting insulin, total cholesterol and BMI in hypothyroidism patients and normal euthyroid individuals using human venous blood sample. 7.4 Has ethical clearance been obtained from your institution in case of 7.3 Yes 8.LIST OF REFERENCES: 1.Reza A,Mansourian, Ezatollah et al.Serum lipid level alteration in subclinical hypothyroid patients in Gorgan(South East of Caspian Sea).Journal of Chinese Clinical Medicine;2008,4 Vol 3 No.4 2.Fitzgerald AP.Endocrine disorders.In:Mcphee JS, Papadakis, Laurance M,Tierney Jr.editors.Current Medical Diagnosis and Treatment.47th eds.LANGE CMDT 2008;p 960 Canaris JG, Monowitz RN, and Ridgway CE.The Colorado Thyroid Disease Prevalence Study.Arch Internal Med.2000;160:526-534. B M Singh,B Gowswami and Mallika.Association between insulin resistance and hypothyroidism in females attending a tertiary care hospital.Indian Journal of clinical Biochemistry 2010;25(2):141-145 Maratou E, Hadjidakis JD, Kollias A et al.Studies of insulin resistance in patients with clinical and subclinical hypothyroidism. European Journal of Endocrinology.2009;160.785-790. Dimitriadis G,Mitrou P,Lambadiari V et al. Insulin action in adipose tissue and muscle in hypothyroidism.J Clinical Endocrinol metab 2006;92:4930-4937. Bauer CD, Ettinger Band Browner SW.Thyroid functions and serum lipids in older women:A Papulation based study. The American Journal of Medicine.1998;104:546-551. Uzunlulu M, Yorulmz E and Ogus A.Prevalence of subclinical hypothyroidism in patients with metabolic syndrome. Endocrine Journal.2007;54:71-76 Hak AE, Pouls HAP, Visser JT et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: Rottendam study. Annals of Internal Medicine.Society2000;132:270-278. Rochon C, Tauveron I, Dejax C et al. Response of glucose disposal to hyper insulineamia in human hypothyroidism and hyperthyroidism. The biochemical society and medical research society 2003;1047:7-15 Demers LM and Spencer C.The Thyroid, pathophysiology and thyroid function testing.In:Burtis CA, Ashwood ER and Bruns DE,eds.Tietz textbook of clinical chemistry and molecular diagnostics,4th edn. New Delhi:Elsiever Co,2006;2053-2095 David B Sacks.Carbohydrates. In:Burtis CA, Ashwood ER and Bruns DE,eds.Tietz textbook of clinical chemistry and molecular diagnostics,4th edn.New Delhi:Elsiever Co,2006;837-901 Wallace TM, Levy JC and Mathews DR.use and abuse of HOMA modeling .Diabetes Care.2004;27:1487-95. Nader R, Warnick GR.Lipids,lipoprotiens and other cardiovascular risk factors. In:Burtis CA, Ashwood ER and Bruns DE,eds.Tietz textbook of clinical chemistry and molecular diagnostics,4th edn.New Delhi:Elsiever Co,2006;916-52 Park.Epidemiology of chronic non communicable diseases and conditions Parks Textbook of Preventive and Social Medicine.19th eds. p 332-336  9. SIGNATURE OF THE CANDIDATE 10 REMARKS OF THE GUIDE This study is recommended to know the biochemical alterations of T3, T4,TSH, insulin resistance(HOMA),BMI and total cholesterol levels in hypothyroidism.11 NAME & DESIGNATION. 11.1 GUIDE 11.2 SIGNATURE  Dr. REKHA M.,MBBS MD READER, DEPARTMENT OF BIOCHEMISTRY J.J.M.MEDICAL COLLEGE DAVANGERE.577 00411.3 CO-GUIDE (if any) 11.4 SIGNATURE Dr. DHANANJAY P E MD PROFESSOR, DEPARTMENT OF MEDICINE J.J.M.MEDICAL COLLEGE DAVANGERE.577 004 11.5 HEAD OF THE DEPARTMENT 11.6 SIGNATURE  Dr. D.S. 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