• No results found

Study of Serum Uric Acid Levels in Normal Population and In Patients with Diabetes Mellitus and to Correlate the Serum Uric Acid Levels with GFR

N/A
N/A
Protected

Academic year: 2019

Share "Study of Serum Uric Acid Levels in Normal Population and In Patients with Diabetes Mellitus and to Correlate the Serum Uric Acid Levels with GFR"

Copied!
125
0
0

Loading.... (view fulltext now)

Full text

(1)

STUDY OF SERUM URIC ACID LEVELS IN NORMAL

POPULATION AND IN PATIENTS WITH DIABETES

MELLITUS AND TO CORRELATE THE SERUM

URIC ACID LEVELS WITH GFR

Dissertation

Submitted to

THE TAMILNADU Dr. M.G.R MEDICAL UNIVERSITY

In partial fulfillment of the requirements for

the award of the degree of

M.D. GENERAL MEDICINE

BRANCH I

(2)

This is to certify that this dissertation entitled “Study of serum uric

acid levels in normal population and in patients with diabetes mellitus

and to correlate the serum uric acid levels with GFR” is a bonafide record

of the work done by Dr. Jaison Varghese under guidance and supervision in the Department of General Medicine during the period of his postgraduate study for M.D General Medicine [Branch-I] from 2014 to 2017.

Dr. BEENA UNNIKRISHNAN

[Co-guide]

Associate Professor

Department of General Medicine Sree Mookambika Institute of

Medical Sciences,

Kulasekharam, Kanyakumari, Tamil Nadu -629 161

Dr. REMA V. NAIR

Director,

Sree Mookambika Institute of Medical Sciences,

Kulasekharam Kanyakumari

Tamil Nadu -629 161

Dr. J. KANIRAJ PETER

[Guide]

Professor & Head

Department of General Medicine Sree Mookambika Institute of

Medical Sciences,

(3)

I solemnly declare that this dissertation “Study of Serum Uric

Acid Levels in Normal Population and in patients with Diabetes

Mellitus and to correlate the serum uric acid levels with GFR” was

prepared by me at Sree Mookambika Institute of Medical Sciences,

Kulasekharam - 629161 under the guidance and supervision of

Dr. J. KANIRAJ PETER, Professor of General Medicine and

Dr. BEENA UNNIKRISHNAN, Associate Professor of General

Medicine, Sree Mookambika Institute of Medical Sciences, Kulsekharam. This thesis is submitted to the Dr. M.G.R. Medical University, Chennai in partial fulfillment of the rules and regulations for the award of MD Degree examination in General Medicine.

Dr. Jaison Varghese

Junior Resident

Department of General Medicine,

Sree Mookambika Institute of Medical Sciences, Kulasekharam

Kanyakumari

(4)
(5)

ACKNOWLEDGEMENT

I thank God almighty, for all blessings without which this work would not have been possible.

I express my heartfelt gratitude to our Director Dr. Rema V. Nair and our Chairman Dr. C.K. Velayuthan Nair for providing me the facilities required and for permitting me to carry out the study in this institution.

I would like to thank our principal Dr. Padmakumar for being supportive of the study till the very end.

I thank my HOD and guide Dr. J. Kaniraj Peter, for the creative suggestions, timely advice and constant encouragement. It has been a wonderful experience to work under his guidance.

I thank my co guide Dr Beena Unnikrishnan for her valuable help, suggestions and supervision throughout the study. She lent her full support in times of difficulties that I encountered during this study period without which this dissertation would not have been completed on time. Her encouragement from the beginning of this research to its completion has been profound.

(6)

Superintendent whose guidance and help were crucial to this study.

I am grateful to Dr. V. Rajendran, Dr. Krishnankutty K, Dr. Thilagar S and Dr. Mohanadhas R for the valuable support and constant encouragement.

I thank Dr. Ajay Kumar, Dr. Sheeba George, Dr. Sharath Babu and Dr. Prashanth Solanke for their valuable guidance

I also extend my sincere thanks to Dr. Rufus Demel, Dr. Sanjeevagouda, Dr. Sreetha Sreenivas, Dr. Aiswarya Dhanapalan and all

the staff members of General Medicine for their support.

Sincere thanks to Dr. Oommen P. Mathew MSc, PG D(Com. Sc), PGD (Bio Stat), PhD (Demography) for all his help concerning my issues with statistics.

I am grateful to my colleagues, Dr. Jayaram J. K., Dr. Shahbaz Zailu,

Dr. Jineesh Raj, Dr. Jacob C Pilla, Dr. Noufal Ahmed Musaliar, Dr. Divya Aleena Jacob, Dr. Arishta Bala and Dr. Aswathi Harikumar for the

various technical aspects of my study.

I am grateful to my family members who supported me a lot and always encouraged me to do better.

Without the whole hearted cooperation of my patients, this thesis would not have reached a conclusion. I express my sincere gratitude to all my patients at Sree Mookambika Institute of Medical Sciences, Kulasekharam.

(7)

BACKGROUND AND OBJECTIVES

A positive association between hyperuricemia and the development of type 2 diabetes mellitus has been reported. The aims were to study the level of serum uric acid levels in normal population and in patients with diabetes mellitus and to correlate the serum uric acid levels with GFR

METHODS

Ethical committee clearance was obtained. After taking consent, hundred patients with type 2 diabetes mellitus and 100 healthy controls were included in this study. All the subjects were in the age group of 25 to 70 years. They were further divided into different groups, based on the age, gender, BMI, duration of diabetes, GFR, proteinuria and the diabetes which was complicated with hypertension. These groups were compared for differences in serum uric acid levels. The serum uric acid levels of the cases and controls were correlated with GFR. The data was analysed by SPSS version 16.0

RESULTS

(8)

Serum uric acid levels were higher in patients with diabetes mellitus than in the normal population. Serum uric acid levels were higher in the age group more than 60 years in both cases and controls. Serum uric acid levels were higher in people with duration of diabetes mellitus more than 5 years compared with those having duration less than 5 years. Serum uric acid levels were also higher in those with hypertension compared to those who did not have hypertension in cases. Those with elevated serum uric acid levels were found to have reduced GFR, which means a negative correlation was observed.

(9)

Sl. No. Contents Page No

1. Introduction 1

2. Aims and Objectives 4

3. Hypothesis and Scientific Justification 5

4. Review of Literature 6

5. Materials and Methods 32

6. Results 41

7. Discussion 66

8. Conclusion 71

9. Limitations 72

10. Summary 73

11. Bibliography 76

(10)

Sl. No Tables Page No

1 Diagnosis of Diabetes Mellitus 18

2 Treatment goals for Adults with Diabetes Mellitus 20

3 JNC-8 classification of blood pressure 28

4 Causes of Hyperuricemia 29

5 Quantification of amount of urinary protein by Dipstick test

36

6 Comparison of age between the groups 41

7 Comparison of percentage of males and females between the groups

42

8 Distribution of cases according to the presence of Hypertension in cases

43

9 Comparison of number and percentage of smokers between

the groups

44

10 Comparison of number of patients with family history of diabetes mellitus between cases and controls

45

11 Descriptive statistics for FBS and PPBS in cases 46

12 Descriptive statistics for Blood pressure and BMI based on group

46

13 Comparison of percentage of patients with neuropathy between groups

46

14 Distribution of sample according to duration of diabetes mellitus(less than 5 years or more than 5 years) in cases

47

15 Percentage distribution of the sample according to CAD in cases

48

(11)

18 Comparison of serum uric acid in cases and controls 51

19 Comparison of percentage of patients with urine albumin in cases and controls

52

20 Comparison of serum uric acid between cases and controls based on urine protein

53

21 Comparison of serum uric acid between cases and control based on gender

55

22 Comparison of serum uric acid between cases and controls based on age(age more than 60 years and age less than 60 years)

57

23 Comparison of serum uric acid between case and control based on BMI

59

24 Comparison of serum uric acid between case and control based on GFR

61

25 Correlation between serum uric acid and GFR in case and control group

63

26 Comparison of serum uric acid based on duration of DM & presence of hypertension in the case group

(12)

Sl. No Figures Page No

1 Worldwide prevalence of diabetes mellitus 8

2 Prevalence of diabetes mellitus in India 9

3 Mechanism of insulin secretion 11

4 Diabetic retinopathy leading to scattered haemorrhages, yellow exudates and neovacularization

13

5 Diabetic Retinopathy(Non proliferative and Proliferative) 13

6 Pathogenesis of diabetic retinopathy 14

7 Diabetic neuropathy 15

8 Time course of development of diabetic nephropathy 15

9 Phases of diabetic nephropathy 16

10 Structure of Uric Acid 21

11 Metabolism of Uric Acid 22

12 Antioxidant prooxidant redox shuttle 23

13 Pathophysiology of the metabolic syndrome 26

14 GFR categories in chronic kidney disease 30

15 Glomerular capillary membrane 30

16 Summary of forces filtration by glomerular capillaries 31

17 Urine Reagent Strips (Dipstick Method) 37

18 AU 480 Automated Analyser (Beckman Coulter) 38

19 Reagent R1 and R2 for S. Creatinine assessment 38

20 Reagent R1 and R2 for Assessment of fasting blood sugars 39

21 Reagent for serum uric acid 40

(13)

groups

24 Percentage distribution according to Hypertension in cases 43

25 Comparison of number and percentage of smokers between

the groups

44

26 Comparison of number of patients with family history of DM between cases and controls

45

27 Percentage distribution of sample according to duration of DM (less than 5 years and more than 5 years) in cases

47

28 Percentage distribution of the sample according to Coronary artery disease in cases

48

29 Comparison of serum creatinine in cases and controls 49

30 Comparison of GFR in cases and controls 50

31 Comparison of serum uric acid in cases and controls 51

32 Comparison of patients with urine protein in cases and controls

52

33 Comparison of serum uric acid between cases and controls based on urine protein

54

34 Comparison of serum uric acid between cases and controls based on gender

56

35 Comparison of serum uric acid between case and control based on age

58

36 Comparison of serum uric acid between case and control based on BMI

60

37 Comparison of serum uric acid level between case and control based on GFR

62

38 Scatter diagram for serum uric acid and GFR in case and control group

63

39 Comparison of serum uric acid based on duration of DM and presence of Hypertension in case group

(14)
(15)

Page 1

INTRODUCTION

Diabetes mellitus is characterized by increased blood sugar levels due to a deficiency of insulin either absolute or relative deficiency. Diabetes can lead to various microvascular diseases and macrovascular diseases. A positive association between hyperuricemia and the development of type 2 diabetes mellitus has been reported. In persons with an impaired glucose tolerance, hyperuricemia was linked with an increased risk for developing Type 2 Diabetes Mellitus.1

Serum uric acid has become a potential risk factor for development of type 2 diabetes mellitus. Hyperuricemia is frequently found in persons with metabolic syndrome. A few risk factors in Type 2 Diabetes Mellitus are found to cluster together. It includes obesity, increased triglyceride levels, reduced high density lipoprotein levels, increased blood pressure, and resistance to insulin.1

(16)

Page 2

Is uric acid the cause of resistance to insulin or secretory deficiency of beta cells, or is it a byproduct of resistance to insulin or increased blood sugar levels? It is important because if uric acid has a causative role, then there is a definite role of intervention with uric acid reducing agents. Otherwise it can be useful as a predictive marker and can be used for other modes of interventions like diet control. Studies have shown that a diet rich in fructose can also increase uric acid levels, but this work was done in rats. 1

Over 90% of serum uric acid is soluble and not bound to protein, and is freely filtered by the kidneys. This makes filtered serum uric acid strongly dependent on glomerular filtration rate (GFR). Further secretion and reabsorption of uric acid takes place in the proximal tubule.

Reabsorption of uric acid is an important mechanism that influences baseline levels of uric acid. Reabsorption occurs by active transport coupled to Na-K-ATPase pump using a variety of transport proteins, the most important of which are urate transporters URAT1 and GLUT9. There are reports that uric acid levels vary considerably within individuals. Transient changes in serum uric acid levels occur on a monthly basis. 7

(17)

Page 3

(18)
(19)

Page 4

AIMS AND OBJECTIVES

● To compare the serum uric acid levels in diabetic group and normal

population

● To correlate the serum uric acid level with the GFR in diabetic group

and normal population

● To study factors associated with increased level of serum uric acid in

(20)
(21)

Page 5

HYPOTHESIS AND SCIENTIFIC JUSTIFICATION

HYPOTHESIS

The alternate hypothesis states that there is a significant association between the serum uric acid levels and diabetes mellitus

SCIENTIFIC JUSTIFICATION

(22)
(23)

Page 6

REVIEW OF LITERATURE

Kodama S et al meta-analysis was the first to describe the relationship between serum uric acid levels and risk of developing diabetes. It indicated that each 1 m/dl increase in serum uric acid will increase the risk of development of diabetes by about 17%. It has been indicated that increased levels of serum uric acid is correlated with alcohol intake and other factors like obesity, hypertension which are typically considered to be diagnostic criteria for metabolic syndrome.6

Bhole V et al in the prospective study of two generations of the Framingham Heart Study, found that the risk of Type 2 Diabetes Mellitus increased with increased serum uric acid levels. For every 1 mg/dl increase in serum uric acid, the risk of type 2 diabetes was increased by 20% in the original cohort and 15% in the offspring cohort. Similar association was found in both sexes and the association was independent of the other known risk factors.2

Choi HK et al in their study , found out that the level of serum uric acid increased with increasing levels of HbA1c and Fasting Plasma Glucose and then decreased when HbA1c increased further (a bell-shaped relation).18

(24)

Page 7

serum uric acid levels at the 2hr Plasma Glucose < 10 mmol/L and decreasing serum uric acid at 2hr Plasma Glucose>10mmol/l was also observed.4

Ohison LO et al showed that the baseline serum uric acid level was able to give an idea about the 2 hour plasma glucose level during 13.5 years follow-up in a Swedish male population.20

Among Chinese T2DM patients the results of the study by Wang J et al showed the standard deviation of hyperuricemia in patients with diabetes mellitus was 13.6 21

Liu et al systematically analyzed the prevalence of increased uric acid levels in Chinese populations using the meta analysis method, and reported that the prevalence in women was 8.6% and 21.6% in men.22 The prevalence of increased uric acid levels in Chinese diabetic patients with central obesity was dramatically higher than in Chinese general populations as reported by Liu et al. 22 Previous studies found men had increased uric acid levels compared with women. The findings of this study suggested the prevalence of increased uric acid levels in women was significantly higher than in men (36.1% vs 28.3%,p<0.001).22

WORLDWIDE PREVALENCE OF DIABETES MELLITUS 23

(25)

Page 8

[image:25.612.129.497.263.496.2]

because of increasing obesity, sedentary lifestyle and aging of the population. Upto 80 % of people with diabetes mellitus live in low income or medium income countries. Diabetes is a major cause of mortality. An estimate in 2013 suggested that 5.1 million deaths or 8% of the deaths worldwide occur due to diabetes mellitus. It was also estimated that 11% of health care expenditure were spent on people with diabetes mellitus

Fig. 1: Worldwide prevalence of diabetes mellitus23

(26)

Page 9

[image:26.612.132.507.316.567.2]

In India, obesity is one of the most important risk factors of diabetes mellitus.27 In India obesity occurs in people with much lesser BMI compared to western countries.27,28 Therefore, lean Indians are at an equal risk as western population with obesity.26 Indians are also prone for coronary artery disease due to dyslipidemia.29 these factors make Indians prone for complications of diabetes at an age of 20-40 years compared with Caucasians (>50 years).It indicates that diabetes mellitus must be carefully monitored in India.29

(27)

Page 10

Continuing medical education for general practitioners is required to start diabetes screening facilities and adherence to treatment, and it will be major step in achieving target glycemic levels and the prevention of complications of diabetes mellitus. Aggressive treatment with early insulin initiation combined with optimal doses of oral hypoglycemic agents and appropriate exercise could also have long-term positive effects in management of diabetes mellitus.30

CLASSIFICATION23

There are two broad categories of diabetes mellitus, designated type 1 DM and type 2 DM. However, other forms of diabetes are recognized in which the pathogenesis is better understood. These have features of type 1 and/or type 2 DM.

INSULIN ACTION23

(28)
[image:28.612.154.489.84.389.2]

Page 11

Fig 3: Mechanism of insulin secretion 23

(29)

Page 12

Decreased utilization of glucose in the periphery is mostly responsible for the post prandial increase in blood sugar levels. In hyperinsulinemia there is lipid accumulation in skeletal muscle cells. It should also be kept in mind that high blood sugar levels impair islet function. Better glycemic control is also accompanied by a better islet function. An increase in free fatty acid level also worsen islet function.23

It results in increased fasting plasma glucose levels and also causes decreased storage of glycogen by the liver in the post prandial state. There is also increased insulin resistance in skeletal muscles which lead to more lipoprotein, VLDL and triglyceride synthesis in liver cells.23

Also some autoimmune markers like GAD autoantibodies are found in patients with Type 2 Diabetes Mellitus and this condition is known as latent autoimmune diabetes of the adult. People with diabetes mellitus should also be screened for albuminuria, dyslipidemia and thyroid dysfunction. Serum C- peptide level is used to differentiate the type of diabetes mellitus. 23

(30)

Page 13

[image:30.612.152.486.415.630.2]

DIABETIC RETINOPATHY23

Fig 4: Diabetic retinopathy leading to scattered haemorrhages,

yellow exudates and neovacularization23

(31)
[image:31.612.130.508.112.531.2]

Page 14

(32)

Page 15

Fig 7 : Diabetic neuropathy 31

(33)

Page 16

Fig 9: Phases of diabetic nephropathy23

People with diabetes mellitus form the maximum number of renal transplant recipients. Diabetic neuropathy is another important complication of diabetes mellitus and includes distal symmetrical polyneuropathy, mononeuropathies, and a variety of autonomic neuropathies causing erectile dysfunction, urinary incontinence, gastroparesis, and nocturnal diarrhea. 31

CLINICAL MANIFESTATIONS OF AUTONOMIC NEUROPATHY31

Cardiovascular

• Alterations in skin blood flow

• Cardiac denervation, painless myocardial infarction

• Heat intolerance

• Orthostatic hypotension

(34)

Page 17

Gastrointestinal

• Constipation

• Diarrhea

• Esophageal dysfunction

• Fecal incontinence

• Gastroparesis diabeticorum

Genitourinary

• Cystopathy

• Erectile dysfunction

• Neurogenic bladder

• Retrograde ejaculation

Metabolic

• Hypoglycemia unawareness

• Hypoglycemia unresponsiveness

Pupillary

• Argyll-Robertson pupil

• Decreased diameter of dark adapted pupil

Sweating Disturbances

• Areas of symmetrical anhydrosis

(35)

Page 18

DIAGNOSTIC CRITERIA OF DIABETES MELLITUS23

• Symptoms of diabetes mellitus plus RBS > 200 mg/dl

• Fasting plasma glucose > 126 g/dl

• HbA1c > 6.5%

• 2 hour plasma glucose >200 mg/dl during a oral glucose tolerance test

Table 01: Diagnosis of Diabetes Mellitus31

Test Normoglycemia IFG IGT Diabetes

FBS <100 100-125 >126 mg/dl

PPBS <140 140-199 >200 mg/dl

RBS >200 mg/dl plus

symptoms of diabetes

RISK FACTORS FOR DIABETES23

● Family history ● Obesity

● Sedentary lifestyle

● History of GDM or delivery of baby > 4 kg ● Hypertension (Blood pressure > 140/90 mm Hg)

● HDL cholesterol level > 35 mg/dl or a triglyceride level > 250 mg/dl ● Polycystic ovary syndrome or acanthosis nigricans

(36)

Page 19

DIABETES-RELATED COMPLICATIONS23

Microvascular

● Retinopathy ● Neuropathy ● Nephropathy

Macrovascular

● Coronary artery disease ● Peripheral arterial disease ● Cerebrovascular disease

Other….

● Gastrointestinal(gastroparesis,diarrhea) ● Genitourinary(Uropathy/Sexual dysfunction) ● Dermatologic

● Infectious ● Cataracts ● Glaucoma

(37)

Page 20

NUTRITIONAL RECOMMENDATIONS FOR ADULTS WITH

DIABETES OR PREDIABETES 23

● Diet that is low in carbohydrate ● Minimal trans fat consumption

● Diet rich in mono unsaturated fatty acids

● Carbohydrate intake has to be monitored with regard to calories ● Sucrose-containing foods may be consumed with adjustments in insulin ● Use glycemic index to determine how much consumption of a

particular food may affect blood glucose

● Fructose preferred over sucrose or starch

● Dietary fiber, vegetable, fruits, whole grains, dairy products and

sodium intake as advised for general population

Table 02: Treatment goals for Adults with Diabetes Mellitus23

Glycemic control Goal

HbA1c < 7%

Preprandial capillary plasma glucose 80-130 mg/dl Peak post prandial capillary plasma glucose <180 mg/dl

Blood pressure < 140/90 mm Hg Low density lipoprotein < 100 mg/dl High density lipoprotein

>40 mg/dl in men >50 mg/dl in women

Triglycerides <150 mg/dl

(38)

Page 21

URIC ACID

Fig 10 : Structure of Uric Acid 33

Uric acid is a C5H4N4O3 (7,9-dihydro-1H-purine-2,6,8(3H)-trione)

heterocyclic organic compound. The normal level for serum uric acid in females is 1.5 to 6.0 mg/dL and in males is 2.5 to 7.0 mg/dl 33

Metabolism32

(39)

Page 22

Fig 11 : Metabolism of Uric Acid32

Abbreviated Mechanisms of Hyperuricemia in Type 2 Diabetes Mellitus 35

● Accelerated atherosclerosis with more apoptosis of vascular cells and

inflammatory necrosis with greater metabolism of purine and more uric acid levels and more oxidative stress through ischemia-reperfusion and xanthine oxidase.

● More stress of reduction associated with toxicity of glucose and

pseudohypoxia

● More oxidative-redox stress

(40)

Page 23

Obesity has rapidly progressed and is one of the most important confounding factor associated with the Metabolic syndrome and Type 2 Diabetes mellitus.36,37

Levels of leptin are increased and linked with resistance to insulin in Metabolic Syndrome and early Type 2 Diabetes Mellitus. Bedir A et al. have

recently discussed the regarding role of leptin as a regulator of serum uric acid concentrations in human beings and even put forward that leptin might be one factor which forms the missing link between obesity and hyperuricemia.39 Also increased triglyceride levels and free fatty acids are related to increased uric acid levels independent of obesity and central body fat distribution. 37,38

ANTIOXIDANT PRO-OXIDANT SHUTTLE 40

(41)

Page 24

The healthy endothelium produces endothelial nitric oxide.The activated, dysfunctional endothelium produces superoxide (O2-) associated

with Metabolic syndrome and Type 2 Diabetes Mellitus.40

Uric acid and highly sensitive C reactive protein (hsCRP) are now believed to be two important risk factors associated with metabolic syndrome. TNF alpha has been linked with serum uric acid levels in congestive heart failure. Olexa P et al. concluded that serum uric acid levels are related to the

severity of systolic dysfunction in patients with congestive cardiac failure.41.It should be kept in mind that CRP and IL6 are important confounding factors while testing the association between serum uric acid level and overall mortality in elderly persons.

(42)

Page 25

result of oxidative - redox stress and it results in remodeling of the glomerulus. Increased ischemia - ischemia reperfusion can lead to increased oxidative stress in the renal architecture and cause remodeling as a result of activation the xanthine oxidase mechanism. Increased uric acid levels could cause more formation of crystals of urate and it can also cause remodeling changes in the medullary tubulo-interstitium in the kidney. The nutritional "gold standard" for treating increased serum uric acid level is a low purine diet like bread, cereal ,low-fat milk ,coffee ,eggs ,whole fruits and vegetables, potatoes and nuts. High purine diet like bacon, liver, sardines, dried peas, dried beans, oatmeal and beer. More attention should be given to control obesity through restriction of calories and adequate exercise to prevent obesity.43

Nutritional support with the help of nutritionist and the diabetic educator is very much important when dealing with the diabetic patient for global reduction of risk43

METABOLIC SYNDROME24

(43)

Page 26

Insulin causes both antilipolysis and stimulation of lipoprotein lipase in adipose tissue. Inhibition of lipolysis in adipose tissue is the most sensitive pathway of insulin action. Insulin resistance causes lipolysis and more fatty acids are produced.in liver, Insulin mediated glucose uptake will get impaired by fatty acids and accumulate as triglycerides. Patients with increased triglyceride levels have increased VLDL and LDL levels and decreased HDL. In metabolic syndrome, due to defective insulin action there will be impaired suppression of glucose production by the liver and kidney and also reduced uptake of glucose and metabolism in insulin sensitive tissues.24

(44)

Page 27

In metabolic syndrome uric acid has an antioxidant effect but becomes a strong oxidant when metabolic syndrome is present hence it induces high oxidative stress in case of hyperuricemia. This phenomenon is called the urate redox shuttle which explains the paradoxical effects of uric acid on oxidative stress.40

HYPERURICEMIA

Hyperuricemia is defined as a serum uric acid concentration >6.0mg/dl in females and > 7.0mg/dl in males.44

The final breakdown product of purine degradation in humans is uric acid.98% of urate is seen as monosodium urate at pH 7.4 mainly in the synovial fluid and extracellular fluid 44. The total-body urate content is the net result between urate production and its excretion. Urate production is influenced by dietary intake of purines and the rates of de novo biosynthesis of purines, nucleic acid turnover, and salvaging phosphoribosyltransferase activities. Normally, major amount of urate is excreted by the Kidney, and remaining through the intestine.44

(45)

Page 28

tubular cells from the apical side of the lumen. Once entering the cell, urate must pass to the basolateral side of the lumen and this process is controlled by the voltage-dependent carrier hUAT. Uric acid compounds directly inhibit URAT1, which is a novel transporter expressed at the apical brush border of the proximal nephron (so-called cis-inhibition). Component model has been used to explain the renal handling of urate / uric acid. 44

Table 03: JNC-8 classification of blood pressure45,46

(46)

Page 29

(47)

Page 30

Fig 14: GFR categories in chronic kidney disease34

[image:47.612.146.493.82.344.2]

GLOMERULAR FILTRATION51

(48)

Page 31

Factors favoring filtration51

a. Glomerular hydrostatic pressure

b. Bowman’s capsule colloid osmotic pressure

Factors opposing filtration

a. Bowman’s capsule hydrostatic pressure b. Glomerular capillary colloid osmotic pressure

Fig 16: Summary of forces filtration by glomerular capillaries51

(49)
(50)

Page 32

MATERIALS & METHODS

Study design: This is a hospital based descriptive study.

Study setting: General Medicine OPD and General Medicine Ward of Sree

Mookambika Institute of Medical Sciences, Kulasekharam during the study period.

Approximate duration of study: August 2015 to August 2016

Number of groups to be studied: 2 groups

Detailed description of the groups:

Group 1-Diabetic group meeting International Guidelines for

diagnosis of diabetes mellitus

Group 2-Normal Population

Sample size of each group: 100

Total sample size of the study: 200

Scientific basis of sample size used in the study:

=

[]

×

Where, = Standard normal variate

(51)

Page 33

S.D = Standard Deviation of variation

S.D of Hyperuricemia in Diabetes Mellitus=13.6 (Jiao)21 d = Precision = 20% of S.D=2.72

=

. ×. .

=

.

. ×.

= 100

Sample size for one group=100

Therefore, sample size for two groups=200

Sampling technique: Systematic Random Sampling Technique (Every 2nd

person will be studied)

Inclusion criteria:

All self-reported diabetic cases and other normal population who attended the General Medicine OPD as well as those admitted in the General Medicine ward in the age group 25-70 years who gave consent for work up for the study. Diabetic cases may be established cases of diabetes mellitus or recently diagnosed.

Exclusion criteria:

(52)

Page 34

3) Patients who were on drugs that modify uric acid levels like diuretics, angiotensin receptor blockers, salicylates etc.

4) Patients who were diagnosed as cancer 5) Patients with chronic liver disease

6) Patients who had PVD/CVA/ Pulmonary Tuberculosis. 7) Renal transplant patients.

8) Patients with any acute illness like fever ,vomiting, diarrhea 9) Patients with gout.

10) Patients who were on dialysis

Procedure (in brief):

After acceptation of the thesis by the ethics committee, an informed consent was obtained from diabetic population and normal population coming to the General Medicine OPD and patients admitted in the General Medicine ward of Sree Mookambika Institute of Medical Sciences. A detailed medical history was taken. A detailed general physical examination was performed.

(53)

Page 35

Fasting blood sugar and Post Prandial blood sugar was examined in each patient. Serum creatinine levels and serum uric acid levels were measured in each patient. The estimated GFR was calculated using the CKD-EPI creatinine equation34.The serum uric acid levels were correlated with GFR. Urine routine examination of each patient was also done to screen for proteinuria. The equation used here is:

GFR = 141 × min(Scr⁄ĸ,1)α

× max(Scr⁄ĸ,1)-1.209 × 0.993Age × 1.018(if female) × 1.159(if black)

ĸ=0.7 if female; ĸ=0.9 if male

α is -0.329 for females and -0.411 for males

min=The minimum of Scr/ĸ or 1

max=The maximum of Scr/ĸ or 1 Scr = serum creatinine (mg/dL)

For patients with previously done investigations recently(1 month), the records were used instead of repeating the same investigations.

Parameters Studied

• Fasting blood sugar (mg/dl)

• Post prandial blood sugar (mg/dl)

• Serum creatinine (mg/dl)

• GFR (ml/min/1.73 m2)

• Serum Uric Acid (mg/dl)

(54)

Page 36

SAMPLE COLLECTION AND METHOD

Assessment of urine routine examination for protein:

A morning sample of uncentrifuged urine, not more than 2 hours old at the time of testing was used by the Strip/Dipstick Method. This is a qualitative semi-quantitative method using Urine Reagent Strips – Urocolor 2 (Biostandard Diagnostics). The reagent coated strips were immersed in the urine sample, removed immediately and compared against the color chart given on the bottle label at 60 seconds after dipping.48Depending upon the color chart, the presence of urinary protein is categorized as:

Table 05: Quantification of amount of urinary protein by Dipstick test

Presence of Urinary Protein Amount in mg/dL (approx)

Trace < 30 mg/dL

(+) 30 – 99 mg/dL

(++) 100 – 299 mg/dL

(+++) 300 – 1999 mg/dL

(55)

Page 37

Fig 17:Urine Reagent Strips (Dipstick Method)

Assessment of serum creatinine:

(56)

Page 38

Fig 18: AU 480 Automated Analyser (Beckman Coulter)

(57)

Page 39

Assessment of blood sugar values:

Glucose oxidase/peroxidase method48 was employed. Serum or plasma, free of haemolysis, was used, after mixing with Reagent (manufactured by Beckman Coulter) and analyzed using AU 480 automated analyzer.

Fig 20: Reagent R1 and R2 for Assessment of fasting blood sugars

Assessment of serum uric acid values:

(58)
[image:58.612.248.409.79.290.2]

Page 40

Fig 21: Reagent for serum uric acid

Urine samples are to be collected in autoclaved, dry, capped glass bottles. At least 10 ml of random, midstream urine samples shall be collected from patients.

Blood sample of not less than 5 ml needs to be collected under asepsis from anterior cubital vein using a sterile disposable syringe.

All the investigations was carried out in the Central Laboratory, Sree Mookambika Institute of Medical Sciences.

Statistical analysis: Data was entered in Microsoft Excel 2007 spread sheet

Significant level decided before starting of study: p 0.05

Statistical tests to be used for data analysis: Student t test, One way

ANOVA test, Correlation

Software(s) to be used for the statistical analysis: SPSS Software

(59)
(60)

Page 41

[image:60.612.127.511.344.593.2]

RESULTS & ANALYSIS

Table 06: Comparison of age between the groups

Age

Case Control

Count Percent Count Percent

<=60 years 60 60.0 88 88.0

>60 years 40 40.0 12 12.0

Mean ± SD 57.1 ± 9 44.6 ± 11.9

t = 8.36**, p = 0.000

Fig 22: Comparison of age between the groups

(61)

Page 42

Table 07: Comparison of percentage of males and females between the

groups

Sex

Case Control

χ2

p

Count Percent Count Percent

Male 37 37.0 39 39.0

0.08

0.771

[image:61.612.131.508.301.603.2]

Female 63 63.0 61 61.0

Fig 23: Percentage distribution of males and females between the groups

(62)

Page 43

Table 08: Distribution of cases according to the presence of Hypertension

[image:62.612.176.464.334.563.2]

in cases

Fig 24: Percentage distribution according to Hypertension in cases

42.0

58.0

Yes No

Hypertension Count Percentage (%)

Yes 42 42.0

(63)
[image:63.612.137.501.312.581.2]

Page 44

Table 09: Comparison of number and percentage of smokers between the

groups

Groups Number Percentage (%)

Cases 12 12.00

Control 6 06.00

Fig 25: Comparison of number and percentage of smokers between the

groups

12

6

0 2 4 6 8 10 12 14

Case Control

Nu

m

b

e

(64)

Page 45

Table 10: Comparison of number of patients with family history of

diabetes mellitus between cases and controls

Groups Number Percentage (%)

Cases 25 25.00

Control 4 4.00

Fig 26: Comparison of number of patients with family history of DM

between cases and controls

0 5 10 15 20 25

Cases Control

25

4

P

er

cen

ta

g

e

(%

[image:64.612.133.506.322.580.2]
(65)

Page 46

Table 11: Descriptive statistics for FBS and PPBS in cases

FBS PPBS

Mean 164.0 269.8

SD 51.4 56.6

Table 12: Descriptive statistics for Blood pressure and BMI based on

group

Cases Control

SBP DBP BMI SBP DBP BMI

Mean 128.3 80.5 24.2 117.7 76.8 23.9

SD 18.2 9.3 2.1 13.0 8.3 2.4

Table 13: Comparison of percentage of patients with neuropathy between

groups

Groups

Neuropathy

Number Percentage (%)

Cases 20 20.00

(66)

Page 47

Table 14: Distribution of sample according to duration of diabetes

mellitus(less than 5 years or more than 5 years) in cases

Duration of DM Count Percent

<=5 years 43 43.0

>5 years 57 57.0

Mean ± SD 6.7 ± 3.7

Fig 27: Percentage distribution of sample according to duration of DM

(less than 5 years and more than 5 years) in cases

43.0

57.0

[image:66.612.175.473.360.592.2]
(67)

Page 48

Table 15: Percentage distribution of the sample according to CAD in

cases

Coronary artery disease Count Percent

Yes 8 8.0

No 92 92.0

Fig 28: Percentage distribution of the sample according to Coronary

artery disease in cases

8.0

92.0

[image:67.612.169.471.315.557.2]
(68)
[image:68.612.156.489.336.603.2]

Page 49

Table 16: Comparison of serum creatinine in cases and controls

Group Mean SD N t p

Case 0.9 0.3 100

9.49**

0.000

Control 0.6 0.1 100

**: - Significant at 0.01 level

Fig 29: Comparison of serum creatinine in cases and controls

(69)
[image:69.612.150.490.327.597.2]

Page 50

Table 17: Comparison of GFR in cases and controls

Group Mean SD N t p

Case 82.6 22.1 100

11.7** 0.000 Control 116.8 19.1 100

**: - Significant at 0.01 level

Fig 30: Comparison of GFR in cases and controls

0.0 20.0 40.0 60.0 80.0 100.0 120.0

Case Control

82.6

116.8

M

e

a

n

V

a

lu

(70)
[image:70.612.163.478.344.596.2]

Page 51

Table 18: Comparison of serum uric acid in cases and controls

Group Mean SD N t p

Case 4.8 1.1 100

9.59** 0.000

Control 3.7 0.5 100

**: - Significant at 0.01 level

Fig 31: Comparison of serum uric acid in cases and controls

(71)

Page 52

Table 19: Comparison of percentage of patients with urine albumin in

cases and controls

Urine albumin

Case Control

Number Percentage (%) Number Percentage

(%)

Nil 38 38.00 95 95.00

Albumin trace 31 31.00 5 5.00

Albumin + 25 25.00 0 00.00

[image:71.612.127.509.133.372.2]

Albumin ++ 6 6.00 0 00.00

Fig 32: Comparison of patients with urine protein in cases and controls

0 10 20 30 40 50 60 70 80 90 100

Nil Albumin trace Albumin + Albumin ++

[image:71.612.127.509.335.650.2]
(72)

Page 53

Table 20: Comparison of serum uric acid between cases and controls

based on urine protein

Group Urine protein Mean SD N F p

Case

Nil 4.3 1.0 38

5.22** 0.002 Albumin trace 5.0 0.8 31

Albumin + 5.0 1.2 25

Albumin ++ 5.8 1.7 6

Control

Nil 3.6 0.4 95

23.61** 0.000 Albumin trace 4.5 0.3 5

Albumin + 0.0 0.0 0

[image:72.612.128.510.130.576.2]
(73)
[image:73.612.131.508.76.328.2]

Page 54

Fig 33: Comparison of serum uric acid between cases and controls based

on urine protein

0.0 1.0 2.0 3.0 4.0 5.0 6.0

Nil Albumin trace Albumin + Albumin ++ 4.3

5.0 5.0

5.8

3.6

4.5

0.0 0.0

M

e

a

n

V

a

lu

e

(74)

Page 55

Table 21: Comparison of serum uric acid between cases and control

based on gender

Sex

Case Control

t p

Mean SD N Mean SD N

Male 4.8 1.2 37 3.6 0.4 39 5.96** 0.000

Female 4.8 1.1 63 3.7 0.5 61 7.44** 0.000

Total 4.8 1.1 100 3.7 0.5 100 9.59** 0.000

[image:74.612.128.512.121.382.2]
(75)
[image:75.612.135.499.76.325.2]

Page 56

Fig 34: Comparison of serum uric acid between cases and controls based

(76)

Page 57

Table 22: Comparison of serum uric acid between cases and controls

based on age(age more than 60 years and age less than 60 years)

Group Age Mean SD N t p

Case

<=60 4.7 1.1 60

1.29

0.201

>60 5.0 1.1 40

Control

<=60 3.6 0.4 88

2.33*

0.022

>60 3.9 0.5 12

[image:76.612.125.511.126.382.2]
(77)

Page 58

Fig 35: Comparison of serum uric acid between case and control based

[image:77.612.136.501.77.333.2]
(78)
[image:78.612.128.514.132.479.2]

Page 59

Table 23: Comparison of serum uric acid between case and control based

on BMI

Group BMI Mean SD N F p

Case

<18.5 5.5 1.5 3

2.24 0.112 18.5 - 24.9 4.6 0.9 57

>=25 5.0 1.3 40

Control

<18.5 3.0 0.0 1

1.47 0.234 18.5 - 24.9 3.6 0.4 81

(79)

Page 60

Fig 36: Comparison of serum uric acid between case and control based

on BMI

0.0 1.0 2.0 3.0 4.0 5.0 6.0

<18.5 18.5 - 24.9 >=25 5.5

4.6

5.0

3.0

3.6 3.8

M

e

a

n

V

a

lu

e

[image:79.612.148.489.76.327.2]
(80)
[image:80.612.127.514.103.547.2]

Page 61

Table 24: Comparison of uric acid between case and control based on GFR

Group GFR Mean SD N F p

Case

>=90 4.5 0.9 45

4.51** 0.005

60 - 89 4.9 1.0 35

45 - 59 5.2 1.4 17

30 - 44 6.4 1.2 3

Control

>=90 3.6 0.4 92

8.11** 0.005

60 - 89 4.1 0.5 8

45 - 59 0.0 0.0 0

30 - 44 0.0 0.0 0

(81)

Page 62

Fig 37: Comparison of serum uric acid level between case and control

based on GFR

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0

[image:81.612.138.500.76.339.2]
(82)

Page 63

Table 25: Correlation between serum uric acid and GFR in case and

control group

Group r Sig.

Case -0.291** 0.003

Control -0.236* 0.018

**: - Significant at 0.01 level, *: - Significant at 0.05 level

Fig 38: Scatter diagram for serum uric acid and GFR in case and control

(83)

Page 64

Table 26: Comparison of serum uric acid based on duration of DM &

presence of hypertension in the case group

Mean SD N t p

Duration DM

<=5 4.5 1.1 43

2.15* 0.034 >5 5.0 1.1 57

HTN

Yes 5.2 0.9 42

3.12** 0.002 No 4.5 1.1 58

[image:83.612.127.510.131.383.2]
(84)

Page 65

Fig 39: Comparison of serum uric acid based on duration of DM and

presence of Hypertension in case group

4.0 4.2 4.4 4.6 4.8 5.0 5.2

<=5 >5 Yes No

Duration DM HTN

4.5

5.0

5.2

4.5

M

e

a

n

V

a

lu

(85)
(86)

Page 66

DISCUSSION

The total number of subjects included in this study was 200.Among those 200 subjects, 100 were cases (type 2 diabetes mellitus)and 100 were controls (normal population).

In my study the age of study population varies from 25 to 70 years. The mean age of the study population was 57.1 and 44.60 in both cases and controls respectively. Among the cases with age more than 60, mean serum uric acid level was 5,whereas subjects with age equal to or less than 60 mean serum uric acid level was 4.7.Among the controls, with age more than 60 mean serum uric acid level was 3.9 whereas subjects with age less than or equal to 60 mean serum uric acid level was 3.6. The subjects with age more than 60 years had higher serum uric acid levels than subjects with age less than 60 years and it is statistically significant. Kuzuya M, Ando F, Iquchi A, Shimokata H had studied about the serum uric acid levels in a large Japanese population group and it was found that serum uric acid levels increases with aging.50

(87)

Page 67 overall prevalence of hyperuricemia was significantly increased in women than in men.21

The mean duration of diabetes mellitus for cases was 6.7 years. Out of the 100 cases of diabetes mellitus 57% had a duration of diabetes mellitus more than 5 years. The mean serum uric acid levels in subjects with duration of diabetes more than 5 years was 5 whereas mean serum uric acid levels with duration of diabetes less than or equal to 5 years was 4.5. The patients with diabetes mellitus, whose duration was more than 5 years had higher serum uric acid levels and it was statistically significant.

It was observed that 8 % of the cases had a history of coronary artery disease. No patients in the control group had a history of coronary artery disease. The percentage of smokers were also more in the cases(12 percent) compared to the controls(6 percent).25 percent of the cases had a family history of diabetes mellitus whereas in controls only 4 percent had a family history of diabetes mellitus. Out of 100 cases of diabetes mellitus, 20 percent had clinical features of neuropathy.

The mean systolic blood pressures in cases were 128.3 and in controls were 117.7. The mean diastolic blood pressure in cases were 80.52 and in controls were 76.8.

(88)

Page 68 The mean serum uric acid level of cases with BMI of 18.5 to 24.9 was 4.6,while mean serum uric acid level of BMI more than 25 in cases was 5.The mean serum uric acid level of controls with BMI less than 18.5 was 3.The mean serum uric acid level of controls with BMI of 18.5 to 24.9 was 3.6,while mean serum uric acid level of BMI more than 25 in controls was 3.8

The mean fasting blood glucose level of cases were 164 compared to only 83.7 in controls. The mean post prandial blood sugar in cases were 269.8 compared to only 127.31 in controls.

(89)

Page 69 The mean serum uric acid in cases were 4.8 and the mean serum uric acid in controls was 3.7. The difference between the groups was also statistically significant. In persons with elevated serum uric acid levels were found to have reduced GFR, which means a negative correlation was observed.

Out of 100 cases who had diabetes mellitus 38 had no proteinuria, 31 cases had trace proteinuria.25 cases had Protein + in urine and 6 cases had Protein ++ in urine. Out of 31 cases who had trace proteinuria 17 had only diabetes whereas 14 had both diabetes and hypertension. Out of 25 cases who had Protein +, 13 had only diabetes whereas 12 had both diabetes and hypertension. Among 6 cases who had Protein 2+, 3 cases had diabetes mellitus whereas 3 cases had both diabetes mellitus and hypertension

It was also observed that when that mean serum uric acid levels were lowest in cases and controls who had no proteinuria and serum uric levels increased when proteinuria increased. Mean serum uric acid level of cases with no proteinuria was 4.3 while it was 5.8 in patients with proteinuria 2+. Mean serum uric acid levels of controls with no proteinuria was 3.6 while mean serum uric acid levels of controls with trace proteinuria was 4.5. The comparison of proteinuria with serum uric acid levels was not statistically significant.

(90)

Page 70 hypertension was 5.2 while the mean of the serum uric acid level in cases without hypertension was 4.5.The differences in serum uric acid levels between hypertensives and non-hypertensives was statistically significant. Wang J et al in their study on serum uric acid levels in Type 2 Diabetes mellitus found out that the serum uric acid levels were significantly higher in patients with hypertension than in patients without hypertension.21

(91)
(92)

Page 71 CONCLUSION

➢ Serum uric acid levels were higher in patients with diabetes mellitus than in the normal population.

➢ Serum uric acid levels were higher in the age group more than 60 years in both cases and controls.

➢ Serum uric acid levels were higher in people with duration of diabetes mellitus more than 5 years compared with those having duration less than 5 years.

➢ Serum uric acid levels were also higher in those with hypertension compared to those who did not have hypertension in cases.

(93)
(94)

Page 72

LIMITATIONS

Limitations of the study include that plasma uric acid and other biochemical markers were measured only once, which made me unable to account for intra-individual variability. Second, women were overrepresented in my study.

(95)
(96)

Page 73

SUMMARY

An elevated serum uric acid level is of much importance to the clinician to get an idea about the global picture of diabetes mellitus. It will help to identify who are at high risk of progression to overt nephropathy. Increased serum uric acid level causes dysfunction of endothelial cells and increased oxidative stress within the kidney and associated increased remodelling fibrosis of the kidney. It leads to direct effect on macro vessels like afferent arterioles.

The study was a hospital based descriptive study conducted in Sree Mookambika Institute of Medical Sciences, Kulasekharam, Kanya Kumari district.

(97)

Page 74

In my study 63 % of cases were females. 61% of controls were also females. About 37% of cases were males and 39 % of controls were males.

The mean serum uric acid levels in both male and female cases were 4.8.The mean serum uric acid levels in male controls was 3.6 and the mean serum uric acid levels in female controls was 3.7.

The mean duration of diabetes mellitus for cases in was 6.7 years. Out of the 100 cases of diabetes mellitus 57% had a duration of diabetes mellitus more than 5 years .The mean serum uric acid levels in subjects with duration of diabetes more than 5 years was 5 whereas mean serum uric acid levels with duration of diabetes less than or equal to 5 years was 4.5.The difference was statistically significant compared between the groups. The patients with diabetes mellitus, whose duration was more than 5 years had higher serum uric acid levels and it was statistically significant.

The mean serum creatinine value in cases were 0.9 and in controls were 0.6. The mean GFR in cases were 82.6 and in controls were 116.8. The mean serum uric acid in cases were 4.8 and the mean serum uric acid in controls was 3.7.

(98)

Page 75

(99)
(100)

Page 76

BIBLIOGRAPHY

1. Cirillo P, Sato W, Reungjui S, Heinig M, Gersch M, Sautin Y, et al. Uric acid, the metabolic syndrome, and renal disease. J Am Soc Nephrol 2006;17(12 suppl 3):S165-8.

2. Bhole V, Choi JW, Kim SW, de Vera M, Choi H. Serum uric acid levels and the risk of type 2 diabetes: A prospective study. Am J Med. 2010;123(10):957-61.

3. Causevic A, Semiz S, Dzankovic MA, Cico B, Dujic T, Malenica M, et al. Relevance of uric acid in progression of type 2 diabetes mellitus. Bosn J Basic Med Sci. 2010;10(1):54-9.

4. Nan H, Pang Z, Wang S, Gao W, Zhang L, Ren J, et al. Serum uric acid, plasma glucose and diabetes. Diab Vasc Dis Res 2010;7(1):40-46. 5. Cook DG, Shaper AG, Thelle DS, Whitehead TP. Serum uric acid,

serum glucose and diabetes: Relationships in a population study. Postgrad Med J. 1986;62(733):1001-6.

6. Kodama S, Saito K, Yachi Y, Asumi M, Sugawara A, Totsuka K, et al. Association between serum uric acid and development of type 2 diabetes. Diabetes Care 2009;32(9):1737-42.

(101)

Page 77

8. Choi HK, Liu S, Curhan G. Intake of purine-rich foods, protein, and dairy products and relationship to serum levels of uric acid: The third national health and nutrition examination survey. Arthritis Rheum 2005;52(1):283-9.

9. Kedar E, Simkin PA. A perspective on diet and gout. Adv Chronic Kidney Dis 2012;19(6):392-7.

10. Hansel B, Giral P, Nobecourt E, Chantepie S, Bruckert E, Chapman MJ, Kontush A. Metabolic syndrome is associated with elevated oxidative stress and dysfunctional dense high-density lipoprotein particles displaying impaired antioxidative activity. J Clin Endocrinol Metab 2004;89(10):4963-71.

11. Hayden MR, Tyagi SC. Uric acid: a new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: the urate r edox shuttle. Nutr Metab (Lond) 2004;1:10. 12. Patterson RA, Horsley ETM, Leake DS. Prooxidant and antioxidant

properties of human serum ultrafiltrates toward LDL: important role of uric acid. J Lipid Res 2003;44:512-21.

(102)

Page 78

14. Nakagawa T, Kang DH, Feig D, Sanchez-Lozada LG, Srinivas TR, Sautin Y, et al. Unearthing uric acid: an ancient factor with recently found significance in renal and cardiovascular disease. Kidney Int 2006;69(10):1722-5.

15. Feig DI, Mazzali M, Kang DH, Nakagawa T, Price K, Kannelis J, et al. Serum uric acid: a risk factor and a target for treatment? J Am Soc Nephrol 2006;17(4):S69-73.

16. Sundstrom J, Sullivan L, D’Agostino RB, Levy D, Kannel WB, Vasan RS. Relations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence. Hypertension 2005;45(1):28-33. 17. Mellen PB, Bleyer AJ, Erlinger TP, Evans GW, Nieto FJ,

Wagenknecht LE, et al. Serum uric acid predicts incident hypertension in a biethnic cohort: the Atherosclerosis Risk in Communities study. Hypertension 2006;48:1037-42.

18. Choi HK, Ford ES. HaemoglobinA1c, fasting glucose, serum C-peptide and insulin resistance in relation to serum uric acid levels-the Third National Health and Nutrition Examination Survey. Rheumatology (Oxford) 2008; 47(5):713-7.

(103)

Page 79

20. Ohlson LO, Larsson B, Bjontorp P, Eriksson H, Svardsudd K, Welin L, et al. Risk factors for type 2 diabetes mellitus. Thirteen and one-half years of follow-up of the participants in a study of Swedish men born in 1913. Diabetologia 1988; 31(11):798-805.

21. Wang J, Chen RP, Lei L, Song QQ, Zhang RY, Li YB, et al. Prevalence and determinants of hyperuricemia in type 2 diabetes mellitus patients with central obesity in Guangdong Province in China. Asia Pac J Clin Nutr 2013;22(4):590-8.

22. Liu B, Wang T, Zhao HN, Yue WW, Yu HP, Liu CX et al. The prevalence of hyperuricemia in China: a meta-analysis. BMC Public Health 2011;11:832-5.

23. Powers C A In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison’s principles of internal medicine.19th ed. New York (NY): The McGraw Hill companies: Medical Publishing Division;2015:2399-24225

24. Eckel RH In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison’s principles of internal medicine.19th ed. New York: The McGraw Hill companies: Medical Publishing Division; 2015:2449-2454

(104)

Page 80

26. Zargar AH, Khan AK, Masoodi SR, Laway BA, Wani AI, Bashir MI, Dar FA. Prevalence of type 2 diabetes mellitus and impaired glucose tolerance in the Kashmir Valley of the Indian subcontinent. Diabetes Res Clin Pract 2000;47(2):135-46.

27. Rao CR, Kamath VG, Shetty A, Kamath A. A cross-sectional analysis of obesity among a rural population in coastal southern Karnataka, India. Australas Med J 2011;4(1):53-7.

28. Mohan V, Deepa R. Obesity and abdominal obesity in Asian Indians. Indian J Med Res 2006;123(5):593-6.

29. Misra A, Khurana L. Obesity-related non-communicable diseases: South Asians vs White Caucasians. Int J Obes 2011;35(2):167-87.

30. Verma R, Khanna P, Mehta B. National programme on prevention and control of diabetes in India: Need to focus. Australas Med J 2012;5(6):310-5.

31. Brownlee M, Aiello LP, Cooper ME, Vinik AI, Nesto RW, Boulton AJM. Carbohydrates and Fat Metabolism In: Kroenberg HM, Melmed S, Polonsky KS, Larsen PR. Williams Textbook of Endocrinology.11th ed. Philadelphia: Elsevier; 2008. p 1417 -78. 32. Chaudhary K, Malhotra K, Sowers J, Aroor A. Uric acid - key

(105)

Page 81

33. Jin M, Yang F, Yang I, Yin Y, Luo JJ, Wang H et al. Uric acid, hyperuricemia and vascular diseases. Front Biosci 2012;17: 656-69. 34. KDIGO 2012 clinical practice guideline for the evaluation and

management of chronic kidney disease. Kidney Int Suppl 2013;3:5-14. 35. Nieto FJ, Iribarren C, Gross D, Comstock GW, Cutler RG. Uric acid

and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis 2000;148(1):131-9.

36. Hayden MR, Tyagi SC. Intimal redox stress. Accelerated atherosclerosis in metabolic syndrome and type 2 diabetes mellitus. Atheroscleropathy. Cardiovasc Diabetol 2002;1:3.

37. Conen D, Wietlisbach V, Bovet P, Shamlaye C, Riesen W, Paccaud F, Burnier M: Prevalence of hyperuricemia and relation of serum uric acid with cardiovascular risk factors in a developing country. BMC Public Health 2004;4(1):9-10.

38. Bonora E, Targher G, Zenere MB, Saggiani F, Cacciatoryi V, Tosi F, et al. Relationship of uric acid concentration to cardiovascular risk factors in young men. Role of obesity and central fat distribution, The Verona Young Men Atherosclerosis Risk Factors Study. Int J Obes Relat Metab Disord 1996;20(11):975-80.

(106)

Page 82

40. Vickers S, Schiller HJ, Hildreth JE, Bulkley GB. Immuno affinity localization of the enzyme xanthine oxidase on the outside surface of the endothelial cell plasma membrane. Surgery 1998;124(3):551-60. 41. Olexa P, Olexova M, Gonsorcik J, Tkac I, Kisel'ova J, Olejnikova M.

Uric acid - a marker for systemic inflammatory response in patients with congestive heart failure?. Wien Klin Wochenschr 2002; 114(5-6): 211-215

42. Bo S, Cavallo-Perin P, Gentile L, Repetti E, Pagano G. Hypouricemia and hyperuricemia in type 2 diabetes: two different phenotypes. Eur J Clin Invest 2001;31(4):318-21.

43. Lyu LC, Hsu CY, Yeh CY, Lee MS, Huang SH, Chen CL. A case-control study of the association of diet and obesity with gout in Taiwan. Am J Clin Nutr 2003; 78(4):690-701.

44. Rao U, Deepthi S. Gout and other crystal arthritides. In: Munjal YP, Sharma SK, Agarwal A, Singal RK, Gupta P, Sundar S et al. API Textbook of Medicine. 10th Edition. Mumbai: Jaypee Brothers Medical Publishers,2015.p.2483-91

(107)

Page 83

46. Saseen J. Essential hypertension. In: Alldredge BK, Corelli RL, Ernst ME, Guglielmo BJ, Jacobson PA, Kradjan WA, Williams BR, editors. Koda-Kimble and Young’s Applied Therapeutics: The Clinical Use of Drugs. 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. Chapter 14 47. Lee WJ, Sobrin L, Lee MJ, Kang MH, Seong M, Cho H. The

Relationship between Diabetic Retinopathy and Diabetic Nephropathy in a Population-Based Study in Korea (KNHANES V-2, 3). Invest Ophthalmol Vis Sci 2014; 55(10):6547-53.

48. Rani P, Raman R, Gupta A, Pal S, Kulothungan V, Sharma T. Albuminuria and Diabetic Retinopathy in Type 2 Diabetes Mellitus Sankara Nethralaya Diabetic Retinopathy Epidemiology And Molecular Genetic Study (SN-DREAMS, report 12). Diabetol Metab Syndrome 2011; 3(1):9.

49. Shabana S, Sireesha M, Satyanarayana U. Uric Acid in Relation to Type 2 Diabetes Mellitus Associated with Hypertension. J Clin Dia Res 2012;6(7):1140-3.

50. Kuzuya M, Ando F, Iquchi A, Shimokata H. Effect of aging on serum uric acid levels: longitudinal changes in a large Japanese population group. J Gerontol A Bio Med Sci 2002;57(10):M660-64

(108)
(109)

Figure

Fig. 1: Worldwide prevalence of diabetes mellitus23
Fig 2 : Prevalence of diabetes mellitus in India30
Fig 3: Mechanism of insulin secretion 23
Fig 4: Diabetic retinopathy leading to scattered haemorrhages,
+7

References

Related documents

We use hybrid encryption with Fuzzy Identity-Based Encryption (Fuzzy-IBE) schemes, and present the first and efficient fuzzy identity-based key encapsulation mechanism (Fuzzy-IB-KEM)

The findings imply that the inclusion of student as game designer approach in chemistry learning is able to help students develop an in-depth knowledge on

MiR-9 and miR-200 regulate PDGFRβ-mediated endothelial differentiation of tumor cells in triple negative breast cancer..

Experimental results with DC Link voltage balancing algorithm and device voltage drop, ON resistance compensation on the UNIFLEX-PM prototype: single DC-Link voltages on phase

Among all the respondents, who have said that conversion brings about changes, 29.7%(89) respondents have opined that conversion removes caste identity 13.0%(39) respondents

The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are

This manuscript describes, with emphasis on postoperative complications, our experience from the first 200 cases of unilateral hip replacement using the direct anterior

Blasted copper slag has a different chemical composition and physical properties compared to virgin copper slag.. as sizes of blasted copper slag would be smaller and impurities