Serum Gamma Glutamyl Transferase levels in Obese South Indian adults with reference to atherogenic lipid risk factors and lipid peroxides by wawanrini

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									                          International Journal of Medical and Health Sciences
                                   Journal Home Page: http://www.ijmhs.net ISSN:2277-4505




     Original article

     Serum Gamma Glutamyl Transferase levels in Obese South Indian adults with
            reference to atherogenic lipid risk factors and lipid peroxides

          Niranjan Gopal*1, Ajeet Selvam2, Srinivasan A R3, Saha S4, Prakash H Muddegowda5
            1
                Assistant Professor,3,4Professor,Department of Biochemistry, Mahatma Gandhi Medical College
                and Research Institute, Sri Balaji Vidyapeeth [SBV] University, Pillaiyarkuppam, Puducherry-
                                                        607402, India.
      2
          Final year MBBS, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth
                      [SBV] University, Pillaiyarkuppam, Puducherry-607402, India.
             5
                 Assistant Professor, Department of Pathology, VMKV Medical College, Salem.



ABSTRACT

Background: Obesity has reached epidemic proportions especially in South India. In recent years, Waist
circumference (WC), which reflects central obesity, has been regarded as an independent predictor of risk.
Generation of free radicals occurs in central obesity and depletes intracellular glutathione, thereby inducing
the production and release of Gamma Glutamyl Transferase [GGT] into circulation. High GGT levels are
known to be associated with Type 2 Diabetes mellitus, hypertension and related vascular complications.
Hence, this study was planned with a view to exploring the nexus among these components of metabolic
syndrome and serum GGT levels, especially as the characteristic biochemical events are not fully
understood and addressed yet.
Materials and methods: In this prospective study we included 41 obese and 39 non-obese adults who were
non-smokers and non-alcoholics, between the ages of 20 and 40 years. Lipid profile, Malondialdehyde
(MDA), Fasting Plasma Glucose (FPG), blood pressure (BP) and GGT activity were measured in both the
groups. Data were compared with un-paired student t-test. Pearson’s correlation was used to find the
association of serum GGT levels with other variables in obese individuals.
Results: Atherogenic dyslipidemia was documented in obese individuals which was associated with
significantly elevated levels of serum GGT (p<0.001). High levels of serum GGT were also associated
significantly with increase in BP (p<0.001), Lipid peroxidation [(serum MDA), (p<0.05)] and atherogenic
lipid ratios [(TC/HDL, LDL/HDL) (p<0.001)].
Conclusions: Elevated serum GGT levels are associated with the components of metabolic syndrome and
high degree of lipid peroxidation in obese South Indian adults.

KEYWORDS: Obesity, GGT, Atherosclerosis, Lipid profile, Oxidative stress.


Int J Med Health Sci. April 2012,Vol-1;Issue-2                                                             35
INTRODUCTION                                             levels, especially in South Indian population,
                                                         where there is a paucity of published reports.
Gamma Glutamyl transferase [GGT] also known
as Gamma Glutamyl Transpeptidase has long
been used in the diagnosis of hepato-biliary             Aim and objectives
diseases, primarily fatty liver and cholestasis. It is   1. To explore the association of GGT levels with
also an excellent diagnostic marker of alcoholic            fasting plasma glucose, waist circumference,
liver disease [1]. GGT is expressed in the liver,           blood pressure, lipid peroxidation, lipid profile
kidney,     cerebrovascular      endothelium     and        and lipid ratios in the obese south Indian
pericytes and is an enzyme responsible for the              population.
extracellular catabolism of antioxidant glutathione      2. To compare the above mentioned parameters
and acts as a pro-oxidant in the extracellular              with non-obese age and gender matched
space. Elevated serum GGT levels may be a                   healthy control group.
reflection of high degree of oxidative stress and
oxidative stress is known to be associated with
central obesity. Serum Malondialdehyde (MDA)             MATERIALS AND METHODS
is a well known marker of degree of lipid
peroxidation in vivo. [2]. High levels of GGT have       Sample size: In this prospective study, we included
also been found to be associated with various            41 obese individuals (cases) and 39 healthy non-
atherosclerotic risk factors such as Diabetes            obese (controls) adults who were non-smokers and
mellitus, hyperlipidemia, and hypertension,              non-alcoholics, between the ages of 20 and 40
independent of alcohol consumption and hepatic           years.
dysfunction. Moreover, certain documented                 Exclusion criteria [for both the groups]: Subjects
evidences are available suggesting a direct link         with liver diseases like alcoholic liver disease,
between increased GGT activity and occurrence            cholestasis and hepatitis were excluded from the
or progression of atherosclerosis [3-6].                 study. People who were on anti epileptics and other
Obesity has reached epidemic proportions in India        drugs were also excluded from the study. A proper
in the 21st century with morbid obesity affecting        informed consent was obtained from all the
5% of the Indian population. Obesity when                subjects. This was a prospective case control study
unchecked does lead to a host of lifestyle diseases      conducted in the Department of Biochemistry at a
[7]. The root cause of all diseases like Diabetes        tertiary centre with equipped clinical laboratory
mellitus, hypertension, coronary artery disease          facilities.
and stroke has been traced to obesity [8-10].            Study Parameters: Waist circumference was
                                                         measured using standard measuring tape at the level
Waist circumference (WC) which reflects central          of the upper hip bone with the tape being snug
obesity is an independent and better predictor of        without compressing on the skin. Blood pressure
risk compared to body mass index and waist hip           was measured by standard sphygmomanometer
ratio. Males with WC more than 40 inches and             (Manual) in supine posture; while the lipid profile
females more than 35 inches are known to be at a         and GGT were estimated with the auto analyzer
higher risk. A high WC is known to be associated         [Hitachi-902 chemistry analyzer] using procedures
with an increased risk of type 2 Diabetes mellitus       approved by International Federation of Clinical
(Type 2 DM), dyslipidemia, hypertension and              Chemistry and Laboratory Medicine [IFCC]. Five
coronary vascular disease. There are ethnic and          ml of fasting (post-absorptive) venous blood sample
age related differences in body fat distribution that    was collected from the subjects and the following
modify the predictive validity of WC as a                parameters were estimated.
surrogate marker of abdominal fat [11, 12]. With               Fasting plasma glucose: glucose oxidase and
the increasing association among obesity,                         peroxidase method.
hypertension, fatty liver and atherosclerosis in the           GGT: Carboxy substrate method
background, we proposed this study to compare                  Total           cholesterol:      cholesterol
the various risk factors, as related to obesity, in               esterase/oxidase method
the light of GGT                                               Triacyl glycerol: Lipase-glycerol kinase
                                                                  method.

Int J Med Health Sci. April 2012,Vol-1;Issue-2                                                            36
    LDL cholesterol: is calculated by                      was considered as significant for all statistical
     Friedwald’s equation                                   purposes. SPSS version17 for Windows was used
    HDL cholesterol: polyanion precipitation               for all statistical analysis. (SPSS Inc.,Chicago,
     method                                                 USA).
    VLDL was calculated by the formula
     VLDL= TAGs/5                                             RESULTS

    Serum MDA by OxiSelect™ Thiobarbituric                   The age and gender distribution of the study
     acid reactive species (TBARS) Assay Kit for              population is depicted in Table 1. There was
     MDA Quantitation by colorimetry.                         no significant difference in the mean age and
                                                              gender of participants between the two
Statistical analysis: Data were expressed as mean             groups. All physiological and Biochemical
+/- SD; un-paired student t- test was used to                 parameters were expressed as mean±SD;
compare the data. For exploring the association               results were compared by using un-paired
between serum GGT levels and other variables                  Student t test.
Pearson’s correlation was used. A p value <0.05

        Table 1: Age and gender distribution of the study population
                   variables                             Cases                      Controls
                                                         (n=41)                       (n=39)
          Gender               Male                   24 (58.53%)                  21 (53.84%)
                               Female                 17 (41.46%)                  18 (46.15%)
          Age group            20-30                  28 (68.29%)                  26 (66.67%)
          (years)              30-40                  13 (31.70%)                  13 (33.34%)



        Table 2: Comparison of Age, blood pressure and waist circumference between the
        cases and controls.
                                                               Controls
                                        Cases (n=41)                            p value
                     Variables                                  (n=39)
                                        [Mean ± SD]
                                                             [Mean ± SD]
                 Age (years)                 35.8 ± 4.82             33.8 ± 6.06
                                                                                          0.09
                SBP (mm/Hg)                  145±14.81                120±2.79
                                                                                        0.0006*

               DBP (mm/Hg)                   93.4 ±10.24             79.7 ± 2.12
                                                                                          0.0004*


                WC (inches)                  45.6 ± 7.15              33.3 ±3.99
                                                                                          0.0006*
  SBP = Systolic Blood Pressure, DBP = Diastolic Blood Pressure, WC = Waist Circumference, SD = Standard
 Deviation, *p value <0.001.


Waist circumference, systolic and diastolic blood           0.001. But there was no significant difference in
pressures were significantly high in obese subjects         the mean ages of the participants between the two
compared to the control group with p value <                groups. (Table 2).


Int J Med Health Sci. April 2012,Vol-1;Issue-2                                                                37
       Table 3: Comparison of serum lipids between the cases and controls.
                                                             Control                 p value
                                   Cases (n=41)
             Parameters                                       (n=39)
                                    [Mean ± SD]
                                                          [Mean ± SD]
           Total cholesterol                                                       0.0004†
                                    215.1 ±35.22           164 ±48.21
                (mg/dL)
           Triacylglycerols                                                         0.021*
                                   166.1 ± 63.98           112 ±52.24
                (mg/dL)
           LDL-Cholesterol                                                       0.0004†
                                     139 ±31.04           100.4 ±40.71
                (mg/dL)
           HDL-Cholesterol                                                       0.0008†
                                     31.6 ±5.90              41 ±8.50
                (mg/dL)
          VLDLCholesterol                                                        0.0006†
                                     45.8 ±14.03           22.4 ±10.45
                (mg/dL)
  LDL=Low Density Lipoprotein, VLDL=Very Low Density Lipoprotein, HDL= High Density Lipoprotein. *p
 value <0.05, † p value < 0.001.

 Table-3 shows that total cholesterol,                  were significantly low in cases. Alteration in
 triacylglycerols and LDL cholesterol levels            the fasting lipid profile indicates pro-
 were significantly high in cases as compared           atherogenic dyslipidemia in obese subjects.
 to controls; while HDL-cholesterol levels
        Table 4: Comparison of lipid ratios between the cases and controls.

                                                             Controls
                                    Cases (n=41)                                   p value
            Lipid Ratios                                      (n=39)
                                    [Mean ± SD]
                                                           [Mean ± SD]

               TC/HDL                  8.2 ±2.4             5.11 ± 1.04           0.0004*

              LDL/HDL                  4.5±1.25              2.5±1.35             0.0007*

 TC= Total Cholesterol, LDL=Low Density Lipoprotein, VLDL=Very Low Density Lipoprotein, HDL= High
 Density Lipoprotein. *p value < 0.001.

 Table-4 shows that the lipid ratios were                ratios support pro-atherogenic dyslipidemia in
 significantly higher in obese individuals as            obese subjects.
 compared to controls. Alterations in the lipid

 Table 5: Comparison of serum GGT, MDA and Fasting Plasma Glucose
          levels between the cases and controls
                                                                 Control
                                          Cases (n=41)                            p value
                Parameters                                        (n=39)
                                          [Mean ± SD]
                                                               [Mean ± SD]
             Serum GGT (IU/L)              33.3±25.50            19.7±7.7           0.002*

           Serum MDA (µmol/L)               2.19 ± 2.2          1.58 ± 1.6          0.003*

                FPG (mg/dl)                86.5 ± 14.7          81.5 ± 11.4          0.08


 GGT = Gamma glutamyl transferase, FPG = Fasting Plasma Glucose, MDA=Malondialdehyde. *p value < 0.05.
Int J Med Health Sci. April 2012,Vol-1;Issue-2                                                            38
 Table-5 depicts GGT levels in cases which                 = 0.03). But there was no statistically
 were significant. (p value = 0.002). Serum                significant difference in Fasting Plasma
 MDA levels were significantly high in obese               Glucose between the two groups.
 individuals compared to the control group (p

 Table 6: Correlation of serum GGT levels with other variables in cases

                                            WC            SBP             DBP           FPG         MDA
    VARIABLES

                              r            0.62           0.54            0.45          0.23         0.33

     Serum GGT                p           0.000*        0.001*           0.002*         0.08        0.03*


 WC = Waist Circumference (Inches), SBP = Systolic Blood Pressure (mmHg), DBP = Diastolic Blood Pressure
 (mmHg), FPG = Fasting Plasma Glucose (mg/dl), MDA= Malondialdehyde (µmol/L), GGT = Gamma Glutamyl
 Transferase (IU/L). *p value < 0.05.


 Table 7: Correlation of serum GGT levels with serum lipids in cases.
                                                                                     VLDL
                                            TC           LDL           TAG                          HDL
     VARIABLES
                                                                                      0.69          -0.43
                               r            0.69         0.64          0.71
      Serum GGT                                                                      0.002*        0.002*
                              p            0.000*       0.000*        0.000*


 TC= Total Cholesterol (mg/dl), LDL=Low Density Lipoprotein (mg/dl), VLDL=Very Low Density
 Lipoprotein(mg/dl), HDL= High Density Lipoprotein (mg/dl), GGT = Gamma Glutamyl Transferase (IU/L). *p
 value < 0.05.


 Tables 6 and 7 shows the results of Pearson’s             when we correlated serum GGT levels with
 correlation analysis between the serum GGT                all the variables, with the exception of FPG
 levels and other variables. Statistically                 levels. A significant negative correlation was
 significant positive correlation was observed             observed with serum HDL levels.

 DISCUSSION
 In the present study, levels of serum GGT                 higher among the cases. It is known that GGT
 were measured in obese subjects (cases) and               has a protective effect in maintaining
 compared with that of healthy non-obese                   appropriate intracellular glutathione levels,
 control population who were life time non-                which is a powerful antioxidant. Therefore, it
 alcoholics. Pukka et al., in their study showed           is possible that the generation of free radicals,
 that GGT levels rise with age in both sexes               which can occur in central obesity, may
 [13]. In this study, the mean age of the cases            deplete intracellular glutathione and thus
 was not significantly different from that of              induce the activity of GGT into the
 controls (Table 1). Alcoholics and the                    circulation. Oxidative stress with the
 subjects with age >60 years in both sexes                 attendant low-grade inflammation has been
 were excluded from our study. The major                   implicated in a number of pathological
 difference between the two groups was the                 conditions, including aging, atherosclerosis
 waist circumference which was significantly               and Diabetes mellitus [14-18].

Int J Med Health Sci. April 2012,Vol-1;Issue-2                                                                 39
 It is known that GGT catalyzes the oxidation       hypertension, Type 2 DM and coronary artery
 of LDL and conversion of LDL to oxidised           disease.
 LDL, a process involved in the pathogenesis
 of atherosclerosis [19, 20]. The study              This study clearly demonstrates that
 demonstrates that dyslipidemia, high systolic       documentation of high serum GGT levels in
 and diastolic blood pressure in obese               individuals may not be attributed only to
 individuals are associated with elevated levels    alcoholism [1] but, it could serve as an
 of GGT- a putative marker of sub-clinical          indicator of higher          oxidative stress,
 atherosclerosis. Although there was no             inflammation and fatty liver in obese
 significant difference in FPG levels between       individuals. Therefore, GGT could function as
 the two groups, the previous studies have          an early predictor and reliable marker of sub-
 confirmed elevated GGT levels in Type 2            clinical atherosclerosis and its complications.
 DM cases [4, 5]. This depicts the fact that        In routine practice sophisticated techniques
 elevated GGT levels with accompanying              such as echocardiography, colour doppler and
 dyslipidemia and hypertension could be used        other radiological imaging modalities are
 as diagnostic predictors, independent of           utilized to detect vascular abnormalities
 pronounced elevation in FPG. Our study             resulting from atherosclerosis. However, the
 clearly demonstrates low HDL, high LDL,            modalities are hampered by lack of
 high total cholesterol/HDL ratio and high          availability in primary and secondary health
 LDL/HDL ratio in cases when compared to            care centres, besides the cost factor.
 the control group. Moreover, we also               Morbidity associated with vascular changes
 documented significant positive correlation of     still goes undetected, especially in view of the
 serum GGT with the components of                   lower socio-economic status of the
 metabolic syndrome. Estimation of serum            population. Estimation of GGT levels in
 GGT levels can thus help us to assess the risk     serum could reflect a pragmatic approach.
 of      impending       complications      like    However, further studies on a larger
 hypertension, atherosclerosis, Type 2 DM and       population would provide a better insight.
 coronary artery disease in obese individuals.
 Elevation of serum GGT activity is a risk          CONCLUSION
 factor for myocardial infarction and stroke
 [21-23].                                           We conclude that there is a significant
                                                    association of elevated serum GGT levels
 Hence,      necessary      non-pharmacological     with the anthropometric, physiological and
 interventions can be initiated in these subjects   biochemical components of metabolic
 that    include      lifestyle   and     dietary   syndrome namely; WC, blood pressure,
 modifications. High serum GGT is associated        impaired FPG, atherogenic dyslipidemia.
 with oxidative stress [13-18]. Even in this        High serum GGT is also associated with a
 study we documented a high degree of lipid         higher degree of lipid peroxidation in
 peroxidation      in      obese     individuals.   individuals with central obesity. GGT in
 Supplementation of anti-oxidants will              serum could thus be used as a screening test
 definitely help in reducing the risk of various    especially in primary and secondary health
 complications related to atherosclerosis and       care centres to assess the risk of developing
 Type 2 DM. GGT estimation can be a useful          various complications related to central
 and cost-effective screening procedure             obesity.
 especially in rural population to assess the
 risk of developing various complications           IMPLICATIONS           &     SCOPE        FOR
 related to atherosclerosis. Hence, GGT could       FUTURE STUDY
 be a simple, sensitive and reliable diagnostic
 tool that can be included in the routine           There is a paucity of published data in this
 armamentarium of investigations pertaining         field, on South Indian population, where there
 to the individuals on treatment for                is a rising incidence of morbid obesity related
                                                    complications especially diabetes mellitus,

Int J Med Health Sci. April 2012,Vol-1;Issue-2                                                         40
 atherosclerosis and coronary artery disease.           aged Japanese men. Diabetes Care
 Documentation of high serum GGT levels                 2004;27: 1427 –1432.
 could help us to advocate pharmacological
 and non-pharmacological interventions to            6. Paolicchi A, Emdin M, Passino C,
 prevent the further complications in                    Lorenzini E, Titta F, Marchi S, et al. Beta-
 individuals with central obesity. Lifestyle and         Lipoprotein- and LDL-associated serum γ-
 dietary modifications, in addition to                   Glutamyl transferase in patients with
 supplementation of anti-oxidants, could                 coronary atherosclerosis. Atherosclerosis
 reduce the incidence of various complications           2006;186:80-85.
 related to atherosclerosis and Type 2 DM.           7. Varghese RT, Vijaykumar K. Prevalence
 However; further studies on a larger                    pattern of obesity across different age
 population are needed in South India on                 groups in a rural setting in Kerala. Calicut
 direct association of GGT with the degree of            Medical Journal 2008;6(1):e3.
 atherosclerotic process. The effects of life        8. Agrawal PK. Emerging obesity in North
 style changes and supplementation of anti-              Indian States: A serious threat for health.
 oxidants on serum GGT can also be explored.             Paper presented at: IUSSP Conference;
                                                         2002, June 10-12;Bangkok.
Acknowledgements:        Authors     gratefully      9. Jousilahti P, Rastenyte D, Tuomilehto J.
acknowledge ICMR for the grant of STS 2011               Serum g-glutamyl 12. transferase, self-
fellowship. We thank Dr. D R Gunasekaran, Vice           reported alcohol drinking, and the risk of
chancellor, SBV University and Dr. N                     stroke. Stroke 2000; 31:1851-5.
Ananthakrishnan, Prof and Head Dept of               10. Lee DH, Jacobs DR Jr, Gross M, Kiefe
Gastroenterology, MGMCRI for their kind                  CI, Roseman J, 11. Lewis CE, et al.
support and encouragement.                               Gamma-glutamyl transferase is a predictor
                                                         of incident diabetes and hypertension : the
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Int J Med Health Sci. April 2012,Vol-1;Issue-2                                                                   42

								
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