Relationship of Metabolic Syndrome Dened by IDF or Revised NCEP with Glycemic Control among Malaysians with Type 2 Diabetes

Background Chronic complication of Type 2 Diabetes (T2D) such as macrovascular disease is amplied with the increase in the number of the metabolic syndrome (MetS) risk factors. Specic criteria for diagnosis of MetS are essential to help in glycemic control and reduce cardiovascular morbidity and mortality in diabetic patients with metabolic syndrome. Methods The study is cross-sectional observational study which involved 485 T2D patients who are receiving treatment at the University Kebangsaan Malaysia Medical Center (UKMMC), Kuala Lumpur, Malaysia. Metabolic syndrome among the T2D patients was diagnosed based on IDF and NCEP-R criteria. C-peptide and glycated hemoglobin (HbA1c) levels were determined by an automated quantitative immunoassay analyzer and high-performance liquid chromatography, respectively. The metabolic syndrome factors, glucose, triglyceride and HDL cholesterol were measured by spectrophotometer Results Application of IDF and NCEP-R criteria respectively resulted in 73% and 85% of T2D subjects being diagnosed with MetS. The concordance of these criteria in diagnosing MetS among T2D was low (κ =0.33, P<0.001). Both IDF and NCEP-R criteria indicated that T2D with ve criteria of MetS had higher insulin resistance (P=2.1×10 -13 , P=1.4×10 -11 ), C-peptide (P=1.21×10 -13 ; 4.1×10 -11 ), blood glucose (P=0.01; 0.021) and HbA1c (P=0.039; 0.018) than those T2D without MetS respectively. Conclusion Although, there is a low concordance between IDF and NCEP-R criteria in the diagnosis of MetS among T2D, both criteria showed that T2D with ve criteria of MetS had higher insulin resistance, blood glucose and HbA1c. diabetes with 4 metabolic syndrome criteria versus diabetes with 3 criteria of metabolic syndrome.


Abstract
Background Chronic complication of Type 2 Diabetes (T2D) such as macrovascular disease is ampli ed with the increase in the number of the metabolic syndrome (MetS) risk factors. Speci c criteria for diagnosis of MetS are essential to help in glycemic control and reduce cardiovascular morbidity and mortality in diabetic patients with metabolic syndrome.
Methods The study is cross-sectional observational study which involved 485 T2D patients who are receiving treatment at the University Kebangsaan Malaysia Medical Center (UKMMC), Kuala Lumpur, Malaysia. Metabolic syndrome among the T2D patients was diagnosed based on IDF and NCEP-R criteria. C-peptide and glycated hemoglobin (HbA1c) levels were determined by an automated quantitative immunoassay analyzer and high-performance liquid chromatography, respectively. The metabolic syndrome factors, glucose, triglyceride and HDL cholesterol were measured by spectrophotometer Results Application of IDF and NCEP-R criteria respectively resulted in 73% and 85% of T2D subjects being diagnosed with MetS. The concordance of these criteria in diagnosing MetS among T2D was low (κ =0.33, P<0.001). Both IDF and NCEP-R criteria indicated that T2D with ve criteria of MetS had higher insulin resistance (P=2.1×10 -13 , P=1.4×10 -11 ), C-peptide (P=1.21×10 -13 ; 4.1×10 -11 ), blood glucose (P=0.01; 0.021) and HbA1c (P=0.039; 0.018) than those T2D without MetS respectively.
Conclusion Although, there is a low concordance between IDF and NCEP-R criteria in the diagnosis of MetS among T2D, both criteria showed that T2D with ve criteria of MetS had higher insulin resistance, blood glucose and HbA1c.

Background
The burden of non-communicable disease in the developing countries is increasing, and leading to high mortality rates [1]. Nowadays Type 2 Diabetes (T2D) is pandemic. According to international diabetes federation report indicates that more than 415 million of people worldwide adults have diabetes and is expected to rise to 642 million by 2040 [2]. The metabolic syndrome (MetS) is complex with high socioeconomic impact due to its association with increased morbidity and mortality [3]. Metabolic syndrome has attracted increased attention due to its signi cant impact on cardiovascular diseases (CVD) and its high prevalence in T2D patients [4][5][6][7][8][9]. Metabolic syndrome can be de ned as a cluster of interconnected cardio-metabolic dysfunctions which is characterized by the increase in fasting blood sugar, waist circumference, blood pressure, triglycerides (TG), and reduction in high-density lipoprotein cholesterol (HDLc) [10,11].
Globally, 20-25% of the adult population has MetS and they are twice as likely to die from it; and they are three times more likely to have a heart attack or stroke compared with people without the syndrome [2,12]. This increase in MetS globally is associated with the worldwide epidemic of obesity and diabetes.
Obesity and physical inactivity are the driving force for MetS and a person with MetS has 5-fold relative risk to develop diabetes [6,[13][14][15]. Overweight and obesity lead to adverse metabolic effects on blood pressure, HDL cholesterol, TG and impaired glucose tolerance (IGT) [16].
The National Cholesterol Education Programs Adult Treatment Panel III (NCEP-ATPIII) proposed a simple set of diagnostic criteria for MetS based on waist circumference, TG, HDL-C, blood pressure, and fasting glucose level [17]. In 2005, the International Diabetes Federation (IDF) modi ed the MetS de nition, which stated that waist circumference is necessary for the diagnosis of MetS along with any two of the other MetS parameters that were suggested by NCEP while IDF included the treatment of the above parameters as well [18]. In the same year the American Heart Association and the National Heart, Lung, and Blood Institute revised the NCEP criteria and a rmed its overall utility and validity and proposed that it continued to be used with minor modi cations and clari cations [19] (Table 1).  [20]. In this meeting, the IDF criteria was modi ed and it was agreed that waist circumference should not be an obligatory component and three abnormal ndings out of 5 would qualify a person for the MetS. However, there is no consensus on the de nition of MetS worldwide.
Studies revealed that the impact of different de nitions of MetS on the risk of future CVD and diabetes is discrepant [21,22].
Several studies have assessed the MetS among normal individual in different populations whereas few studies assessed the MetS among T2D. Taking into consideration, diabetic patients who had MetS also have cardiovascular risk factors, therefore the diagnosis of MetS in those patients is very important for detection, prevention, and treatment of the underlying risk factors and for the reduction of the cardiovascular disease burden in the general population [23,24]. This research aims to study the relationship of metabolic syndrome, diagnosed by International Diabetes Federation or the revised National Cholesterol Education Programs (NCEP-R) criteria, with glycemic control including fasting glucose, glycated hemoglobin, C-peptide and insulin resistance in T2D patients.

Study design and subjects
The current study was cross-sectional observation study. Four hundred and eighty-ve previously diagnosed T2D patients aged between 30 and 70 years attending the University Kebangsaan Malaysia Medical Center, Kuala Lumpur, Malaysia were randomly recruited into the study after obtaining their informed consent. Ethical approval was obtained from the National University of Malaysia Research and Ethics committee.

Sample and data collection
Waist circumference was measured midway between the lower rib margin and the superior iliac spine at the end of gentle expiration in a standing position. Blood pressure (BP) measurements were taken from each patient's right arm in the seated position by using an Omron IntelliSense Automatic Blood Pressure Monitor after 10 min rest in a quiet room. Two to three successive BP readings were obtained at 5 minutes intervals and averaged. Fasting blood (5ml) was collected from each subjected and divided into two tubes, EDTA tube for HbA1c measurement and plain tubes for biochemical investigations. The plain tubes were centrifuged for 10 minutes at 3000 × g within 30 minutes of blood collection and the serum from each sample was separated into two Eppendorf tubes and immediately kept at −20°C until analysis.

Statistical analysis
The analyses were assessed by SPSS version 11.5 software (SPSS, Inc, Chicago, USA). The fasting blood glucose, glycated hemoglobin, C-peptide, and insulin resistance were log transformed as they were not normally distributed. Mean and 95% con dence intervals were transformed back and reported. The Cohen's Kappa (κ) test was used to evaluate the concordance between the IDF and NCEP-R criteria. The general linear model adjusted for age, sex, race and history of diabetes (as covariates) was used to study the correlation of MetS with glycemic control; fasting blood glucose, glycated hemoglobin, C-peptide and insulin resistance (as a set of dependent variables).

Results
Four hundred and eighty-ve previously diagnosed T2D subjects agreed to participate in this project. These patients were on insulin and/or oral antidiabetic medications (98%) followed by antihyperlipidemic agents (65%) and antihypertensive medications (64.5%). Three hundred fty-six (73%) and 415 (85%) out of the 485 T2D had MetS when de ned by the of IDF and NCEP-R criteria respectively ( Table 2). Application of the harmonizing de nition of the metabolic syndrome on T2D resulted in more than 97% of T2D with metabolic syndrome, thus this de nition could not be included in this study. The IDF and NCEP-R criteria concurred the diagnosis of MetS in 331 (68%) T2D, while 25 (5%) were diagnosed as MetS by the IDF but not by NCEP-R and 84 (17%) by NCEP-R criteria but not by IDF (κ 0.33, P<0.001). NCEP-R criteria showed that not much differences in the prevalence of MetS between diabetic women (87%) and diabetic men (84%); while IDF criteria showed that the prevalence of MetS was higher in diabetic women (82%) than in diabetic men (62%). NCEP-R criteria showed that the highest prevalence of MetS was found in Malay (88%) followed by Malaysian Indian (85%) and Malaysian Chinese (81%); whereas IDF criteria showed that the highest prevalence of MetS was found among Malaysian Indians (83%) followed by the Malays (74%) and the lowest was among the Malaysian Chinese (67%). Both criteria showed higher prevalence's of MetS among women than men within the three races with low concordance particularly among the Malaysian Indian women (κ =0.08, P=0.54) table (2).
Multivariate analysis of covariance in both IDF and NCEP-R criteria revealed a signi cant relationship for metabolic syndrome, Λ' = 0.865 and 0.855 P= 4.8×10 -10 and 4.7×10 -11 with powers to detect relationship were at 0.99998 and 0.99997 respectively. Type 2 diabetic patients with 5 MetS factors de ned by IDF or NCEP-R criteria had signi cantly higher FBG (P= 0.01, P=0.021) than T2D without metabolic syndrome (Table 3 and 4). While both criteria did not show statistical difference between T2D with 4 or 3 MetS parameters and T2D without metabolic syndrome. HbA1c was higher in T2D with ve criteria of MetS than T2D without metabolic syndrome (P= 0.039, P= 0.018) in both IDF and NCEP-R criteria. Whereas IDF criteria showed that T2D patients with 5 criteria of MetS had a signi cantly higher HbA1c than T2D with 4 or 3 criteria of MetS (P= 0.034, P= 0.005 respectively).   C-peptide was signi cantly higher in T2D having ve MetS factors (P= 1.21×10 -13 , P= 4.1×10 -11 ) or four MetS factors (P= 2.33×10 -5 , P= 1.5×10 -7 ) than those who were T2D without metabolic syndrome using both IDF and NCEP-R criteria respectively (Table 3 and 4). The NCEP-R criteria showed that T2D with three MetS factors had a signi cantly higher C-peptide than T2D without metabolic syndrome (P= 0.004), whereas the IDF criteria showed no difference (P= 0.096). Both IDF and NCEP-R criteria showed a signi cantly higher C-peptide in T2D who had 5 MetS factors than those who had 4 (P= 0.006; 0.005) or 3 factors of metabolic syndrome (P= 7.1×10 -5 ; 1.4×10 -6 ).

Discussion
In the present study, the prevalence of MetS among T2D was higher according to NCEP-R criteria compared to IDF and the concordance between these two criteria was low. However, in German Type 2 diabetes, IDF criteria showed more MetS than NCEP-R with a higher concordance (0.69) [25]. Whereas in United Kingdom the modi ed NCEP Criteria (BMI 28.8 kg/m 2 used instead of waist circumference) showed a higher prevalence than IDF with 0.60 concordance between these criteria [26]. Recent study among Ethiopen showed that NCEP criteria was higher than IDF (70% vs 60% with moderate concordance K=0.54) [27]. The low agreement between the IDF and revised NCEP criteria in this study is essentially explained by differences in the contribution of waist circumference to the de nition of these two criteria.
The IDF stated that waist circumference is necessary for the diagnosis of MetS along with two other MetS factors; while revised NCEP de ned MetS as any three MetS factors. The difference in concordance between the MetS diagnostic criteria in different populations is probably due to ethnic characteristics, dietary habits, and lifestyle, thus making it di cult to use a single diagnostic criterion for all populations.
The prevalence of MetS in our Malaysian T2D de ned by IDF was similar to that reported in Ethiopians [28], Nepalese [29], Iranian [30], sub-Saharan Africans [31], and White American (70%) but higher than the Black (65%) and Mexican Americans (62%) [32] even though NCEP criteria were used in their study. On the other hand, a lower prevalence of MetS was reported from India 45.8, 57.7 and 28% using NCEP-ATP III, WHO and IDF criteria respectively [9] and Ghana 43.83% with NCEP-ATP III, 63.58% with WHO, and 69.14% with IDF criteria [34]. Similarly, lower prevalence of MetS was reported in recent studies from Ethiopia 53.5% in IDF whereas 66.7% in the NCEP-ATPIII criteria [35] and from Sri Linka 28.9%, 43.8%, and 70.6% using NCEP-ATP III, IDF, and WHO criteria, respectively [36]. A previous study reported higher prevalence of MetS in Malaysia Type 2 diabetics 96.1%and 84.8% according to NCEP ATP III and IDF de nitions, respectively [37].
The increased waist circumference was more frequent in women (89% and 59%) than men (68% and 23%) when de ned by IDF and NCEP-R respectively resulting in a higher prevalence of MetS in women than men, which is in agreement with previous studies [26,29,36,38,39]. According to a large population survey conducted, female diabetics were more obese compared to male diabetics (13% and 10%, respectively) [40]. In addition, diabetic women are more likely than men to have hypertension, low levels of HDL cholesterol and high levels of triglycerides [41]. Higher prevalence of MetS in females may be due to the higher HDL cut-off and lower waist circumference cut-off values in females as compared to males. Hence, more females than males can be recognized as having metabolic syndrome.
In general, IDF and NCEP-R criteria are the most applicable for epidemiological studies and clinical diagnosis ofMetS. However, the concordance between these two criteria was low for the diagnosis of MetS among Malaysian T2D. NCEP-R criteria utilized American data while IDF criteria based on accumulated international data. There is an ethnic difference in waist circumference, which was considered by IDF. Although IDF and NCEP-R criteria were in low concordance for the diagnosis of MetS among Malaysian patients with Type 2 diabetes, there was a similar relationship of MetS particularly in the patients with 5 criteria, as de ned either by IDF or NCEP-R, with glycemic parameters (insulin resistance, C-peptide, blood glucose and HbA1c). Type 2 diabetic patients with MetS have higher central obesity, which is associated with higher insulin resistance and higher blood pressure [16]. Accumulation of lipids in the liver and muscle of T2D has been shown to aggravate the insulin resistance [42]. This resulted in increased glucose production by the liver and less glucose conversion into glycogen by muscles. Consequently, beta cells compensated the insulin resistance via increased insulin production.

Conclusion
The relationship of metabolic syndrome, as de ned by either IDF or NCEP-R criteria, with insulin resistance and poor glycemic control were similar with a low concordance between IDF and NCEP-R criteria in the diagnosis of MetS among T2D. Based on the nding of our study as well as many other studies, it is clear that the different de nitions of MetS give rise to different prevalence. In fact, the difference between the two criteria is in the de nition of MetS which requires more consideration as chronic complication of T2D is ampli ed with metabolic syndrome. Availability of data and materials The data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate The study was approved by National University of Malaysia Research and Ethics committee. Written informed consent was obtained from each participant before the sample collection.

Consent for publication
Not applicable.