|ORIGINAL RESEARCH REPORT
|Year : 2016 | Volume
| Issue : 1 | Page : 17-22
The role of inflammation in the metabolic syndrome
Ifeoma C Udenze1, Casmir E Amadi2, Nicholas A Awolola3, Christian C Makwe4, Obiefuna I Ajie1
1 Department of Clinical Pathology, College of Medicine, University of Lagos, Lagos, Nigeria
2 Department of Medicine, College of Medicine, University of Lagos, Lagos, Nigeria
3 Department of Anatomic and Molecular Pathology, College of Medicine, University of Lagos, Lagos, Nigeria
4 Department of Obstetrics and Gynaecology, College of Medicine, University of Lagos, Lagos, Nigeria
|Date of Web Publication||2-Feb-2016|
Ifeoma C Udenze
Department of Clinical Pathology, Faculty of Clinical Sciences, College of Medicine, University of Lagos, Idi-Araba, Lagos PMB 12003, Lagos
Source of Support: None, Conflict of Interest: None
Aims and Objectives: The aim of this study is to determine the plasma levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα) and C-reactive protein (CRP) in adult Nigerians with the metabolic syndrome and to determine the relationship between components of the metabolic syndrome and CRP in adult Nigerians. Materials and Methods: This was a cross-sectional analytical study of 50 adult men and women with metabolic syndrome and 50 age- and sex-matched men and women without metabolic syndrome. Metabolic syndrome was defined based on the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) criteria. Written informed consent was obtained from the participants. Blood pressure and anthropometric measurements were taken and venous blood was collected after an overnight fast. The Ethics Committee of the Lagos University Teaching Hospital, Lagos, Lagos State, Nigeria approved the study protocol. Comparisons of the continuous variables and the categorical variables were done using the Student's t-test and Chi-square test, respectively. Regression analysis was used to determine the associations between the variables. Statistical significance was set at P < 0.05. Results: The study subjects differed in some clinical and laboratory parameters such as diastolic blood pressure (P = 0.048), waist circumference (P = 0.002), body mass index (BMI) (P = 0.012), waist/hip ratio (P = 0.023), high-density lipoprotein (HDL) (P = 0.012), and insulin resistance (P = 0.042). There was a statistically significant increase in the inflammatory marker, CRP (P = 0.019), cytokines, IL-6 (P = 0.040), and TNFα (P = 0.031) between the subjects with and without metabolic syndrome. There was also a positive significant association between CRP, waist circumference, and insulin resistance and a negative significant association between CRP and HDL in metabolic syndrome (P < 0.05). Conclusion: This study reports increased plasma levels of the inflammatory cytokines, IL-6, TNFα and in the inflammatory marker and CRP in metabolic syndrome. Understanding the role of inflammation in the metabolic syndrome may provide novel strategies for the management of metabolic syndrome and related disorders.
Keywords: Inflammation, insulin resistance, metabolic syndrome, obesity
|How to cite this article:|
Udenze IC, Amadi CE, Awolola NA, Makwe CC, Ajie OI. The role of inflammation in the metabolic syndrome. J Clin Sci 2016;13:17-22
| Introduction|| |
Metabolic syndrome was first described by G. Reaven  in 1988 when he described the clustering of metabolic abnormalities of insulin resistance/glucose intolerance, hypertension, dyslipidemia [high triglyceride and low high-density lipoprotein (HDL) cholesterol concentrations], and obesity in one individual. The components of the syndrome are risk factors for atherosclerosis, making metabolic syndrome a significant risk for coronary heart disease. Obesity and insulin resistance also provide significant risk for developing type 2 diabetes. Reaven called it the insulin resistance syndrome because he believed that insulin resistance accounted for every component of the syndrome.
Other new features have been added to the metabolic syndrome criteria over time such as increased plasminogen activator inhibitor-1 (PAI-1) and, more recently, increased C-reactive protein (CRP) simply because they were frequently found in association with metabolic syndrome. It is now hypothesized that the presence of inflammation in metabolic syndrome can explain these new relationships and the existing ones.
There is an ongoing debate about the cause of the onset of the metabolic disturbances that constitute the syndrome and there have been several attempts to define the metabolic syndrome with special attention to one or another component. The National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) in 2002 gave equal weightage to each component of the syndrome requiring a combination of at least any three of the five criteria to make a diagnosis; abdominal circumference ≥102 cm in males or ≥ 88 cm in females, HDL cholesterol < 1.03 mmol/L (<40 mg/dL) (in males) or <1.3 mmol/L (<50 mg/dL) (in females), triglycerides ≥1.7 mmol/L (≥150 mg/dL), blood pressure ≥ 130/85 mmHg, or the patient receiving hypotensive treatment and fasting glycemia >6.1 mmol/L (>110 mg/dL). The International Diabetes Federation (IDF) in 2005 published its guidelines  for the diagnosis of metabolic syndrome that had race/region-specific cutoffs for abdominal obesity, abdominal obesity being the first requirement for diagnosis, plus any other two components of the syndrome. The World Health Organization (WHO) criteria have insulin resistance as a mandatory criterion.
Current concepts on the pathophysiology of metabolic syndrome showed that inflammation is the link between abdominal obesity, insulin resistance, and cardiovascular disease in it. Tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) are proinflammatory cytokines that have been linked with abdominal obesity and metabolic syndrome.,,, IL-6 has been linked with an increased production of CRP in the liver, atherosclerosis, and cardiovascular mortality. Current concepts of insulin as an anti-inflammatory hormone have been reported , and impairment of the insulin action in insulin resistance occasioned by the proinflammatory state of excess adiposity would explain the link between abdominal obesity, insulin resistance, and metabolic syndrome.
Current management of metabolic syndrome involves a multipronged approach targeted at several risk factors to reduce cardiovascular risks and prevent the development of type 2 diabetes in individuals with metabolic syndrome. Few studies have assessed dysmetabolic features in relation to inflammation in adult Nigerians. The awareness of the importance of inflammation in the metabolic syndrome may help to develop new strategies for the prevention and treatment of metabolic syndrome and related disorders.
This study aims to determine the plasma levels of IL-6, TNF-α, and CRP in adult Nigerians with metabolic syndrome and to determine the relationship between the components of the metabolic syndrome and CRP in adult Nigerians.
| Materials and Methods|| |
This is a cross-sectional analytical study of 50 adult men and women with metabolic syndrome and 50 age- and sex-matched men and women without metabolic syndrome.
The Ethical Research and Review Committee of the hospital approved the study protocol and informed consent was obtained from the participants.
The study was carried out by recruiting those patients attending the Obesity and Metabolic Clinic of the Lagos University Teaching Hospital, Lagos, Lagos State, Nigeria. Adult men and women between the age of 30 years and 70 years (the age range was chosen to include the age of the clinic attendees) and who agreed to participate in the study were consecutively recruited. Sociodemographic and clinical data were obtained from the participants using a structured questionnaire. Anthropometric measurements such as the weight, height, waist and hip circumference, and blood pressure readings were taken. Their lipid profile results were also determined. The diagnosis of the metabolic syndrome was based on the NCEP-ATPIII criteria.
Those subjects who did not meet the criteria for metabolic syndrome were matched for age and sex with the cases and recruited as controls.
The inclusion criteria included adult males and females between 30 years and 70 years of age who had any three of the following: Abdominal circumference ≥102 cm in males or ≥88 cm in females, HDL cholesterol <1.03 mmol/L (<40 mg/dL) (in males) or <1.3 mmol/L (<50 mg/dL) (in females), triglycerides ≥1.7 mmol/L (≥150 mg/dL), blood pressure ≥130/85 mmHg, or the patient receiving hypotensive treatment and fasting glycemia >6.1 mmol/L (>110 mg/dL).
Persons known to have diabetes and pregnant women were excluded from the study.
The study participants reported on the morning of the study after an overnight (10-12 h) fast. Then 5 mL of venous blood was collected from the antecubital vein and transferred into plain tubes for lipid profile, insulin, IL-6, TNFα, and CRP assays and into fluoride oxalate tubes for glucose analysis.
Abdominal obesity was determined by measurement of the waist circumference. The measurement was taken at the end of several consecutive natural breaths at a level parallel to the floor, midpoint between the top of the iliac crest and the lower margin of the last palpable rib in the mid axillary line. The hip circumference was measured at a level parallel to the floor, at the largest circumference of the buttocks.
The blood pressure was determined using the Accoson Mercury Sphygmomanometer(A.C. Cossor & son (surgical) ltd, Harlow, Essex) (cuff size 15 × 43 cm). The subjects were seated and rested for 5 min before the measurement. The systolic blood pressure was taken at the first Korotkoff sound and diastolic at the fifth Korotkoff sound.
The total low-density lipoprotein (LDL) cholesterol, HDL cholesterol, triglyceride, and glucose concentrations were determined on fasting serum samples using reagents from Randox Laboratories, Antrim, County Antrim, UK, BT 29 4QY on semiautomatic biochemistry analyzer BS3000P-SINNOWA Medical Science and Technology Co., Ltd., Nanjing, Jiangsu province, China (211135). Serum levels of IL-6, TNFα, CRP, and insulin were determined using reagents from BioVendor Laboratories (BioVendor R and D), 62100 Brno, the Czech Republic by an enzyme-linked immunoassay technique  on Acurex Plate Read of Accurex Diagnostics, (Accurex Biomedical Pvt. Ltd.) Ohio, USA (419-872-4775). Insulin resistance was calculated using the following homeostatic model assessment (HOMA) for insulin resistance (IR) formula: [fasting glucose (mmol/L) × fasting insulin (μU/mL)]/22.5.
The data were analyzed using the IBM SPSS version 19.0 (Sun Microsystems, USA) package. Independent Student's t-test was used to test the differences in the mean values for the continuous variables. Chi-square test was used to test the differences in proportion of the catergorical variables. Regression analysis was used to determine the association between the variables. Statistical significance was set at P < 0.05.
| Results|| |
A total of 150 people were recruited for the study. Of them, 50 subjects met the criteria for metabolic syndrome and were recruited as cases. Another 50 subjects without metabolic syndrome were matched for age and sex with the cases and recruited as controls.
The study population included 20 men and 30 women with metabolic syndrome, with the mean age being 47.84 ± 6.4 years and the age- and sex-matched controls. [Table 1] shows the sociodemographic characteristics of the study participants.
The age- and sex-matched cases and controls did not differ in their sociodemographic characteristics.
[Table 2] shows the clinical and laboratory characteristics of the study participants.
|Table 2: Clinical and laboratory characteristics of the study participants|
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The age- and sex-matched cases and controls differed in some of the metabolic syndrome parameters. The inflammatory markers, IL-6, TNFα, and CRP were significantly higher in the group with metabolic syndrome.
[Table 3] shows the regression of CRP on the components of metabolic syndrome.
CRP showed a positive association with waist circumference and insulin resistance and a negative association with HDL.
| Discussion|| |
This study reports significantly elevated levels of the proinflammatory cytokines IL-6, TNFα, and the acute phase protein CRP in the subjects with metabolic syndrome compared to the control subjects without metabolic syndrome. This is similar to the findings of the study conducted by Indulekha et al.Choi et al. reported significantly elevated high-sensitivity CRP (hs-CRP) levels in elderly Korean women with impaired glucose tolerance compared to the controls with normal glucose tolerance but also reported comparable levels of TNFα and IL-6 in women with and without impaired glucose tolerance. Kistos et al. carried out a study on obese young adults and reported elevated IL-6 levels but comparable TNFα levels between obese young adults and those with normal weight. The different study populations, the different criteria for defining metabolic syndrome as endorsed by different organizational bodies,,, and the different combinations of dysmetabolic features that characterize the syndrome may account for some of the observed differences of these studies. A recurring factor of these studies, however, is an increase in the concentration of one or more markers of inflammation in relation to the different components that make up the syndrome.
The reason for the inflammation in the metabolic syndrome is not yet fully understood. An explanation may be that larger adipose tissue mass in obesity leads to increased release of IL-6 and TNFα into the circulation, which in turn accounts for a greater production of CRP by the liver., Another possibility is that insulin resistance itself is responsible for the higher production of the cytokines., These reports corroborate our findings in this study of a positive association between CRP and waist circumference, a surrogate marker for abdominal obesity, and insulin resistance in metabolic syndrome.
The original description of metabolic syndrome by Reaven  consisted of a clustering of dysmetabolic features accounted for by resistance to the classic metabolic functions of insulin. Thus, hyperinsulinemia, glucose intolerance, type 2 diabetes, hypertriglyceridemia, and low HDL concentrations can be explained by resistance to the actions of insulin on glucose and carbohydrate metabolism. The defects of insulin action in glucose metabolism include failure to suppress gluconeogenesis in the liver and failure to mediate glucose uptake in insulin sensitive tissues (i.e. muscle and adipose tissue). To compensate for the defects in insulin action, insulin secretion must be increased to sustain euglycemia, leading to a state of hyperinsulinemia. Failure of this compensatory mechanism will result in glucose intolerance and hyperglycemia.
In the adipocytes, insulin enhances the incorporation of free fatty acids into triglycerides by its activation of lipoprotein lipase; insulin also inhibits the activity of hormone sensitive lipase, thereby decreasing the efflux of free fatty acids from adipocytes. In a state of insulin resistance, the adipocytes are resistant to the effects of insulin. The increased free fatty acid flux to the liver causes increased hepatic very-low-density lipoprotein (VLDL) production. A higher proportion of triglyceride is transferred from the triglyceride-rich VLDL to LDL and HDL by the cholesteryl ester transfer protein. The hydrolysis of the triglyceride-rich LDL produces a preponderance of small dense HDL particles that are filtered by the kidney, resulting in low HDL concentrations. The increased free fatty acid flux worsens the insulin resistant state through specific actions that block insulin signal transduction.
The finding of increased CRP levels and an association between CRP, a marker of inflammation and the metabolic syndrome components of waist circumference, insulin resistance, and low HDL, a marker of cardiovascular risk in this study supports the reports from other studies with regard to the inclusion of elevated levels of CRP as a new feature associated with metabolic syndrome.,
The current concepts of insulin as an anti-inflammatory hormone and obesity as a proinflammatory condition provide a conceptual framework that places a substantial number of apparently unrelated biological events into a pathophysiological construct and account for the link between inflammation, abdominal obesity, insulin resistance, and cardiovascular disease in the metabolic syndrome.
Novel nonmetabolic actions of insulin as an anti-inflammatory hormone has been supported by recent observations that insulin has been shown to suppress several proinflammatory transcription factors and the genes regulated by them;, an impairment of insulin action in insulin resistance would thus lead to the activation of these proinflammatory transcription factors and expression of their corresponding genes. Further studies have also shown that insulin reduced the plasma concentrations of CRP and other inflammatory mediators in subjects with type 2 diabetes and severe hyperglycemia , and recent observations on the interference of insulin signal transduction by inflammatory mechanisms in obesity further supports the inflammation hypothesis.
Observations made in the USA on patients with the metabolic syndrome who were being treated for inflammatory arthritis with the anti-inflammatory drug etanercept revealed that the patients had reduced levels of CRP and other inflammatory cardiovascular risk markers following weeks of therapy. This underscores the place of inflammation in the metabolic syndrome and its potential for therapy for metabolic syndrome and related disorders.
| Conclusion|| |
Plasma levels of the inflammatory cytokines, IL-6, TNFα, and in the inflammatory marker CRP were increased in adult Nigerians with the metabolic syndrome. CRP was also associated with some of the dysmetabolic features of the syndrome.
Understanding the role of inflammation in the metabolic syndrome may provide novel strategies for the management of metabolic syndrome and related disorders.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]