How to cite this article: Peralta-Amaro AL, Cruz-Domínguez MP, Olvera-Acevedo A, Vera-Lastra OL. Prevalence of metabolic syndrome and insulin resistance in system sclerosis. Rev Med Inst Mex Seguro Soc. 2015 Jul-Aug;53(4):476-83.
Received: October 22nd 2014
Accepted: March 6th 2015
Ana Lilia Peralta-Amaro,a María del Pilar Cruz-Domínguez,b Arturo Olvera-Acevedo,c Olga Lidia Vera-Lastrad
aDepartamento de Medicina Interna
bDivisión de Investigación
cDepartamento de Medicina Interna
dDepartamento de Medicina Interna
Hospital de Especialidades, Centro Medico Nacional La Raza, Instituto Mexicano del Seguro Social, Distrito Federal, México
Communication with: Olga Lidia Vera-Lastra
Telephone: (55) 5724 5900, extension 23161
Background: The metabolic syndrome (MS) is a group of cardiovascular risk factors whose prevalence is increased in rheumatic diseases. The aim of this study was to estimate de prevalence of MS and insulin resistance (IR) in systemic sclerosis (SSc).
Methods: Fifty five patients with SSc were included. The World Health Organization criteria were used to define MS. Demographic, anthropometric and blood pressure data were recorded. Blood glucose, high density lipoprotein cholesterol (HDL-c), triglycerides and insulin were measured. Oral glucose tolerance curve was performed to identify impaired glucose tolerance and diabetes mellitus in those patients with normal fasting blood glucose. The HOMA index was calculated as well as a quantified proteinuria in urine of 24 hours.
Results: The prevalence of MS was 36.4 % (20 of 55 patients). Seventy percent of the patients with MS had limited SSc and 30 % diffuse SSc. An increased IR was observed in the limited SSc in comparison with the diffuse SSc (2.948 vs. 1.817 ± 0.3844 ± 0.2771, p = 0.03). An association between IR and MS was found in the limited SSc (p = 0.0001). Regarding the rest of the MS criteria, hypertriglyceridemia and an abnormal waist/hip ratio were the variables most often encountered, 95 % and 85 % respectively. Fifty percent of MS patients had low levels HDL-c and 40 % of them were hypertensive. None of the patients had proteinuria.
Conclusions: The prevalence of MS in SSc was 36.4 %, similar to the found in other rheumatic diseases, but higher compared to the found in the Mexican population.
Keywords: Systemic scleroderma; Metabolic syndrome X; Insulin resistance
Systemic sclerosis (SSc), or scleroderma is a connective tissue disease of unknown origin with multisystem clinical manifestations following a variable course.1,2 The main features of scleroderma are: the production of collagen, vascular disorders and autoimmune disorders involving basically three types of cells: fibroblasts, endothelial cells and immune system cells.3,4 The etiology is unknown, but genetic, ethnic, environmental, hormonal and immunological factors, and infectious agents are proposed.4-7
Metabolic syndrome (MS) is described as a set of cardiovascular risk factors (CRV) including: glucose metabolism disorders, atherogenic dyslipidemia, central obesity, hypertension and tobacco use.8,9 Several organizations have established criteria for MS, so it is important to identify these individuals to establish changes in lifestyle and reduce their CRV.8-11
Within the diagnostic criteria for MS, are those of the World Health Organization (WHO): alterations in glucose metabolism (diabetes mellitus, impaired fasting glucose, impaired glucose tolerance, insulin resistance because of HOMA) and at least two of the following criteria: waist/hip ratio> 0.90 in men and> 0.85 in women; triglycerides > 150 mg/dl or HDL cholesterol <35 mg/dL in men and <39 mg/dl in women; albumin excretion rate in urine > 20 mg/min; blood pressure > 140/90; emphasizing insulin resistance.9
Insulin resistance (IR) plays a key role in the pathophysiology of MS and it develops in the context of a proinflammatory environment favored by central obesity which determines a prothrombotic state and endothelial dysfunction, contributing to the development of MS.8,9,12
Autoimmune rheumatic diseases (ARD) such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis, gout and Sjogren's syndrome occur with greater CRV and a high prevalence of MS. In these rheumatic diseases, it has been found that MS is associated with disease activity, with an IR favored by inflammation, besides there being hypofunction of pancreatic beta cells, higher concentrations of C-reactive protein (CRP) , homocysteine, lipoprotein A and cholesterol.8,10,13
There are no data in the literature regarding the prevalence of MS in SSc; however, it has been found that high levels of insulin are related to the inflammatory component of the disease, creating a vicious cycle because insulin increases the ability of fibroblasts to synthesize collagen in response to connective tissue growth factor.14,15 Therefore, the objective of this study is to determine the prevalence and clinical significance of MS and IR in patients with SSc.
A cross-sectional study was performed from May 1 to July 31, 2010, in patients with SSc at the scleroderma clinic at the Hospital de Especialidades Médicas “Dr. Antonio Fraga Mouret” at the Centro Médico Nacional La Raza. Inclusion criteria were: patients diagnosed with SSc in accordance with the 1980 criteria of the American College of Rheumatology, diffuse and limited range, over 16 years and willing to participate in the study. We excluded patients with other diseases that induce IR (sepsis), inflammatory diseases such as ulcerative colitis, other connective tissue diseases such as RA, SLE, overlap syndrome, mixed connective tissue disease, and patients on lipid-lowering treatments.
First phase: Determination of clinical parameters
Appointments were made with all patients that constituted the cohort of scleroderma (300 patients), of which 100 patients had inclusion criteria, and of these, only 55 agreed to participate in the study. Patients who entered the study underwent a clinical history and answered a questionnaire aimed at evaluating MS components. Anthropometric measurements were taken of: waist and hip in centimeters (cm), weight, blood pressure. The latest fasting glucose data were pulled from patients’ clinical records.
Second phase: Determination of biochemical parameters
All patients with 10-hour fast gave a blood sample of 10 milliliters from the basilica vein, to determine glucose (Color-enzymatic method GOD-PAP) expressed in mg/dl; total cholesterol mg/ dl; high density cholesterol (HDL-C) mg /dl; low density cholesterol (LDL-c) mg/dl (Color-enzymatic method CHOD-PAP); and triglycerides mg/dl (Color-enzymatic method GPO-PAP). Serum insulin (chemiluminescence method) mIU/mL was also determined in order to estimate IR. IR was calculated by the HOMA method (IR: fasting insulin (mIU/mL) x fasting glucose (mg/dl) /18/22.5).16
Patients with less than 100 mg/dl glucose underwent an oral glucose tolerance curve (OGTC) with 75 grams of glucose (150 ml of glucose solution 50%), and a blood sample was collected (5 ml ) at 2 hours, to measure the blood glucose level. OGTC was not performed in four patients with known diagnosis of DM2.
In all patients, a urine sample was collected within 24 hours to determine microalbuminuria.
Third stage: Classification of patients with MS
WHO criteria were used to determine the diagnosis of MS: Alterations in glucose metabolism (diabetes mellitus, impaired fasting glucose, impaired glucose tolerance, insulin resistance by HOMA) and at least two of the following criteria: waist/hip ratio > 0.90 in men and > 0.85 in women, triglycerides > 150 mg/dl or cholesterol <35 mg/dL in men and <39 mg/dl in women, rate of urinary albumin excretion > 20 mg/min, blood pressure > 140/90.9
Of the subjects who came to their appointments, five did not bring a urine sample, and another five could not get a blood sample due to the characteristics of their skin and did not accept the removal of blood from other venous or arterial sites, making for a total of 55 patients included in the study.
Fourth phase: statistical analysis
This was done with SPSS version 11.1 for Windows and the statistical program epidat.3.1 of the WHO for Windows. Measures were determined for central tendency (averages), dispersion (range, standard deviation [SD]), confidence intervals 95% (95% CI) and the chi-square value was set at p <0.05. For the analysis, they separated the patients with and without MS.
55 patients in the cohort of SSc patients were included; the main demographic data highlighting the female data is described in Table I. The average age was 52.4 ± 12 years and the most prevalent type of SSc was the limited variety. The number of patients with personal and family history of cardiovascular risk factors are shown in Table II.
|Table I Demographic data and type of systemic sclerosis|
|Patients N = 55||Frequency (%)|
|Average ± SD||52.4 ± 12.9|
|Type of SSc|
|Table II Background of cardiovascular risk factors in systemic sclerosis|
|Patients N = 55||Frequency (%)|
Ischemic heart disease
According to the WHO definition for MS, it was found that its prevalence in SSc was 36.4% (20/55 patients). In patients with MS, 70% corresponded to the limited form of the disease and 30% to the diffuse variety. As for the type of SSc, in the limited variety the prevalence of MS was 43.8% (14/32 patients) and in the diffuse variety prevalence was 26.1% (6/23 patients).
Table III shows values for basal fasting glucose, insulin, HOMA index, HDL-C and triglycerides in each SSc type; it shows that patients with the limited form of the disease have greater insulin resistance than those with diffuse variety, with a statistically significant difference (Figure 1). In both types of the disease hypertriglyceridemia and low HDL-C values were found, with no statistically significant difference between them.
|Table III WHO biochemical criteria of metabolic syndrome according to type of systemic sclerosis N = 55|
|Fasting glucose (mg/dl)||Insulin||HOMA||HDL-c (mg/dl)||Triglycerides (mg/dl)|
|Average||92.18 17.65 ±||12.70 ± 8.66||2.94 ± 2.17||41.02 ± 12.57||186.12 ± 89.44|
|Average||92.47 ± 11.50||8.07 5.69 ±||1.81 ± 1.29||44.31 ± 10.02||162.30 ± 96.79|
|Average||92.30 ± 15.26||10.81 7.87 ±||2.48 ± 1.93||42.40 ± 11.59||176.16 ± 92.46|
Figure 1 HOMA index according to type of systemic sclerosis
Table IV shows percentages documenting each WHO diagnostic criteria for MS in both the whole group of patients and in the groups with and without MS. Figure 2 shows the values of fasting glucose, glucose after OGTC, HDL-C, triglycerides, insulin and HOMA index of patients with and without MS, with statistically significantly higher values in patients with MS versus those without MS.
|Table IV WHO criteria for metabolic syndrome in patients with SSc N = 55|
|Patients with systemic sclerosis with or without metabolic syndrome|
|WHO diagnostic criteria||Total patients
N = 55 (%)
|Patients with SSc with MS
n = 20 (36.4%)
|Patients with SSc without MS
n = 35 (63.9%)
|Glucose metabolism impairments||Impaired fasting glucose||3 (5.4%)||3 (15%)||0|
|Diabetes mellitus||9 (16.36%)||7 (35%)||2 (5.7%)|
|Glucose intolerance||* 11 (22.44%)||* 7 (43.75%)||* 4 (12.12%).|
|Insulin resistance||20 (36.36%)||13 (65%)||7 (20%)|
|Triglycerides > 150 mg/dl||30 (54.54%)||19 (95%)||11 (31.42%)|
|waist/hip ratio > 0.90 in men and > 0.85 in women||38 (69.09%)||17 (85%)||21 (60%)|
|HDL cholesterol < 35 mg/dl in men and < 39 mg/dl in women||24 (43.63%)||9 (45%)||15 (50%)|
|Blood pressure > 140/90 mmHg||8 (14.54%)||8 (40%)||0 (0%)|
|Rate of albumin excretion in urine > 20 mg/min||0||0||0|
| * Percentages calculated with 49 patients.
** Percentages calculated with 16 patients.
*** Percentages calculated with 33 patients.
Figure 2 Changes in glucose metabolism in patients with and without metabolic syndrome
Of the 55 patients, 20 (36%) had insulin resistance, and of these 13 (65%) met the other criteria for MS. Table III and Figure 1 shows that HOMA index was higher in patients with limited SSc than the diffuse form (2.948 ± 0.3844 vs. 0.2771 ± 1.817, p = 0.03), with statistically significant results between IR and MS in the limited form of SSc (p = 0.0001) (Figure 2).
The rest of MS variables found that hypertriglyceridemia and abnormal waist/hip ratio (WHR) are the variables that most often coincide with MS. 95% of MS patients had triglyceride levels above 150 mg/dl and 85% had a WHR greater than 0.85.
As for HDL-C, 45% of patients had a number less than 39 mg/dl, the three men involved in the study had a HDL-C within normal figures. Of these patients, 40% met other criteria for MS, or, 50% of patients with MS had an HDL cholesterol number less than 39 mg/dl. 40% of patients with MS (n = 8) were hypertensive. No patient proteinuria was detected.
MS includes a number of abnormalities in glucose metabolism, lipid disorders, obesity, hypertension and microalbuminuria, which gives patients who suffer from it an increased risk of cardiovascular mortality.8,9,11,17 The ERA present with endothelial dysfunction, accelerated atherosclerosis and increased cardiovascular mortality, which have led to various studies to examine the prevalence of MS in them.8,10,12,13,18-26 In the case of RA , CRV has been documented 4 times higher compared to the general population, and is a risk factor independent of classic CRV factors. In the case of SLE, 25% of deaths were attributed to cardiovascular diseases.8 For SSc, cardiovascular mortality is 20%.27
In our study, a prevalence of MS of 36.4% was found, according to the WHO criteria, similar to that observed in other ERA as recent-onset RA (31%) and long-standing RA (42%), also using the WHO criteria.19 In SLE patients a prevalence was reported between 28.6-38.2%, according to WHO.21-25 In ankylosing spondylitis, the prevalence of MS is 45.8% .8 In psoriasis, it has also been documented that cardiovascular mortality increased with the inflammatory disease state; however, no studies determined the prevalence SM.28
With respect to the general population, the prevalence of MS in SSc was higher than that reported in the Mexican population, according to the Encuesta Nacional de Enfermedades Crónicas, and according to WHO criteria, it is 13.6% and 26.6% according to the NCEP-ATP III.17
The diffuse variety of SSc was observed in 58.18%, compared to the limited variety. Considering the type of SSc, the prevalence of MS was 26.08% in the diffuse form, while the most IR was found in the limited range; however, the presence of MS was not correlated with the type of SSc nor with sex.
In our study group, to define MS, glucose and insulin (mIU/ml) were measured to detect alterations of glucose metabolism. Impaired fasting glucose was found in 3 patients (5.4%), one of whom already had a known diagnosis of DM2. OGTC test was performed in 51 patients (92.7%), the remaining four already had known diagnoses of DM2. Serum glucose two hours after OGTC (n = 49) was normal in 67.4% of patients subjected to it, and glucose intolerance was detected in 22.4% and DM2 in 10.2%. Accordingly, nine of the 55 patients had diagnosis of DM2 (16.36%); however, two of the diabetics did not meet two of the other criteria for MS, so that the prevalence of type 2 diabetes in patients with MS was 35%.
The determination of the HOMA index, which reflects IR, allowed us to detect three patients who fulfilled at least two of the other criteria for MS, since they had normal fasting glucose and OGTC (15% of patients with MS). HOMA index in patients without MS was 1.95 ± 0.2 and in patients with MS 3.5 ± 0.57. Patients with greater than 2.5 HOMA index who met MS criteria was 24.10%; a HOMA index of greater than 2.5 but without the rest of the MS criteria was seen in 12.96% of the total population. Thirty-four patients (62.94%) had a HOMA lower than 2.5, six of whom had impaired glucose metabolism expressed by other parameters, and met criteria for MS (10.9%), the remaining 50.91% did not meet criteria. Within the group of patients with MS, IR measured by HOMA index had a prevalence of 65%. 35% of MS patients were diabetic, the remaining patients met criteria of impaired fasting glucose, OGTC and HOMA index, while the three patients with impaired fasting glucose and MS, two confirmed with HOMA index greater than 2.5, and one with OGTC and HOMA index.
Independently, greater IR was observed in the limited form of the disease than in the diffuse form (± 2.948 1.817 ± 0.3844 vs. 0.2771, p = 0.03), finding an association between IR and MS in the limited form of SSc (p = 0.0001).
In relation to other criteria for MS, hypertriglyceridemia and waist-hip ratio were the criteria most frequently found to define MS (95 and 90% of patients with MS, respectively). By order of frequency, low levels of HDL-C ranked fourth to classify patients with MS, 50% of them had low levels of HDL cholesterol. Arterial hypertension was found in eight of 20 patients with MS (40%). No proteinuria was found to define MS in the SSc.
Knowing the IR by HOMA index is important because it identifies patients with MS with fasting glucose and normal OGTC. On the other hand, the IR is the most accepted and unifying hypothesis to describe the pathophysiology of MS, which in turn leads to higher CRV, which is explained by changes in blood flow since insulin does not exert its beneficial vasodilator effect to stimulate the production of nitric oxide and, therefore, improve bloodflow.12,29-33 IR develops in a proinflammatory environment that, while in the general population is favored by central obesity, in the case of SSc this inflammatory state is given by inflammation of the disease per se, with the involvement of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin (IL) -6, IL-4 and IL1-B. TNF-alpha is significantly involved in IR as well as in the development of the disease itself.8,29-33
IR is defined as reduced sensitivity or responsiveness to metabolic actions of insulin on its target organs, which determines hyperinsulinemia whose aim is to maintain a normal glucose level.9,12 However, in our results, hyperinsulinemia is only found in two out of the 55 patients, and both met criteria for MS, which again translates to a statistically significant association between IR and MS.
MS in SSc can contribute to cardiovascular mortality in this population, so that timely identification of this syndrome by detecting IR will establish early preventive and therapeutic measures aimed at improving insulin sensitivity.
The prevalence of MS in SSc was 36.4%, similar to that found in other ERA; however, it is higher than that reported in the Mexican population, which can be attributed to a chronic inflammatory state of SSc patients with IR conditions.
IR with hypertriglyceridemia and abnormal waist/hip ratio were the criteria most frequently found in SSc to define MS.
Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.