Is sarcoidosis related to metabolic syndrome and insulin resistance?

Abstract

Aim: To investigate the relationship between sarcoidosis and metabolic syndrome (MetS) and insulin resistance (IR).

Method: In our study, 47 patients with sarcoidosis who applied to our outpatient clinic and 45 healthy individuals without chronic disease were included. All patients were evaluated for MetS according to the National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATP III) criteria. The presence of three of the five factors defined by ATP III for MetS was accepted as a diagnosis of MetS. IR is calculated using the HOMA-IR index.

Results: The mean age of the 47 patients with sarcoidosis was 50.7 ± 12.2 years and the mean age of the 45 control groups was 42.9 ± 14.4 years. Almost 80% of the patients were diagnosed as stage 2 sarcoidosis. Distribution of the patients according to the use of steroid is; almost half of the patients (47%) received steroid previously or recently. Patients with sarcoidosis have a 7.66 relative risk for MetS, whereas they also have a 5.48 relative risk of insulin resistance development.

Conclusion: This study shows that MetS is associated with increased sarcoidosis risk. MetS and IR diagnosis was higher in patients with sarcoidosis.

Keywords:

• Insulin resistance
• HOMA-IR
• metabolic syndrome
• NCEP-ATP III
• sarcoidosis

Introduction

Sarcoidosis is a chronic systemic disorder characterized by granulomatous inflammation in response to an unidentified antigen [1]. It shows a consistent predilection for adults. Significant diversity in prevalence, disease presentation, and severity occur among different ethnic and racial groups. The diagnosis of sarcoidosis needs an appropriately clinical picture, histological demonstration of non-caseating granulomas, and excluding of other diseases capable of producing a correlative histological or clinical picture [2]. Sarcoidosis presenting features are protean, ranging from asymptomatic but abnormal findings on chest radiography in many patients to progressive multiorgan failure in an unfortunate minority [3].

Metabolic syndrome (MetS) is a multifactorial pathological condition characterized by the presence of any three of the following five risk factors: hypertension, hyperglycemia, hypertriglyceridemia, low level of high-density lipoprotein (HDL)-cholesterol, and an enlarged waist circumference [4]. Obesity increases the risk of morbidity of cardiovascular disease, type 2 diabetes mellitus, dyslipidemia, stroke, osteoarthritis, gallbladder disease, sleep apnea, respiratory problems, and some cancers [5]. Obesity has also been associated with increased risk of different autoimmune diseases including psoriasis, rheumatoid arthritis, and inflammatory bowel disease [6–9].

The role of obesity as a risk factor for sarcoidosis has been investigated in few studies. We aimed to investigate the relationship between sarcoidosis and MetS and insulin resistance (IR). To our knowledge, this study is the first study to examine the relation of MetS and sarcoidosis.

Materials and methods

Sample of the study population

In our study, 47 patients with sarcoidosis who applied to our outpatient clinic and 45 healthy individuals without chronic disease were included. This study was approved by the Ethics Committee with a waiver of the need to obtain informed consent. All participants’ data were obtained from our database.

MetS and IR calculation

All patients were evaluated for MetS according to the National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATP III) criteria [10] (Table 1). The presence of three of the five factors defined by ATP III for MetS was accepted as a diagnosis of MetS.

Table 1. ATP III metabolic syndrome diagnostic criteria.

1. Abdominal obesity (waist circumference)

Men >102

Women >88

2. Serum triglyceride >150 mg/dL or using hyperlipidemic drug

3. HDL-cholesterol

Male <40 mg/dL

Women <50 mg/dL

4. Blood pressure ≥130/85 mmHg or using antihypertensive drug

5.Fasting blood sugar ≥100 mg/dL

The body mass index (BMI) was calculated according to the weight (kg)/height (m) = kg/m².

IR was calculated using the (HOMA-IR) index [11]. It was determined using serum glucose and insulin values. Blood values were evaluated after a 12-h fasting period. IR was not calculated in patients with DM and under DM treatment. IR values greater than 2.5 were considered positive: IR: fasting insulin × fasting glucose/405.

Statistical analysis

SPSS-21 program was used for statistical analysis. Descriptive statistics were used. Odds ratio values were calculated by performing Chi-square and risk analysis for MetS and IR in sarcoidosis patients. p < .05 was considered statistically significant.

Results

The mean age of the 47 patients with sarcoidosis was 50.7 ± 12.2 years and the mean age of the 45 control groups was 42.9 ± 14.4 years. Thirty-six sarcoidosis patients were female (76.6%), 11 (23.4%) were male. Gender distribution of controls was compatible to the study group (female/male: 27/18, 60%/40%, p = .068). General characteristics and biochemistry values related to MetS are shown in Table 2.

Table 2. General characteristics of sarcoidosis and control group, biochemistry values related to MetS.

Parameters	Sarcoidosis (n:47) mean ± SD	Control (n:45) mean ± SD	p value
Age (years)	50.7 ± 12.2	42.9 ± 14.4	.006
BMI (kg/m^2)	31.5 ± 4.9	27.7 ± 5.0	.001
Waist circumference	101.2 ± 11.7	94.4 ± 14.8	.017
Glucose	113.2 ± 42.1	89.0 ± 9.7	.001
HDL	47.6 ± 11.0	48.6 ± 11.7	.688
Triglycerides	164.72 ± 68.5	110.6 ± 53.9	<.001

BMI, body mass index; HDL, high density lipoprotein; SD, standard deviation; y, year.

Mean age, BMI, waist circumference, triglyceride, and glucose values of patients with sarcoidosis were significantly higher than those of the controls.

Distribution of the patients according to the stages of sarcoidosis is shown in Figure 1. Almost 80% of the patients were diagnosed as stage 2 sarcoidosis. Distribution of the patients according to the use of steroid is shown in Figure 2. Almost half of the patients received steroid previously or recently.

Figure 1. Stage of sarcoidosis patients.

Figure 2. Use of steroid among sarcoidosis patient.

Patients with sarcoidosis have a 7.66 relative risk for MetS, whereas they also have a 5.48 relative risk of IR development (Table 3).

Table 3. Relative risk ratios for metabolic syndrome and insulin resistance among sarcoidosis patients.

Odds ratios for patients with sarcoidosis/controls			95% Confidence interval
	Value	p	Lower	Upper
Metabolic syndrome: No. of patients (92)	7.66	<.001	2.946	19.918
Insulin resistance: No. of patients (65)	5.484	.007	1.302	23.101

Discussion

Sarcoidosis is a multisystem granulomatous disorder that most often affects the lungs and may cause significant morbidity. Sarcoidosis can manifest as neurological disease, uveitis, blindness, end-stage pulmonary fibrosis, pulmonary hypertension, dysrhythmias, cardiomyopathy, hypercalcemia, and renal failure. While the etiology of sarcoidosis is still unknown, recent insights into its immunopathogenesis have moved investigators closer to find more effective treatments [12].

This study showed that the frequency of MetS and IR was increased in patients with sarcoidosis compared to the control group. Obesity; both as a result of sarcoidosis treatment and as a result of the pro-inflammatory environment of obesity. Obesity can occur as a result of sarcoidosis treatment, similarly the pro-inflammatory environment of obesity may contribute to the development of sarcoidosis.

Immunological mechanisms involved in the pathogenesis of sarcoidosis and MetS considered these two diseases may be the cause or result by each other [6, 13]. In our study, we found that the etiology of sarcoidosis is unknown. It is thought that there is an immunological over-response against unknown antigens in people with genetic background [14]. Antigens which are phagocytosed by macrophages and dendritic cells known as antigen-presenting cells (ASHs) creates epitopes on the surface of the ASH that can match with the MHC (major histocompatibility complex) class II found on the surface of T lymphocytes. As a result of this pairing, natural T lymphocytes are transformed into the Th1 phenotype and many cytokines and chemokines are secreted, leading to the development of sarcoid granuloma formation [15].

Chronic low-grade inflammation invariably accompanies MetS and is associated with adverse proinflammatory cytokine profile both in serum and adipose tissue [16]. Obesity is an important criterion of MetS. Laboratory studies support the possibility that obesity and weight gain increase inflammation. Pohl et al. observed enhanced and prolonged inflammatory responses to acute systemic challenge with lipopolysaccharide in diet-induced obese adult rats [17]. Similarly, challenged rats that experienced induced cumulative weight gain from birth to adulthood resulting in adult overweight or obesity were found to have elevated plasma levels of proinflammatory cytokines, including tumor necrosis factor-a, IL-1 beta, and IL-6 [18].

Today, obesity is considered as a low-grade systemic inflammatory condition including high levels of inflammatory markers such as leptin, C-reactive protein, tumor necrosis factor-a, and interleukin-6 [19]. The etiology of sarcoidosis is unknown, but the disease involves immunological changes similar to those seen in obesity, including the production of TNF-α. Obesity-induced changing immunology may have a role in the development of sarcoidosis [9].

Sarcoidosis is an autoimmune disease [20]. There are studies suggesting that autoimmune diseases (rheumatoid arthritis, psoriasis, autoimmune thyroid diseases) increase with BMI increase [21–26]. Hapsoe et al. in a study investigating BMI and autoimmune diseases; 75,008 women have been followed for 11 years. The relationship between BMI and 43 autoimmune diseases was investigated; 2430 women developed autoimmune disease and 140 of them developed sarcoidosis. It was stated that obesity increased the risk of sarcoidosis three times [20].

In Dumas et al., 116,430 women were followed up for 14 years and 270 cases developed sarcoidosis. There was a positive correlation between BMI and sarcoidosis patients [27]. Similarly, in our study, the BMI of sarcoidosis patients was significantly higher than the control group.

A study made around African-American women has found that obesity is associated with a higher risk of sarcoidosis in the long term. A subsequent study involving data from The Black Women’s Health Study, a follow-up study of 59,000 African-American women, also prospectively assessed the association between obesity and incident sarcoidosis over a 16-year follow-up period (1995–2011) during which 454 cases were reported. Obesity at study baseline (1995) was associated with a 42% increased incidence of sarcoidosis [13].

It is well known that white adipose tissue are not only a storage organ, but play an active role in producing and releasing various mediators used in physiological processes [28,29]. These mechanisms may simultaneously trigger autoimmunity that leads to sarcoidosis.

Of all the ADs, the highest risk (more than threefold) in obese women was observed for sarcoidosis, a disease that, to our knowledge, has not previously been related to obesity besides increased BMI in patients with existing sarcoidosis. In a clinical study of 184 patients with sarcoidosis and age- and sex-matched control subjects, higher BMI was associated with lower FVC %, higher fatigue, and poorer self-reported health status [30].

Leptin is an appetite-regulating peptide hormone that is synthesized from white adipose tissue. The leptin value in the blood is directly proportional to adipose tissue [31,32]. It has been reported that leptin receptors are expressed on B and T cells and leptin has direct effects on lymphocytes. Leptin can stimulate T cell proliferation, stimulate a Th1 response, affect T cell activation, and increase phagocytic activity by activating macrophages and monocytes. In animal models, leptin deficiency has been associated with immune suppression [33]. Sarcoidosis is characterized by chronic granulomatous inflammation, which is believed to be a result of a persistent T-helper 1 polarized immune response [1]. Obesity and leptin may trigger the development of sarcoidosis by creating T Helper response.

Systemic steroid therapy may cause weight gain in patients [34]. Steroid treatment may be used in some clinical conditions in patients with sarcoidosis. More than half of our patients were not on steroid treatment.

It was considered in obesity that macrophage increase in adipose tissue results in metabolic inflammation. Chronic, subacute inflammatory conditions accompanied by obesity affects the adipose tissue, liver, and vascular system. Obesity-induced inflammatory changes occur in both immune and non-immune cells. Then inflammation leads to the abnormal production of cytokines and chemokines by activating immune cells [35]. Research in obese rodents has shown that increase in adipocyte-induced TNF-a will result in systemic IR [35,36].

Nishimura et al. showed that obesity increase the number of CD8 + [35]. MetS is well known to be associated with a high inflammatory condition [37,38]. Inflammatory molecules such as C-reactive protein (CRP), TNF-alpha, plasma resistin, IL-6, and IL-18 are found to be significantly increased in adipose tissue of MetS [37]. The degree of expression of TNF-alpha in adipose tissue was found to be directly proportional to plasma insulin value [37,39]. Plasma TNF is also associated with fasting insulin and IR (HOMA) [37,39,40]. Therefore, it can be said that, TNF-alpha plays a role in the pathogenesis of IR.

IL-10 is a major anti-inflammatory cytokine associated with IR, obesity, MetS, and Type 2 DM [41]. Serum IL-10 levels were significantly correlated with IL-6, CRP, and TNF-alpha levels, but did not correlate with adiponectin in healthy subjects. Therefore, IL-10 is significantly associated with adiponectin, especially in subjects with MetS [42]. For this reason, IL-10 may be play a role in the inflammatory process of MetS [37,42].

Pleiotropic proinflammatory cytokine IL-18 plays a role in the inflammatory cascade that promotes the production of both TNF and IL-6 [37]. It has been reported that there is an inverse relationship between IL-18 and antiatherogenic adipokine adiponectin in obesity, IR, CVD, and MetS [37,43].

In conclusion, this study show that MetS is associated with increased sarcoidosis risk. MetS and IR diagnosis was higher in patients with sarcoidosis. The question is unclear: Is MetS risk factor for sarcoidosis? or Is sarcoidosis risk factor for MetS? MetS, which is an important cause of morbidity and mortality, has a high rate of sarcoidosis, suggests that it may play a role in the pathogenesis of that disease.

Disclosure statement

No potential conflict of interest was reported by the authors.