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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 27  |  Issue : 2  |  Page : 215-225

Study of insulin resistance in patients with systemic lupus erythematosus and rheumatoid arthritis


1 Department of Internal Medicine, Faculty of Medicine, Menoufiya University, Menoufiya, Egypt
2 Department of Internal Medicine, Rheumatology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
3 Department of Clinical Pathology, Faculty of Medicine, Menoufiya University, Menoufiya, Egypt

Date of Submission04-Feb-2013
Date of Acceptance09-Apr-2013
Date of Web Publication26-Sep-2014

Correspondence Address:
Khaled El-zorkany
Department of Internal Medicine, Rheumatology Unit, Faculty of Medicine, Menoufiya University, Menoufiya
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.141634

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  Abstract 

Objective
The aim of the study was to study insulin resistance (IR) and pancreatic b-cell function in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and their relationship with disease activity.
Background
IR is an important contributor to the increased cardiovascular risk attributed to the metabolic syndrome, a constellation of cardiovascular risk factors that includes central obesity, dyslipidemia, hypertension, and disturbed glucose metabolism, in patients with RA or SLE.
Patients and methods
The study included 35 SLE and 35 RA patients and 20 controls. Disease activity was assessed by Systemic Lupus Activity Measure score and Disease Activity Score-28. BMI, C-reactive protein, erythrocyte sedimentation rate, lipid profile, fasting glucose and insulin, and c-peptide were determined. The homeostasis model of assessment (HOMA) was used to evaluate IR and secretion.
Results
SLE patients had high-grade systemic inflammation, IR, and secretion compared with controls (P < 0.05). RA patients revealed high-grade systemic inflammation, IR, and secretion compared with controls (P < 0.001). Active SLE and RA patients were more insulin resistant than nonactive patients.
Conclusion
The present study demonstrated that both SLE and RA patients had a higher IR and abnormal insulin secretion than age-matched apparently healthy controls. This conclusion was based on the measurement of fasting insulin concentration, HOMA IR, and HOMA b-cells. IR and abnormal insulin secretion were associated with markers for inflammation (erythrocyte sedimentation rate and C-reactive protein) and disease activity indices (Systemic Lupus Activity Measure and Disease Activity Score-28). Higher IR and abnormal insulin secretion were found in RA patients in comparison with SLE patients.


How to cite this article:
Gazareen S, Fayez D, El-Najjar M, Dawood A, Essa E, El-zorkany K. Study of insulin resistance in patients with systemic lupus erythematosus and rheumatoid arthritis. Menoufia Med J 2014;27:215-25

How to cite this URL:
Gazareen S, Fayez D, El-Najjar M, Dawood A, Essa E, El-zorkany K. Study of insulin resistance in patients with systemic lupus erythematosus and rheumatoid arthritis. Menoufia Med J [serial online] 2014 [cited 2019 Nov 20];27:215-25. Available from: http://www.mmj.eg.net/text.asp?2014/27/2/215/141634


  Introduction Top


Systemic lupus erythematosus (SLE) is a chronic, multifaceted inflammatory disease that can attack every organ system of the body. SLE is protean in its manifestations and follows a relapsing and remitting course [1].

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown etiology. The classic feature of this disease is persistent symmetric polyarthritis that usually involves the peripheral joints in a symmetric distribution but can affect any joint lined by a synovial membrane [2].

Insulin resistance (IR), a common metabolic state defined as a suboptimal biological response to given physiological levels of insulin, plays an important role in the pathogenesis of several human metabolic disorders such as obesity and diabetes mellitus [3].

Several factors that are associated with increased cardiovascular risk are more prevalent in SLE and RA than in the general population. These factors include microalbuminuria, hyperhomocysteinemia, proinflammatory lipid profiles including proinflammatory high-density lipoprotein (HDL), and IR [4].

There are several mechanisms that could contribute to altered insulin sensitivity and that may be important in patients with RA or SLE, and they provide insights into the pathogenesis of IR associated with inflammation. These include obesity [5], glucocorticoids, which are commonly used in SLE and RA therapy and are expected to contribute to IR [6], and chronic inflammation, which also appears to predispose to development of both IR and diabetes mellitus [7].

Therefore, the present study was designed to study IR and pancreatic b-cell function in patients with SLE and RA and their relationship with disease activity.


  Patients and methods Top


Patients and controls

Thirty-five SLE patients who fulfilled the 1997 revised American College of Rheumatology criteria of SLE [8] and 35 RA patients who fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA [9] attending the outpatient clinic and inpatient Rheumatology and Internal Medicine Departments in Menoufiya University and Ain Shams University Hospitals, Egypt between June 2010 and June 2012 were included in the study.

Disease activity was assessed by measuring Systemic Lupus Activity Measure (SLAM) and Disease Activity Score-28 (DAS28) for SLE and RA patients, respectively.

Twenty apparently healthy nonsmokers, matched for age and sex with the patient groups were enrolled in the study as controls.

All participants gave written informed consent. The study design was approved by the local ethical committee.

We excluded patients with history of smoking, BMI of at least 30 kg/m 2 , diabetes, hypertension, and concomitant renal, hepatic, cardiac, or endocrine diseases.

Experimental assays

Blood was drawn in the morning after an overnight fast for at least 12 h. Whole blood was used for hematocrit and hemoglobin; EDTA-plasma was used for glucose, insulin, and lipids; and serum was used for other biochemical assays. Glucose was measured by the glucose oxidase method. Total cholesterol and triglycerides (TGs) were measured enzymatically (Beckman TG Reagent). HDL cholesterol was measured after precipitating apolipoprotein B-containing lipoproteins with dextran sulfate and magnesium chloride. Non-HDL cholesterol was calculated by subtracting HDL cholesterol from total cholesterol. Low-density lipoprotein (LDL) cholesterol was calculated according to the Friedewald formula [10]. Other measurements were made by routine methods.

Quantitative measurement of patients' fasting insulin concentrations was conducted using the enzyme-linked immunosorbent assay method. Homeostasis model of assessment (HOMA) IR and HOMA b-cell were calculated according to the formulas in the HOMA model [11].

On the basis of the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA) data, we defined a HOMA index of greater than 2.114 as representing the top quartile of a nondiabetic population [12].

Statistical analysis

Data obtained were tabulated and analyzed by SPSS statistical package version 18 on IBM compatible computer. Quantitative data were expressed as mean and SD (X+SD). Qualitative data were expressed as number and percentage and analyzed by applying the c2 -test. Comparisons between groups were conducted using the unpaired t-test. Pearson's correlation (r) was used to detect association between quantitative variables. P-values of less than 0.05 were considered significant.


  Results Top


Demographic and clinical characteristics of SLE patients and controls

There was no statistically significant difference with respect to age, sex, BMI, fasting blood glucose, and lipid profiles (P > 0.05) between SLE patients and healthy controls. SLE patients had significantly higher fasting insulin, HOMA IR, HOMA b-cell, and c-peptide (P < 0.05) than healthy controls, and they also showed statistically significant higher mean erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) [Table 1].
Table 1: Demographic and laboratorial characteristics of SLE patients and controls

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Clinical and laboratory characteristics of SLE patients according to the SLAM scoring

There were significantly higher TGs, ESR, CRP, fasting blood glucose, fasting insulin, HOMA IR, HOMA b-cell, and c-peptide in SLE patients with high SLAM scoring, but there was no statistically significant difference with respect to age, BMI, disease duration, total cholesterol, LDL, and HDL [Table 2].
Table 2: Characteristics of SLE patients according to SLAM scoring

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Characteristics of patients with SLE according to IR

SLE patients with IR (HOMA IR > 2.11) had significantly higher TGs, ESR, serum CRP, SLAM score, fasting serum glucose, fasting insulin, HOMA b-cell, and c-peptide (P < 0.05) than SLE patients without IR, but there was no statistically significant difference with respect to age, BMI, disease duration, total cholesterol, and LDL [Table 3].
Table 3: Characteristics of patients with SLE according to IR

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Correlations between HOMA IR, SLAM score, and the clinical and laboratorial parameters in SLE patients

Pearson's correlation revealed a statistically significant positive correlation between HOMA IR and fasting serum insulin values, TGs, ESR, serum CRP, SLAM scoring [Figure 1], fasting glucose, HOMA b-cell, and c-peptide in SLE patients [Table 4].
Figure 1:

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Table 4: Correlations between HOMA IR, SLAM score, and the clinical and laboratorial parameters in SLE patients

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Demographic and clinical characteristics of RA patients and controls

There was no statistically significant difference with respect to age, sex, BMI, total cholesterol, LDL, and HDL (P > 0.05) between RA patients and healthy controls. RA patients had higher TGs, fasting blood glucose (P < 0.05), fasting insulin, HOMA IR, HOMA b-cell, and c-peptide (P < 0.001) than healthy controls, and they also showed statistically significant higher mean ESR and serum CRP (P < 0.001; [Table 5]).
Table 5: Demographic and clinical characteristics of RA patients and controls

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Clinical and laboratory characteristics of RA patients according to DAS28 scoring

There was no statistically significant difference with respect to age, BMI, disease duration, LDL, HDL, and fasting blood glucose between active and nonactive RA patients, but there was significantly higher total cholesterol, TGs, fasting insulin, HOMA IR, HOMA b-cell, and c-peptide in active RA patients [Table 6].
Table 6: Clinical and laboratory characteristics of RA patients according to DAS28 scoring

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Characteristics of patients with RA according to IR

RA patients with IR (HOMA IR > 2.11) had significantly higher total cholesterol, TGs, ESR, serum CRP, DAS28 score, fasting insulin, HOMA b-cell, and c-peptide (P < 0.001) and significantly lower HDL (P < 0.05) than RA patients without IR, but there was no statistically significant difference with respect to age, BMI, disease duration, LDL, and fasting serum glucose (P > 0.05; [Table 7]).
Table 7: Characteristics of patients with RA according to IR

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Correlations between HOMA IR, DAS28 score, and the clinical and laboratorial parameters in RA patients

Pearson's correlation revealed a statistically significant positive correlation between HOMA IR and fasting serum insulin values, total cholesterol, TGs, LDL, ESR, serum CRP, DAS28 score [Figure 2], fasting glucose, HOMA b-cell, and c-peptide in RA patients [Table 8].
Figure 2:

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Table 8: Correlations between HOMA IR, DAS28 score, and the clinical and laboratorial parameters in RA patients

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Insulin sensitivity profile in SLE and RA patients

RA patients had significantly higher fasting blood glucose, fasting insulin, HOMA IR, HOMA b-cell, and c-peptide (P < 0.05) than SLE patients [Table 9].
Table 9: Insulin sensitivity profile in SLE and RA patients

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  Discussion Top


IR represents a major public health problem, as it plays a major role in the pathophysiology of type 2 diabetes mellitus; it is also associated with increased cardiovascular risk and atherogenic dyslipidemia and is a central component of the cluster of metabolic abnormalities that comprise the metabolic syndrome [13].

In the general population, IR may be fundamental to the increased cardiovascular risk attributed to the metabolic syndrome. Individuals in the highest quartile of IR had more than twice the increased risk for incident cardiovascular events compared with those in the lowest quartile. Thus, identification of IR and the mechanisms underlying it are of interest [14].

A bimodal mortality pattern is observed in patients with SLE. Early mortality is more likely to be related to disease itself such as lupus nephritis, whereas late mortality is mainly associated with comorbidities, coronary artery disease being one of the most common causes of morbidity and mortality at this stage of disease [15].

As in the general population, cardiovascular diseases are the leading cause of death in RA patients. Large epidemiological studies in the last several decades confirmed that patients with RA are 30-60% more likely to suffer a cardiovascular event than individuals from the general population [16].

In the present study, there was no statistically significant difference between SLE patients and controls in one hand and between SLE patients with or without IR on other hand with respect to age, sex, and BMI, and this is in agreement with the studies by other investigators [17],[18],[19],[20],[21].

In the current study, there were no statistically significant differences between SLE patients and controls with respect to total cholesterol, TGs, LDL, and HDL, and this is in agreement with the study by Tso and Huang [3] who found similar results in a study conducted on 87 SLE patients and 32 healthy controls, but this did not agree with the studies by Wierzbicki [22] and Formiga et al. [23] who found that lipid and lipoprotein profiles in SLE are often abnormal compared with those of the general population.

Sabio et al. [18] and Chung et al. [19] also found that patients with lupus had significantly lower levels of total and LDL cholesterol and higher TGs than controls, and Lozovoy and colleagues [20] reported that patients with lupus had significantly higher levels of TGs and lower HDL than controls in a study conducted on 58 SLE patients and 105 controls.

In the present study, although the mean levels of lipids and lipoproteins in our patients are within normal range based on the National Cholesterol Education Program (NCEP) criteria, we found that SLE patients with IR had higher TG levels than SLE patients without IR and HOMA IR, and fasting serum insulin positively correlated with TGs in SLE patients. This is in agreement with the study by Chung et al. [24] who found that SLE patients with IR had higher TG levels than SLE patients without IR in a study conducted on 102 SLE patients and 101 controls and also with the study by Lozovoy and colleagues [20].

This is also supported by the study by Tso and Huang [3] who found that SLE patients with hyperinsulinemia had higher plasma TG levels than SLE patients without hyperinsulinemia, and fasting insulin levels positively correlated with TG in patients overall.

There are three sources of higher TG observed in IR individuals. First, lipolysis of TG from the adipose tissue causes elevated serum fatty acid levels, which results in increased fatty acid flux to the liver. Second, because lipoprotein lipase (LPL) levels are decreased, there is an inhibition of lipolysis of chylomicrons and very low-density lipoprotein and TG, which leads to elevations in TG-rich remnants that eventually are delivered to the liver. Third, IR states lead to increased hepatic de-novo TG synthesis [25].

We also found that SLE patients with high SLAM scoring had higher TG levels than SLE patients with low score. The underlying mechanism of this lipid pattern is unclear, but a possible role of tumor necrosis factor-a (TNF-a), by its ability to inhibit LPL, has been suggested by Mikdashi et al. [26]. LPL hydrolyzes circulating TGs, and LPL impairment results in hypertriglyceridemia. In SLE, the binding of auto-Abs to LPL impairs its enzymatic activity, and titers of anti-LPL Ab correlate with TG levels, disease activity, and markers of inflammation [27],[28].

Corticosteroids in SLE patients can also promote an increase in triacylglycerol levels, which seems mediated by increased plasma insulin levels and lipid production by the liver and also by impaired lipid catabolism [29].

In the present study, with respect to acute-phase reactants (ESR and CRP), there was statistically significant higher ESR and CRP in SLE patients than in controls; there was statistically significant higher ESR and CRP in SLE patients with IR and high SLAM scoring; and there was positive correlation between IR and ESR and serum CRP. This is in agreement with the studies by Chung et al. [24] and Lozovoy et al. [20] who showed that SLE patients with hyperinsulinemia had significantly higher ESR and CRP. This was supported by the study by Hotamisligil [30] who concluded that systemic chronic inflammation has been proposed to have a prominent role in the pathogenesis of IR and metabolic syndrome.

The association between inflammation and IR is also supported by Lakka et al. [31] and Reilly et al. [12], and this is considered to be fundamental to the increased cardiovascular risk.

In the general population, CRP is also associated with the presence of metabolic syndrome, especially in women [32].

In current study, there was significantly higher SLAM score in SLE patients with IR than in SLE patients without IR, and there was positive correlation between IR and SLAM scoring. This is in agreement with the studies by Sabio et al. [18] and Negrón and colleagues [15] who concluded that there was an association of metabolic syndrome with higher disease activity but did not agree with the study by Tso and Huang [3] who reported that SLEDAI as an activity index was not significantly different among SLE patients with or without hyperinsulinemia.

El Magadmi et al. [17] and Chung et al. [24] revealed that they did not find any association of metabolic syndrome with lupus disease activity.

IR is associated with a state of chronic low-grade inflammation, and several mediators released from various cell types, including immune cells and adipocytes, have been identified as being involved in the development of IR. Among those are several proinflammatory cytokines such as TNF-a, interleukin (IL)-1, IL-6, and various adipocytokines [33].

Inflammation and IR are closely linked and inflammatory cytokines such as TNF, IL-6, IL-1, and IL-8 may inhibit insulin signaling by multiple mechanisms [34]. TNF induces phosphorylation of IRS-1 at serine instead of tyrosine residues and promotes IR. Both IL-6 and TNF may inhibit the transcription of IRS-1 and glucose transporter (GLUT)-4 genes, thus reducing glucose transport and enhancing IR in obese patients [35].

Inflammation in SLE leads to tissue injury, and thus increases reactive oxygen species and reactive nitrogen species and subsequent oxidative stress. Oxidants and oxidative stress may contribute to the pathogenesis of IR or vice versa [36].

However, whether lupus activity is a factor in the development of IR or IR is contributing to disease activity is unclear.

In present study with respect to insulin sensitivity profile, SLE patients have significantly higher fasting insulin, HOMA IR, HOMA b-cell, and c-peptide (P < 0.05) than controls, and there is positive correlation between IR and fasting glucose, HOMA b-cell, and c-peptide in SLE patients. This relationship is independent of age, sex, BMI, total cholesterol, LDL, and HDL.

This is similar to what is reported by other investigators such as Gheita et al. [37] who found that SLE patients had high HOMA IR and HOMA b-cell and are associated with increase in disease activity and damage.

These data also are supported by Tso and Huang [3] who found that there was an elevation of fasting insulin levels and IR in SLE patients, and this is associated with cardiovascular disease risk in SLE.

In contrast, Ormseth et al. [21] found no statistically significant difference between SLE patients and controls with respect to HOMA IR.

In the current study, HOMA b-cell was significantly higher in SLE patients than in controls and was positively correlated with HOMA IR and fasting insulin, which suggests that slight adjustments for IR might occur, resulting in abnormal b-cell function and increased insulin secretion in patients with SLE, and this is in agreement with the study by Tso and colleagues [38].

In the present study, in RA patients, there was no statistically significant difference between RA patients and controls with respect to age, sex, and BMI, and this is in agreement with other studies [39],[40],[41],[42],[43].

In the present study, there was no statistically significant difference between RA patients and controls with respect to total cholesterol, LDL, and HDL, but there was significantly higher TGs in RA patients than in healthy controls, and this is in agreement with other studies [41],[44],[45].

In contrast, other investigators [39],[40],[46] found that there were no differences in lipid profiles between patients with RA and controls, and Ormseth et al. [43] found that RA patients had higher LDL cholesterol but not TGs than controls.

In the present study, RA patients with IR have higher total cholesterol and TG levels than RA patients without IR, and HOMA IR and fasting serum insulin positively correlated with total cholesterol, TGs, and LDL in RA patients, and this is in agreement with the studies by other investigators [41],[44],[45] but is not in agreement with the study by Dessein and Joffe [47] who reported no difference in lipid profile between RA patients with and without IR except for lower HDL in RA patients with IR.

In the current study, RA patients with high DAS28 scoring have higher TG and total cholesterol levels than RA patients with low score. This is in agreement with the findings of other investigators [40],[41],[44],[45],[48].

Systemic inflammation may contribute to the alteration in lipid profile [49]. This is supported by Feingold et al. [50] who found that increased TNF-a in patients with RA led to increase in hepatic lipogenesis in the form of hypertriglyceridemia, and circulating cholesterol and TG levels are elevated after TNF-a administration; this is also supported by Papa et al. [51] and Steiner and Urowitz [52] who reported improvement in lipid profile following immunointervention.

This does not agree with the study by Dessein and Joffe [47] who reported no difference in lipid profile between RA patients with low-grade and high-grade inflammation except for lower HDL in RA patients with high-grade inflammation.

In the present study with respect to acute-phase reactants (ESR and CRP), there was statistically significant higher ESR and CRP in RA patients than in controls, and this is in agreement with the studies by Shahin et al. [41] and Ormseth et al. [43]; in addition, there was statistically significant higher ESR and CRP in RA patients with IR, and there was positive correlation between IR and fasting insulin, ESR, and serum CRP. This is in agreement with the findings of other investigators [40],[41],[44],[46],[47],[53] and also in agreement with the study by Seriolo et al. [54] who found that IR correlates with CRP levels and can also be reduced with successful control of RA activity.

This does not agree with the studies by Karimi et al. [45] and Stagakis et al. [48] who found no statistically significant higher ESR and CRP in RA patients with an without IR.

In the current study with respect to insulin sensitivity profile, RA patients had significantly higher fasting insulin, HOMA IR, HOMA b-cell, and c-peptide (P < 0.05) than healthy controls, and this is in agreement with the studies by other investigators [39],[41],[43],[55],[56].

A possible explanation for basal hyperinsulinemia in RA patients is that insulin is not merely metabolic related to glucose metabolism; it has an anti-inflammatory effect. Insulin has shown to suppress several proinflammatory transcription factors and their regulating genes [57]. This was supported by the finding in the present study that basal hyperinsulinemia was correlated to markers of systemic inflammation. This higher HOMA b-cell score indicates the potential to compensate for reduced insulin sensitivity.

The current study showed that more than 54% of the studied RA patients demonstrated IR as assessed by HOMA IR index. This is in agreement with previous reports by Chung et al. [40]; higher figures were reported by La Montagna et al. [39], Shahin et al. [41], and Dessein and Joffe [47], whereas lower figures were estimated by Douglas and coworkers [58]. The contradiction in prevalence of IR in RA patients in different studies is likely to depend on differences in study design, methods used to assess IR, and genetic background.

In the present study, RA patients with IR (HOMA IR > 2.11) have significantly higher total cholesterol and TGs and lower HDL, ESR, serum CRP, DAS28 score, fasting insulin, HOMA b-cell, and c-peptide. This is in agreement with the studies by Chung et al. [40], Dessein and Joffe [47], and Stagakis et al. [48].

To our knowledge, the only study that contradicts the relationship between IR and RA is provided by Garcia Díaz et al. [59] who found no differences in HOMA and QUICKI values between RA patients and controls, and no relationship was found between IR and disease activity and CRP.

In the present study, there were significant correlations of IR with DAS28, a composite disease activity index in RA, ESR, and CRP, which support the role of systemic inflammation in the pathogenesis of IR in RA, confirming previous findings of other investigators [40],[47],[48],[60]. This was also supported by Sattar et al. [49] who reported that RA is a disease characterized by increased level of circulating proinflammatory cytokines that induce IR through direct interfering with insulin signaling and by Escαrcega et al. [57] who found that IR promotes further inflammation by an increase in free fatty acid fluxes and interference with the anti-inflammatory effects of insulin. This does not agree with the study by Karimi et al. [45].

In the present study, RA patients have significantly higher fasting blood glucose, fasting insulin, HOMA IR, HOMA b-cell, and c-peptide (P < 0.05) than SLE patients. This is in agreement with the study by Chung et al. [40]. This can be explained by some factors such as older age in RA patients than SLE and longer duration of disease in RA patients reflecting the burden of such disease.

Some differences are noted between the present study and others examining IR in SLE and IR. These differences could be related to variability in the study sample (e.g. ethnicity), length of disease duration, and methodology to assess clinical and outcome variables.

The present study has some limitations. First, as this is a cross-sectional study, it is possible that some patients had IR before study visit. Second, other factors known to be associated with IR, particularly proinflammatory cytokines or procoagulant factors such as TNF-a, IL-6, fibrinogen, and PAI-1, were not measured [61],[62],[63],[64]. The presence of these factors could have a role in the emergence of IR in SLE and RA patients.


  Conclusion Top


The present study demonstrated that both SLE and RA patients had a higher IR and abnormal insulin secretion than age-matched apparently healthy controls. This conclusion was based on measurement of fasting insulin concentration, HOMA IR, and HOMA b-cells. IR and abnormal insulin secretion were associated with markers for inflammation (ESR and CRP) and disease activity indices (SLAM and DAS28) and also with dyslipidemia and could be risk factor for cardiovascular disease in these patients. Higher IR and abnormal insulin secretion were found in RA patients in comparison with SLE patients. Hence, there is a pressing need for strategies for control of inflammation, dyslipidemia, and evaluation of IR in patients with SLE and RA and for intervention studies for modifying IR in SLE and RA patients and whether drugs that ameliorate IR such as metformin and thiazolidinedione could be part of the treatment and regimen of these patients.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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