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Adiponectin Levels and Expression of Adiponectin Receptors in Association with Insulin Resistance in Patients with Systemic Lupus Erythematosus

Author: ZhouLei
Tutor: FengPing;GongLu
School: Tianjin Medical University
Course: Internal Medicine
Keywords: adiponectin adiponectin receptors insulin resistance systemic lupus erythematosus
CLC: R593.241
Type: PhD thesis
Year: 2011
Downloads: 50
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Abstract


Background and Aims Systemic lupus erythematosus (SLE) is a common autoimmune disease characterized by immunological hyperactivity and multi-system organ damage. In recent years, the progress in the diagnosis and treatment has resulted in a marked improvement in either organ damage or prognosis for SLE patients, vascular diseases, including coronary heart disease (CHD), stroke and peripheral vascular disease, have become increasingly importantcauses of morbidity and mortality. Insulin resistance (IR), a common metabolic state defined as a subnormal biologic response to given physiological levels of insulin, plays an important role in the pathogenesis of several human metabolic disorders, such as diabetes, hypertension, hyperlipidemia and CHD. Although metabolic disordersare frequently observed in SLE, the prevalence and significance of IR remain to be elucidated. Adiponectin is an adipocyte-derived cytokine with anti-inflammatory, antidiabetic, and antiatherogenic properties, plays an important role in the pathophysiological process of metabolic diseases and IR, even it is described as a key regulater of insulin sensitivity. To date, it has not yet been clarified wherther adipokine levels in SLE are related to metabolic alterations and/or to the inflammatory milieu. The effects of adiponectin are mediated by (AdipoRs) that include AdipoRl and AdipoR2. AdipoRl is abundantly expressed in skeletal muscle; AdipoR2 predominates in the liver. Both AdipoRl and AdipoR2 are found in pancreaticβcell, adipose tissue, bone-forming cells, myocardium and placenta. However, little has been reported on the expression of AdipoRs on peripheral blood mononuclear cells (PBMCs). Pang el. used flow cytometric studies (FACS) to examine the expression of AdipoRl/2 on peripheral blood mononuclear cells (PBMCs) in the healthy subjects for the first time. The presence of two adiponectin receptors on T, B, and NK lymphocytes suggests that adiponectin may have a wider immunomodulatory role than previously recognized. It may be the "bridge" factor which makes metabolic disorder, IR and inflammatory associated with immune. The aim of this study was to assesse IR and (3-cell function in a large cohort of patients with SLE, study the serum adiponectin level and the relationship between adiponectin and IR in this population, examine the expression of AdipoRl/2 on the PBMCs in SLE patients and healthy controls as the initial step in understanding the immunomodulatory role of adiponectin in SLE and other autoimmune diseases. Method 1.120 SLE patients and 41 healthy, age-and sex-matched controls were studied. All qualified patients fulfilled the 1997 revised American College of Rheumatology criteria. Patients’ disease activity was assessed at time of enrollment in the study using the SLE Disease Activity Index (SLEDAI). In all the participants, height, weight, waist, hips, blood pressure and other clinical data and fasting blood lipids, glucose and insulin were measured to calculate insulin resistance index (HOMA-IR), Homa-βcell function index (HBCI) and insulin sensitivity index (ISI). All patients were classified into subgroups according to SLEDAI scores [moderate group (SLEDAI<10; n=73) vs. active group (SLEDAI≥10; n=47)], age [age≥35 years (n=48) vs. age<35 years (n=72)], diagnostic standard for obesity in the Asia Pacific region [obese group (BMI≥25kg/m2; n=93) vs. non-obese group (BMI<25kg/m2; n=27)], FINS [high FINS group (FINS≥15mIu/L; n=39) vs. normal FINS group (FINS<15mIu/L; n=81)], HOMA-IR (a valuae of HOMA-IR≥2.2 was considered to be IR) [with IR group (n=51) vs. no-IR group (n=69)] and corticosteroid dose in the past 3 months [glucocorticosticoid unused group (n=32) vs. <7.5mg/d (n=18) vs.≥7.5mg/d of prednisone or equivalent (n=70)], and compared with the groups respectively. We approached related factors of HOMA-IR in patients with SLE by using linear correlation analysis and multiple regression analysis.2. Based on the first part of the study,60 SLE patients and 25 healthy, age-and sex-matched controls were enrolled in this part of the study. Blood specimens were obtained after an overnight fast. Serum adiponectin was measured by enzyme-linked immunosorbent assay (ELISA). Clinical and biochemical data, and serum adiponectin concentration were compared between the SLE group and healthy control group. Beside, we divided the SLE patients into moderate and active group, age≥35 years and<35 years group, the obese group and no-obese group, high FINS group and the normal FINS group, IR group and no-IR group by the grouping methods in the first part. Serum adiponectin concentration and other clinical and biochemical data were compared between these SLE groups. Linear correlation analysis and multiple regression analysis were conducted to investigate the correlation between adiponectin and other risk factors.3. The expression of AdipoRl and AdipoR2 on CD14+monocytes, CD3+T lymphocytes, CD19+B lymphocytes and CD56+NK cell of 15 SLE patients and 20 healthy subjects was detected by FACS. Patients and controls were compared in the expression levels of AdipoR1 and AdipoR2 on the 4 kind of mononuclear cells of blood. And the patients with SLE were classified into moderate and active group, corticosteroid used and unused group, IR group and no-IR group. We compare each group of the expression of AdipoR1 and AdipoR2 on the mononuclear cells to discuss the impact of SLE activity, corticosteroid therapy and combined IR to the expression of AdipoR1/R2.Results 1. SLE patients had significantly higher WHR, BF%, TG, and lower HDL than healthy controls, these suggest that SLE patients have body fat, abdominal obesity and abnormal lipid metabolism. Compared with control subjects, SLE patients showed significantly higher FINS, HOMA-IR and HOMA-HBCI, and lower ISI, it’s suggest that SLE patients have IR. Group comparison showed that BMI, BF%, the diastolic blood pressure and HDL in≥35 years group higher than that in<35 years group, suggesting that overweight body mass, body fat content increased, hypertension and hyperlipidemia seen more in older patients. Compared with non-obese group, obese group showed significantly higher FINS and HOMA-IR, and lower ISI, suggest that IR more common in obese patients. Further more, WHR, BF%, CRP, TG and HOMA-IR in SLE patients, both the active group and remission group, were higher than that in the control group, FBG and FINS levels in active group were higher than that in the control group, while there was no significance in the remission group and normal controls. Difference of FINS, HOMA-IR and HOMA-HBCI in the prednisone<7.5mg/d,≥7.5mg/d and unused group, showed no significance. Patients with hyper-fasting insulin group showed significantly higher HOMA-IR, and lower ISI. In IR group, BMI, WHR, FBG and FINS were significantly higher than that in no-IR group, meanwhile, ISI was significantly lower in IR group. These suggested that IR was more common in obese patients, especially the patients with abdominal obesity. HOMA-IR was positively correlated with BMI, CRP, FBG, FINS and HOMA-HBCI, but was negatively correlated with TG, ISI. Multiple regression analysis show that BMI, CRP, TG, HOMA-IR and ISI were the independent factors for FINS, and BMI, ISI, FINS, and FBG were the independent factors for HOMA-IR.2. Serum adiponectin levels were higher in SLE patients than controls. Among the SLE patients, obesity group showed significantly lower adiponectin levels than non-obesity group. Adiponectin did not differ between SLE activity group and remission group,≥35 years group and <35 years group. Adiponectin levels were also lower in patients with higher FINS and IR compared with patients with normal FINS, and no-IR. Regarding SLE patients, no significant difference was observed between the not using hormone group,<7.5mg/d group and≥7.5mg/d of prednisone or equivalent group in adiponectin levels. Among SLE patients, adiponectin levels were positively correlated with CRP and ISI, but negatively correlated with BF%, WHR, FBG, FINS and HOMA-IR. The adiponectin level was not correlated with age, BMI, blood pressure, Lipid, disease duration and disease activity index (SLEDAI, IgG, C3 and ds-DNA)in SLE patients. The result of multiple regression analysis is that ISI, HOMA—IR and CRP is independent factors to serum adiponectin levels in SLE patients.3. Flow cytometric studies showed that both AdipoRl and AdipoR2 expressed on peripheral blood CD14+monocytes, CD3+T lymphocytes, CD19+B lymphocytes and CD56+NK cells in SLE patients and healthy controls. The expression levels of AdipoRl and AdipoR2 on the CD3+cell were lower in SLE patients than controls, and both AdipoR on CD19+and CD56 cell were higher in SLE patients than controls. Correlation analysis showed that the expression of AdipoRl on CD56+cell surface were positively correlated with serum adiponectin levels only in the normal control group, the expression of AdipoR2 on CD14+and CD19+cell were positively correlated with serum adiponectin levels, no correlation was observed between adiponectin levels and the expression of both receptors on other mononuclear cells in the two groups. Together the SLE patients and the controls as a whole, the correlation analysis show that apart from CD3+cell, the expression level of AdipoR 1/R2 on the CD14+, CD19+and CD56+cell were positively correlated with serum adiponectin levels. AdipoRl correlated with AdipoR2 in all 4 PBMCs.Conclusion 1. SLE patients have a higher risk of insulin resistance and abnormal lipid metabolism. Body fat and abdominal obesity is the important risk factors of the insulin sensitivity reduction and IR. In addition to the classic risk factors, chronic inflammatory state and treatment drugs are also associated with the presence of IR in SLE patients. In particular, glucocorticoids, is still the basis medical treatment of SLE, might promote IR throughout the development of visceral fat and promote hypertriglyceridaemia, drug therapy should be kept to the lowest effective dose.2. Serum adiponectin levels were higher in SLE patients than controls, and free from disease duration, disease activity and steroid therapy. Meanwhile, adiponectin levels negatively correlated with FINS and HOMA-IR, but positively correlated with ISI, showed that adiponectin play an important role in developing IR in SLE patients, supporting the notion that adiponectin is an insulin-sensitising hormone. Further more, serum levels of adiponectin were significantly negatively correlated with HOMA-IR in SLE patients, patients with IR showed significantly lower adiponectin levels than patients without IR, HOMA-IR was the independent factor for serum adiponectin levels. High adiponectin levels and decreased adiponectin effects coexist in SLE patients. All above’paradoxical’would imply the existence of a’functional adiponectin resistance’, which occurs in SLE.3. AdipoRl and AdipoR2 are present on human peripheral blood CD14+ monocytes, CD3+T lymphocytes, CD19+B lymphocytes and CD56+NK cells. The presence of AdipoR on T, B, and NK lymphocytes suggests that adiponectin may have a wider immunomodulatory role than previously recognized, it may be the "bridge" factor which mediate the link between metabolic disorders, IR, inflammation and islet immunity in human beings. AdipoRl positively correlated with AdipoR2 on PBMCs, meanwhile, both AdipoR positively correlated with serum adiponectin levels. The expression levels of AdipoRl and AdipoR2 on B lymphocytes and NK cells were higher in SLE patients than in healthy controls, this may be secondary to the chronic persistent inflammatory in SLE patients. Further analysis of expression of AdipoR or signaling pathways may clarify the biological roles of adiponectin in SLE and other autoimmune diseases.

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CLC: > Medicine, health > Internal Medicine > Systemic disease > Autoimmune diseases > Autoimmune diseases, connective tissue disease > Lupus erythematosus > Systemic lupus erythematosus
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