Unbalanced M1/M2 Phenotype of Peripheral Blood Monocytes in Obese Diabetic Patients

Abstract

Effect of pioglitazone T he monocyte-macrophage system exists in at least two distinct phenotypes of differentiation: proinflammatory (M1) and anti-inflammatory (M2) (1,2). Macrophages, when infiltrated into obese adipose tissue, exhibit a phenotypic switch from M2 to M1 polarization, thereby contributing to obesity-induced adipose tissue inflammation and insulin resistance (1). Expression of both M1 and M2 markers is detected in circulating peripheral blood mononuclear cells as well as in atherosclerotic plaques (3). However, there have been no detailed studies on the M1/M2 phenotype of monocytes and their association with cardiovascular risks in obese subjects with type 2 diabetes. On the other hand, we demonstrated that pioglitazone, a thiazolidinedione class of insulin sensitizer, exerts an antiatherogenic effect independent of its antidiabetic effect (4). Here, we investigated the M1/M2 phenotype of peripheral blood monocytes and pulse wave velocity (PWV), an established index of arterial stiffness, and also the effect of pioglitazone in obese diabetic patients.A total of 161 subjects (95 men and 66 women, mean age 50.4 years), including 45 normal-weight control subjects, 62 obese nondiabetic patients, and 54 obese diabetic patients with or without pioglitazone treatment for 3 months (30 mg daily), were recruited in our clinic. Peripheral blood monocytes were prepared using magnetic-assisted cell sorting and flow cytometry with anti-CD14. Expression of M1/M2 markers was analyzed by real-time quantitative PCR method and flow cytometry. The number and percentage of CD14 ϩ cells among peripheral blood monocytes from obese diabetic patients were significantly increased relative to those of control subjects (P Ͻ 0.05).The CD14 ϩ cells from obese nondiabetic patients showed significantly higher expression of M1 markers, tumor necrosis factor-␣, and interleukin (IL)-6 and lower expression of an M2 marker, IL-10, relative to control subjects (P Ͻ 0.01). This is consistent with a report that peripheral blood mononuclear cells in obesity are in an inflammatory state (5). In addition, expression of IL-10 and CD163 in CD14 ϩ cells from obese diabetic patients was significantly decreased relative to that of obese nondiabetic patients (P Ͻ 0.01). Multivariate regression analysis showed that expression of tumor necrosis factor-␣ is independently associated with age and BMI and that expression of IL-6 is independently associated with BMI and LDL cholesterol (P Ͻ 0.01); expression of IL-10 was negatively and independently associated with diastolic blood pressure, A1C, and triglycerides, and expression of CD163 was negatively and independently associated with insulin concentration, A1C, and PWV (P Ͻ 0.05). Moreover, only age and CD163 were independently correlated with PWV (P Ͻ 0.05). Interestingly, 3-month treatment with pioglitazone significantly increased IL-10 and CD163 and decreased IL-6 (P Ͻ 0.05) in parallel with the improvement of fasting plasma glucose, A1C, insulin conc e n t r a t i o n , h o m e o s t a s i s m o ...

High-Resolution Genetic Maps Identify Multiple Type 2 Diabetes Loci at Regulatory Hotspots in African Americans and Europeans

“…37 It has been shown that unbalanced proinflammatory/anti-inflammatory markers of CD14 þ cells is associated with metabolic disorder in obese T2D-affected individuals. 38 KLF4 is a critical regulator of monocyte differentiation 39 and EPB41L4B expression in subcutaneous and omental adipose is strongly associated with BMI in morbidly obese individuals. 20 Therefore, these T2D intragenic variants and the regulated cis-genes (KLF4 and EPB41L4B) are likely to be involved in an inflammatory pathway for obesity and T2D.…”

Adipose tissue inflammation and ectopic lipid accumulation [Review]

“…Interestingly, a recent study suggests that antidiabetic effects of thiazolidinediones may be mediated, at least partly, through PPARγ in macrophages [33]. Moreover, both M1 and M2 markers are detected in circulating monocytes [34,35]. Prior to macrophage infiltration at the site of chronic inflammation, monocytes in obese and/or obese type 2 diabetic patients exhibit higher expression of M1 markers and lower expression of M2 markers than those in normal-weight controls, which is associated with arterial stiffness [34].…”

“…Moreover, both M1 and M2 markers are detected in circulating monocytes [34,35]. Prior to macrophage infiltration at the site of chronic inflammation, monocytes in obese and/or obese type 2 diabetic patients exhibit higher expression of M1 markers and lower expression of M2 markers than those in normal-weight controls, which is associated with arterial stiffness [34]. Interestingly, pioglitazone treatment significantly improves arterial stiffness along with the unbalanced M1/M2 phenotype of monocytes [34,35].…”

“…Prior to macrophage infiltration at the site of chronic inflammation, monocytes in obese and/or obese type 2 diabetic patients exhibit higher expression of M1 markers and lower expression of M2 markers than those in normal-weight controls, which is associated with arterial stiffness [34]. Interestingly, pioglitazone treatment significantly improves arterial stiffness along with the unbalanced M1/M2 phenotype of monocytes [34,35]. Collectively, phenotypic modulation of adipose tissue macrophages may offer a novel therapeutic strategy to prevent or treat the progression of obesity-induced complications such as diabetes and atherosclerosis.…”

An unbalanced monocyte polarisation in peripheral blood and bone marrow of patients with type 2 diabetes has an impact on microangiopathy

“…To date, the polarization status of circulating monocytes in type 2 diabetes is poorly characterized, and mainly derived from gene expression analyses [20,21]. In this study, we aimed to determine the pro-versus anti-inflammatory monocyte polarization balance in type 2 diabetic patients compared to control subjects by identifying, characterizing and quantifying novel discrete cell populations.…”