Chemerin is a recently discovered metabolic regulator hormone. The pathophysiologic role of this hormone in humans remains unknown. In this study, we have compared plasma chemerin levels in patients with type 2 diabetes mellitus with or without hypertension and in control subjects. We also assessed the association of plasma chemerin with body composition and metabolic parameters in these subjects. Plasma chemerin levels were found to be markedly increased in patients with type 2 diabetes mellitus with hypertension as compared with patients with type 2 diabetes mellitus and normal controls (P < 0.01). Multiple regression analysis showed that waist circumference, diastolic blood pressure, 2-hour plasma insulin after glucose overload, and HbA1c were independently related factors influencing plasma chemerin levels. The present work indicates the potential link of chemerin with the pathogenesis of insulin resistance, obesity, and metabolic syndrome.
- type 2 diabetes mellitus
- body composition
- metabolic parameters
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Adipose tissue has been identified as an important endocrine organ that not only stores energy but also regulates energy homeostasis and metabolism.1Adipose tissue communicates with the liver, the skeletal muscles, and the brain via secreted protein hormones (adipokines). These adipokines have diverse roles and may regulate long-term energy balance (eg, leptin) or insulin sensitivity of insulin responsive tissues (eg, adiponectin and resistin2). Recently, chemerin, also known as retinoic acid receptor responder protein 2 (RARRES2) or tazarotene-induced gene 2 protein (TIG2), was isolated as a new member of the adipocytokine family. It is a chemoattractant protein that serves as a ligand for the G protein-coupled receptor CMKLR1 (also known as ChemR23 in humans and DEZ in mice) and has a role in adaptive and innate immunity. Chemerin and chemerin receptor messenger RNA expressions are high in adipose tissues, and the expressions dramatically increase during the differentiation of 3T3-L1 cells and preadipocytes into adipocytes.3Recently, it has been reported that chemerin is an autocrine-paracrine hormone and stimulates insulin-dependent glucose uptake concomitant with the enhanced insulin signaling in adipocytes.4More recently, it has been reported that plasma chemerin levels showed a strong and independent association with key markers of metabolic syndrome including obesity, high-plasma triglycerides, and high blood pressure.5These findings suggest that chemerin may play a role in the development of these metabolic syndrome phenotypes.
Although the change of plasma chemerin has been investigated in patients with type 2 diabetes mellitus (T2DM),5plasma chemerin levels in T2DM patients with hypertension have not been demonstrated. In addition, the association between chemerin and insulin resistance (IR) has not been well described. Therefore, in the present study, we have measured plasma chemerin levels in both newly diagnosed T2DM patients and T2DM patients with hypertension. We also assessed the association of plasma chemerin with body composition and several metabolic parameters in these subjects.
MATERIALS AND METHODS
Eighty-one subjects with newly diagnosed T2DM (42 men and 39 women; mean (SD) age, 52.7 (11.5) years: T2DM group), 33 patients with newly diagnosed T2DM with hypertension (18 men and 15 women; mean (SD) age, 53.4 (8.1) years: T2DMH group), and 60 subjects with normal glucose tolerance (NGT; 22 men and 38 women; mean (SD) age, 50.7 (12.3) years: NGT group) participated in the study. The diagnosis of T2DM was based on oral glucose tolerance tests and World Health Organization criteria (1998),6and hypertension was also based on World Health Organization criteria (1999).7Excluded were patients with type 1 diabetes, macrovascular or microvascular complications, urinary tract infections, urolithiasis, liver cirrhosis, congestive heart failure, overt proteinuria, or other known major diseases. All patients' conditions were newly diagnosed, and they were not treated with oral hypoglycemic agents or diet control. Subjects without clinical evidence of major disease, family history of T2DM, and hypertension were recruited from an unselected population that underwent routine medical checkups and were used as controls. None of the control subjects were taking medications known to affect glucose tolerance. The study was approved by the human research ethics committee of Chongqing Medical University, and informed consent was obtained from all patients and controls.
Anthropometry and Plasma Samples
Anthropometric parameters measured included the body mass index (BMI), the waist-to-hip ratio (WHR), and blood pressure (BP). Waist and hip circumferences were measured to the nearest 0.1 cm at the narrowest point between the lowest rib and the uppermost lateral border of the right iliac crest. The hips were measured at their widest point. Seated blood pressure was taken by a trained nurse after the subjects had rested for 10 minutes.
Plasma Biochemical Parameters and Chemerin
Blood samples were drawn after an overnight fast, and plasma samples were kept at −80°C until assayed. Plasma insulin was measured in deproteinized serum by radioimmunoassay using human insulin as standard (Linco, St. Charles, MO). Free fatty acids (FFA) were measured in plasma with a kit (Randox Laboratories Ltd, Antrim, UK). Plasma glucose was assayed using the glucose oxidase method. Glycosylated hemoglobin (HbA1c) was measured by isoelectric focusing. Plasma triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations were determined enzymatically. Plasma chemerin levels were determined using a commercially available enzyme-linked immunosorbent assay (Phoenix Pharmaceuticals, Belmont, CA), The intra-assay coefficient of chemerin was 4.7%; the interassay coefficient was 8.0%. The linear ranges of the assay were 31 to 2000 pg/mL for chemerin. The homeostasis model assessment of insulin resistance (HOMAIR) and the homeostasis model assessment of β-cell insulin secretion (HOMAIS) were calculated from fasting insulin and glucose levels with the following equations: HOMAIR = insulin [μU/mL] × glucose [mmol/L] / 22.5 and HOMAIS = [20 × insulin (μU/mL)] / [FBG (mmol/L) − 3.5].8
The data are shown as mean (SD). All statistical analyses were performed using the SPSS 8·0 software (SPSS Inc, Chicago, Ill). Baseline characteristics of case and control subjects were compared by 1-way Wilcoxon rank sum test or χ2 test. The general linear modeling function analysis was used to control for potential confounders. Because the distributions of plasma insulin and HOMAIR values were skewed, logarithmically transformed values were used for statistical analysis. As our primary approach, we included plasma chemerin levels as continuous independent variables in the multivariable models. Simple and multiple regression analyses were used to examine the association between plasma chemerin levels and the values of other biomarkers.
The clinical characteristics of our subjects are shown in Table 1. The T2DMH group had higher weight, systolic blood pressure, diastolic blood pressure (DBP), BMI, WHR, low-density lipoprotein cholesterol, fasting blood glucose (FBG), and 2-hour plasma insulin after glucose overload (2-h Ins) than the T2DM and control groups. However, HOMAIS in the T2DMH patients was lower than that in the NGT group. The T2DM group had higher TG, FFA, FBG, 2-h PBG, HbA1c, HOMAIR, and lower HOMAIS than the controls (Table 1).
Plasma chemerin levels were found to be markedly increased in the T2DMH group compared with the T2DM and NGT groups (74.6 ± 6.4 vs 68.6 ± 12.5 and 62.1 ± 19.2 μg/L, P < 0.01, Fig. 1). However, there was no significant difference between T2DM and NGT. In addition, no difference was observed in plasma chemerin levels between men and women. Plasma chemerin levels were also found to be markedly increased in obese subjects when compared with subjects with a BMI of 25 kg/m2 or less (74.0 ± 10.4 vs 63.2 ± 16.3, P < 0.01). Moreover, the fasting chemerin levels remained significantly different between T2DMH and T2DM or NGT after adjustment for age, sex, BMI, WHR, and percentage of fat in vivo (FAT%; P < 0.05). Bivariate correlation analyses were performed to assess relationships between plasma chemerin concentrations and body composition or metabolic parameters. Fasting plasma chemerin was found to be positively correlated, and significantly, with age (r = 0.20, P < 0.05), weight (r = 0.25, P < 0.01), DBP (r = 0.27, P < 0.01), FAT% (r = 0.30, P < 0.01), BMI (r = 0.34, P < 0.01), WHR (r = 0.24, P < 0.01), TG (r = 0.25, P < 0.01), FFA (r = 0.16, P < 0.05), FBG (r = 0.17, P < 0.05), 2-h PBG (r = 0.21, P < 0.01), fasting insulin (Fins; r = 0.18, P < 0.05), 2-h Ins (r = 0.21, P < 0.05), HOMAIR (r = 0.21, P < 0.01), and HbA1c (r = 0.21, P < 0.01, Table 2). Multiple regression analysis showed that waist circumference, DBP, 2-h Ins, and HbA1c were independently related factors influencing plasma chemerin levels (Y = 25.7174 + 0.421XDBP + 4.228XTC − 1.580XHOMA-IR; Table 2).
The plasma chemerin levels were significantly associated with hypertension even after controlling for anthropometric variables (age, sex, BMI, WHR, and FAT%: Table 3). Multiple logistic regression analysis in fully adjusted odds ratios in the second and third tertiles were 17.308 (95% confidence interval [CI], 3.451-86.810) and 14.062 (95% CI, 2.853-69.325), respectively (Table 4).
Insulin resistance plays a primary role in the development of T2DM9and is a characteristic feature of other health disorders including obesity, dyslipidemias, hypertension, and cardiovascular disease.10The molecular basis of IR has not been fully elucidated11; however, secreted proteins have been proposed as central regulators of metabolism and play key roles in food intake, insulin sensitivity, and energy metabolism. Several studies support the idea that the endocrine/systemic actions of cytokines contribute to obesity-related diseases. For example, cytokines, such as resistin, tumor necrosis factor α, and IL-6, that promote IR are elevated in obese patients and in rodent models of obesity.12-14Other cytokines, such as adiponectin, have antidiabetic and anti- inflammatory properties that decrease muscle mass, lower liver triglyceride accumulation, and increase insulin sensitivity in muscle tissue.11,15Recently, it has been reported that chemerin is a novel adipokine that regulates insulin sensitivity in adipose tissue, and the circulating levels of chemerin were significantly associated with characteristics of metabolic syndrome (circulating triglycerides, high blood pressure, high body fat content and insulin resistance) in NGT human subjects.5So far, however, the circulating levels of chemerin have only been reported in subjects with T2DM and normal controls but not in subjects with hypertension. In the present study, we found that plasma chemerin levels were significantly increased in T2DMH compared with T2DM and NGT. Furthermore, fasting plasma chemerin was found to correlate positively and significantly with age, weight, DBP, FAT%, BMI, WHR, TG, FFA, FBG, 2-h PBG, fasting plasma insulin, 2-h Ins, HOMAIR, and HbA1c. Multiple regression analysis showed that waist circumference, DBP, 2-h Ins, and HbA1c were independently related factors influencing plasma chemerin levels. In addition, plasma chemerin levels were also found to be markedly increased in obese patients when compared with subjects with a BMI 25 kg/m2 or less. Thus, plasma levels of chemerin showed a strong and independent association with key markers of metabolic syndrome, especially obesity and high blood pressure. These results were consistent with the study by Bozaoglu et al.5The effect of chemerin on blood pressure may relate to its high expression within the kidneys, a key site of blood pressure regulation. Our results suggest that chemerin may play a pathophysiologic role in obesity and metabolic syndrome phenotypes. Moreover, it raises the possibility that chemerin may be of value as a biomarker for these disorders.
In summary, we have for the first time demonstrated that plasma chemerin levels are significantly increased in T2DMH, and plasma chemerin levels are also found to be markedly increased in obese subjects. However, more work is needed to clearly define the functional consequences of hormone-induced and hypertension- or obesity-induced increases in plasma levels.
The authors thank Amelia Griggs, University of Mississippi Medical Center, for correcting grammatical errors of the manuscript.
The authors declare that they have no conflicts of interest.