Serum Corticosteroid-Binding Globulin Concentration and Insulin Resistance Syndrome: A Population Study

Abstract

It has been suggested that a low grade inflammatory state could predispose for developing insulin resistance and contribute to the development of obesity and type 2 diabetes. Corticosteroid-binding globulin (CBG), the main plasma protein transport for cortisol, has been shown to be negatively regulated by insulin and IL-6, at least in vitro, suggesting that insulin resistance and inflammation may both contribute to decreasing CBG levels. In the present study we measured CBG concentrations in a human healthy population and investigated the relationships of CBG with anthropometric and biochemical markers for inflammation and/or insulin resistance. The data showed that the mean serum CBG level was significantly lower in males (n = 151) than in females (n = 113; 32.5 +/- 9.1 vs. 39.2 +/- 13.9 mg/liter; P < 0.0001). In both sexes serum CBG levels were correlated negatively with age (r = -0.12; P = 0.04), body mass index (r = -0.31; P < 0.0001), waist to hip ratio (WHR; r = -0.39; P < 0.0001), systolic (r = -0.15; P < 0.01) and diastolic (r = -0.15; P = 0.01) blood pressures, and HOMA, an index of insulin resistance (r = -0.12; P = 0.04). In addition, the CBG concentration was negatively associated with serum IL-6 concentrations (r = -0.23; P = 0.017) and with the soluble fraction of TNFalpha receptors, soluble TNF receptor 1 (sTNFR1; r = -0.35; P < 0.0001), and sTNFR2 (r = -0.56; P < 0.0001) in women. A stepwise regression analysis using CBG as an independent variable showed that sex (P < 0.00001), body mass index (P = 0.0002), and HOMA (P = 0.0005), but not systolic blood pressure, diastolic blood pressure, IL-6, sTNFR1, or sTNFR2, constituted significant independent factors that explained 21% of the CBG variance (14%, 2%, and 5%, respectively). In a subsample of 120 men and 68 women, fasting serum free cortisol (calculated as the ratio fasting cortisol/CBG) was significantly associated with WHR (r = 0.24; P = 0.001), systolic (r = 0.18; P = 0.01) and diastolic (r = 0.19; P = 0.007) blood pressures, and HOMA value (r = 0.20; P = 0.005), but not with BMI or age. BMI (P < 0.0001), free cortisol (P = 0.003), and CBG (P = 0.009), but not WHR and age, contributed to 20%, 6%, and 8%, respectively, of HOMA variance in women in a multiple regression analysis. In this model only BMI (P < 0.0001) independently contributed to HOMA variance in men. These findings support the hypothesis that the CBG level is an interesting indicator for both insulin resistance and low grade inflammation. Whether the decrease in CBG levels is genetic by nature or directly associated to increased insulin and/or IL-6 merits further investigation. Nevertheless, because CBG has been shown to be expressed by the adipose tissue, decreased CBG could create locally increased cortisol disposal, with no change in circulating cortisol, and facilitate fat accumulation, insulin resistance, and type 2 diabetes.

The cortisol response to ACTH in pigs, heritability and influence of corticosteroid-binding globulin

“…Several clinical studies have shown a relationship between CBG levels or CBG gene polymorphisms and metabolic parameters related to insulin resistance syndrome (e.g. Fernandez-Real et al, 2002;Barat et al, 2005;Richard et al, 2009), and the CBG locus has been shown to be linked with metabolic traits in several studies (see Moisan, 2010and Mormede et al, 2011aand 2011b for review), including in pigs (Desautes et al, 2002;Ousova et al, 2004), and we showed previously that CBG was a better predictor of carcass composition than cortisol levels (Ousova et al, 2004). In most cases, the physiological effects of CBG have been interpreted as resulting from the influence of CBG on the level and bioavailability of cortisol (Perogamvros et al, 2012;Moisan, 2013).…”

Cortisol clearance and associations with insulin sensitivity, body fat and fatty liver in middle-aged men

“…Recently, a negative correlation between CBG concentration and BMI, waist to hip ratio and insulin resistance in normal healthy subjects has been demonstrated [38], and it was also shown that plasma adiponectin was associated with serum CBG in men (r=0.26, p=0.03) [39]. Furthermore, CBG concentration has now been shown to be inversely related to measures of inflammation [38]. Therefore, the CBG concentration may be a marker of an acutephase response rather than directly reflecting insulin sensitivity.…”

Association of serum cortisol levels with parameters of metabolic syndrome in men and women

“…Cross-sectional studies showed that morning cortisol levels are signi cantly correlated with the symptoms of metabolic syndrome, such as visceral obesity, high blood pressure and a poor lipid pro le [3][4][5]. Further studies suggest that metabolic syndrome is a less profound form of Cushing's syndrome, which is characterized by a rise in serum cortisol levels [4,[6][7][8][9].…”

“…Cross-sectional studies showed that morning cortisol levels are signi cantly correlated with the symptoms of metabolic syndrome, such as visceral obesity, high blood pressure and a poor lipid pro le [3][4][5]. Further studies suggest that metabolic syndrome is a less profound form of Cushing's syndrome, which is characterized by a rise in serum cortisol levels [4,[6][7][8][9].is hypothesis is based on the simple observation that patients with Cushing's syndrome develop central obesity, which improves with the resolution of hypercortisolism [10,11].It is known that men with metabolic syndrome are more frequently a ected with android obesity. Central fat distribution is signi cantly associated with increased cortisol levels [12,13], so it could be hypothesized that men with metabolic syndrome have a higher serum cortisol levels, due to increased abdominal obesity compared with women.…”

“…Further studies suggest that metabolic syndrome is a less profound form of Cushing's syndrome, which is characterized by a rise in serum cortisol levels [4,[6][7][8][9].…”