Plasma total and glycosylated corticosteroid-binding globulin levels are associated with insulin secretion

In humans, steroid hormones circulate in the blood mainly bound to specific steroid transport proteins, namely corticosteroid-binding globulin (CBG) f or cortisol and sex hormone-binding globulin (SHBG) for testosterone and es tradiol. The binding activities of these proteins are believed to modulate the biodisposal of steroids to target cells. It has been shown in vitro tha t insulin is a potent inhibitor of both CBG and SHBG secretion by a human h epatoblastoma cell (HepG2) line. To further investigate this potential effe ct of insulin in vivo, we prospectively studied three groups of lean subjec ts, obese subjects, and obese subjects with glucose intolerance, all of of whom were otherwise healthy. The three groups were comparable in sex and ag e, and in the two obese groups, body mass index, waist to hip ratio, and bl ood pressure were similar. Plasma total CBG concentrations (38.2 +/- 5.4 vs . 31.7 +/- 4.05 mg/L; P = 0.016) and glycosylated CBG levels (37.3 +/- 5.2 vs. 31 +/- 3.9 mg/L; P = 0.018) were significantly increased in obese subje cts with glucose intolerance. Plasma CBG correlated positively with fasting glucose levels (r = 0.49; P = 0.002), hemoglobin A(1c) levels (r = 0.35; P = 0.03), and area under the curve of glucose after an oral glucose toleran ce test (r = 0.45; P = 0.005) and correlated negatively with the insulin re sponse to iv glucose (AIRg; -0.38, P = 0.02) as well as to oral glucose (r = -0.40; P = 0.01) challenge tests. CBG levels did not covariate with insul in sensitivity. Multiple linear regression analysis showed that only AIRg c ontributed to the variability of the CBG concentration (P = 0.03), explaini ng 41% of its variance. Morning cortisol levels did not differ between the groups and did not correlate to any of the glucose or insulin metabolism pa rameters. Because carbohydrate chains influence the biological activity and half-life of glycoproteins, we analyzed the migration profile of CBG by Western blot and the interaction of CBG with lectin, Con A. The results indicated that the CBG mol wt and interaction with Con A did not differ between lean and o bese patients. These data favor the hypothesis that the inhibitory effect o f insulin on CBG Liver secretion might be relevant in vivo and therefore co ntribute to decrease CBG levels in obese patients with enhanced insulin sec retion. In both men and women, SHBG levels correlated negatively with fasting gluco se (r = -0.55; P < 0.0001) and hemoglobin A(1c) (r = -0.38; P = 0.02) and p ositively with insulin sensitivity (S-1; r = 0.65; P = 0.003 and r = 0.63; P = 0.007 in men and women, respectively), but not with insulin secretion. The disposition index (S-1 x AIRg) was significantly decreased in the obese , glucose-intolerant subjects, suggesting that AIRg was inadequate for thei r degree of insulin resistance. The disposition index correlated positively with plasma SHBG levels (r = 0.52; P = 0.001) and negatively with plasma C BG levels (r = -0.54; P = 0.001). Our data suggest that CBG is a marker of insulin secretion in a similar way as SHBG is a marker of insulin sensitivity. As high plasma CBG levels have been associated with increased incidence of type 2 diabetes, this importan t issue merits further investigations.