Plasma Levels of Sex Hormone-binding Globulin, Corticosteroid-binding Globulin and Cortisol in Overweight Subjects who Develop Impaired Fasting Glucose: A 3-Year Prospective Study

Abstract

Circulating sex hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), and total and calculated free cortisol were measured in 206 overweight subjects to investigate whether or not they were markers of insulin resistance. Measurements were carried out on two occasions 36 months apart and subjects were grouped according to fasting plasma glucose. Fifty-one subjects, with a normal basal fasting glucose (<5.6 mmol/l) developed impaired fasting glucose 3 years later (≥5.6 mmol/l). Analysis either in toto or based on gender showed a highly significant increase in fasting insulin and insulin resistance, a modest increase in body mass index (BMI), but importantly no change in plasma SHBG, CBG, or cortisol concentrations. Subjects (n=101) with a normal fasting glucose both at baseline (<5.6 mmol/l) and at 36 months showed no significant change in fasting insulin, insulin resistance, SHBG, CBG, cortisol, or BMI. Cross-sectional analysis of the study population showed that plasma SHBG correlated negatively with insulin resistance both in men and women. Overall SHBG at baseline was not predictive of changes in fasting glucose. In females, plasma CBG correlated negatively with BMI. The major finding is that overweight subjects who developed impaired fasting glucose showed no significant change in plasma SHBG, CBG or cortisol, and therefore these indices are probably not early markers of insulin resistance in overweight subjects.

cortisol - glucose - insulin resistance - obesity - insulin

References

• 1 Weinberg ME, Manson JE, Buring JE, Cook NR, Seely EW, Ridker PM, Rexrode KM. Low sex hormone-binding globulin is associated with the metabolic syndrome in postmenopausal women.  Metab Clin Exp. 2006;  55 1473-1480
• 2 Kajaia N, Binder H, Dittrich R, Oppelt PG, Flor B, Cupisti S, Beckmann MW, Mueller A. Low sex hormone-binding globulin as a predictive marker for insulin resistance in women with hyperandrogenic syndrome.  Eur J Endocrinol. 2007;  157 499-507
• 3 MacElduff A, Hitchman R, MacElduff P. Is sex hormone-binding globulin associated with glucose tolerance?.  Diabetic Medicine. 2005;  23 306-312
• 4 Haffner SM, Valdez RA, Morales PA, Hazuda HP, Stern MP. Decreased sex hormone-binding globulin predicts noninsulin-dependent diabetes mellitus in women but not in men.  J Clin Endocrinol Metab. 1993;  77 56-60
• 5 Akin F, Bastemir M, Kaptanoglu B. Relationship between insulin and sex hormone-binding globulin levels during weight loss in obese women.  Ann Nutr Metab. 2007;  51 557-562
• 6 Lewis JG, Shand BI, Elder PA, Scott RS. Plasma sex hormone-binding globulin rather than corticosteroid-binding globulin is a marker of insulin resistance in obese adult males.  Diabet Obes Metab. 2004;  6 259-283
• 7 Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen T-P, Salonen R, Rauramaa R, Salonen JT. Sex hormones, inflammation and the metabolic syndrome: a population-based study.  Eur J Endocrinol. 2003;  149 601-608
• 8 Muller M, Grobbee DE, Tonkelaar den I, Lamberts SWJ, Schouw van der YT. Endogenous sex hormones and metabolic syndrome in aging men.  J Clin Endocrinol Metab. 2005;  90 2618-2623
• 9 Plymate SR, Matej LA, Jones RE, Friedl KE. Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin.  J Clin Endocrinol Metab. 1988;  67 460-464
• 10 Fernández-Real J-M, Pugeat M, Emptoz-Bonneton A, Ricart W. Study of the effect of changing glucose, insulin, and insulin-like growth factor-I levels on serum corticosteroid binding globulin in lean, obese, and obese subjects with glucose intolerance.  Metabolism. 2001;  50 1248-1252
• 11 Fernández-Real J-M, Pugeat M, Grasa M, Broch M, Vendrell J, Brun J, Ricart W. Serum corticosteroid-binding globulin concentration and Insulin Resistance Syndrome: A population study.  J Clin Endocrinol Metab. 2002;  87 4680-4690
• 12 Lewis JG, Möpert B, Shand BI, Doogue MP, Soule SG, Frampton CM, Elder PA. Plasma variation of corticosteroid-binding globulin and sex hormone-binding globulin.  Horm Metab Res. 2006;  38 241-245
• 13 Grasa MM, Cabot C, Fernández-Real J-M, Remesar X, Alemany M. Modulation of corticosterone availability to white adipose tissue of lean and obese Zucker rats by corticosteroid-binding globulin.  Horm Metab Res. 2001;  33 406-411
• 14 Ward AMV, Fall CHD, Stein CE, Kumaran K, Veena SR, Wood PJ, Syddall HE, Phillips DIW. Cortisol and the metabolic syndrome in south Asians.  Clin Endocrinol. 2003;  58 500-505
• 15 Ousova O, Guyonnet-Duperat V, Iannucceli N, Bidanel J-P, Milan D, Genet C, Llamas B, Yerle M, Gellin J, Chardon P, Emptoz-Bonneton A, Pugeat M, Mormede P, Moisan M-P. Corticosteroid binding globulin: A new target for cortisol driven obesity.  Mol Endocrinol. 2004;  18 1687-1696
• 16 Petersen HH, Andreassen TK, Breiderhoff T, Bräsen JH, Schulz H, Gross V, Gröne H-J, Nykjaer A, Willnow TE. Hyporesponsiveness to glucocorticoids in mice genetically deficient for the corticosteroid binding globulin.  Mol Cell Biol. 2006;  26 7236-7245
• 17 American Diabetes Association . Diagnosis and classification of diabetes mellitus.  Diabetes Care. 2008;  31 S55-S60
• 18 Lewis JG, Longley NJ, Elder PA. Monoclonal antibodies to human sex hormone-binding globulin (SHBG): Characterization and use in a simple enzyme-linked immunosorbent assay (ELISA) of SHBG in plasma.  Steroids. 1999;  64 259-265
• 19 Lewis JG, Lewis MG, Elder PA. An enzyme-linked immunosorbent assay for corticosteroid-binding globulin using monoclonal and polyclonal antibodies: decline in CBG following synthetic ACTH.  Clin Chim Acta. 2003;  328 121-128
• 20 Lewis JG, Manley L, Whitlow JC, Elder PA. Production of a monoclonal antibody to cortisol: application to a direct enzyme-linked immunosorbent assay of plasma.  Steroids. 1992;  57 82-85
• 21 Coolens J-L, Baelen H Van, Heyns W. Clinical use of unbound plasma cortisol as calculated from total cortisol and corticosteroid-binding globulin.  J Steroid Biochem. 1987;  26 197-202
• 22 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
• 23 Stroud LR, Solomon C, Shenassa E, Papandonatos G, Niaura R, Lipsitt LP, LeWinn K, Buka SL. Long-term stability of maternal prenatal steroid hormones from the National Collaborative Perinatal Project: Still valid after all these years.  Psychoneuroendocrinol. 2007;  32 140-150
• 24 Dahan MH, Goldstein J. Serum sex hormone-binding globulin levels show too much variability to be used effectively as a screening marker for insulin resistance in women with polycystic ovary syndrome.  Fertil Steril. 2006;  86 934-941
• 25 Katsuki A, Sumida Y, Murashima S, Fujii M, Ito K, Tsuchihashi K, Murata K, Yano Y, Shima T. Acute and chronic regulation of serum sex hormone-binding globulin levels by male noninsulin-dependent diabetes mellitus patients.  J Clin Endocrinol Metab. 1996;  81 2515-2519
• 26 Selva DM, Hogeveen KN, Innis SM, Hammond GL. Monosaccharide-induced lipogenesis regulates the human hepatic sex-hormone-binding globulin gene.  J Clin Invest. 2007;  117 3979-3987
• 27 Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, MacKinlay JB. Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men.  J Clin Endocrinol Metab. 2006;  91 843-850
• 28 Pasquali R, Vicennati V. Steroids and the metabolic syndrome.  J Steroid Biochem Mol Biol. 2008;  109 258-265
• 29 Holt HB, Wild SH, Postle AD, Zhang J, Koster G, Umpleby M, Shojaee-Moradie F, Dewbury K, Wood PJ, Phillips DI, Byrne CD. Cortisol clearance and associations with insulin sensitivity, body fat and fatty liver in middle-aged men.  Diabetologia. 2007;  50 1024-1032
• 30 Wang M. The role of glucocorticoid action in the pathophysiology of the metabolic syndrome.  Nutr Metab. 2005;  2 3-16
• 31 Manco M, Fernández-Real J-M, Volera-Mora ME, Déchaud H, Nanni G, Tondolo V, Calvani M, Castagneto M, Pugeat M, Mingrone G. Massive weight loss decreases corticosteroid-binding globulin in healthy obese patients: an adaptive phenomen?.  Diabetes Care. 2007;  30 1494-1450
• 32 Ho JT, Keogh JB, Bornstein SR, Ehrhart-Bornstein M, Lewis JG, Clifton PM, Torpy DJ. Moderate weight loss reduces renin and aldosterone but does not influence basal or stimulated pituitary-adrenal axis function.  Horm Metab Res. 2007;  39 694-699
• 33 Duclos M, Pereira PM, Barat P, Gatta B, Roger P. Increased cortisol bioavailability, abdominal obesity, and the metabolic syndrome in obese women.  Obesity Res. 2005;  13 1157-1166

Correspondence