Skip to main content
Top
Published in: Cardiovascular Diabetology 1/2012

Open Access 01-12-2012 | Original investigation

Associations of sex hormone-binding globulin and testosterone with diabetes among men and women (the Saku Diabetes study): a case control study

Authors: Atsushi Goto, Akemi Morita, Maki Goto, Satoshi Sasaki, Motohiko Miyachi, Naomi Aiba, Yasuo Terauchi, Mitsuhiko Noda, Shaw Watanabe, the Saku Cohort Study Group

Published in: Cardiovascular Diabetology | Issue 1/2012

Login to get access

Abstract

Background

Sex hormone-binding globulin (SHBG) levels and sex hormones have been implicated in the pathogenesis of type 2 diabetes and cardiovascular diseases. As fatty liver has been suggested to be a major determinant of SHBG levels, we examined whether the associations of SHBG and testosterone with diabetes were independent of fatty liver.

Methods

We conducted a case–control study that included 300 diabetes cases (215 men and 85 women) and 300 matched controls from the Saku cohort study. Diabetes was defined by either fasting plasma glucose levels ≥126 mg/dL, 2-h post-load glucose levels ≥200 mg/dL after a 75 g oral glucose tolerance test, or diabetes diagnosed by physicians. We fitted conditional logistic regression models to examine the associations between SHBG and total testosterone levels with diabetes by sex. To evaluate the impact of fatty liver, we used the fatty liver index (FLI), a validated measure derived from serum triglyceride levels, body mass index (BMI), waist circumference, and γ-glutamyltransferase levels.

Results

After adjusting for age, family history of diabetes, smoking, physical activity, BMI, and FLI, SHBG levels were inversely associated with diabetes among women (odds ratio [OR] comparing the highest with the lowest quartiles, 0.13 [95% confidence interval {CI}, 0.02–0.96]), but not among men. Similar patterns were observed in a subgroup analysis restricted to postmenopausal women"(OR, 0.12 [95% CI, 0.01–1.17]). In contrast, testosterone levels were inversely associated with diabetes among men (OR, 0.45 [95% CI, 0.23–0.89]), but not among women.

Conclusions

Our findings suggest that SHBG in women and testosterone in men may be inversely associated with diabetes.
Appendix
Available only for authorised users
Literature
1.
go back to reference Ding EL, Song Y, Malik VS, Liu S: Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2006, 295 (11): 1288-1299. 10.1001/jama.295.11.1288.CrossRefPubMed Ding EL, Song Y, Malik VS, Liu S: Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2006, 295 (11): 1288-1299. 10.1001/jama.295.11.1288.CrossRefPubMed
2.
go back to reference Ding EL, Song Y, Manson JE, Hunter DJ, Lee CC, Rifai N, Buring JE, Gaziano JM, Liu S: Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med. 2009, 361 (12): 1152-1163. 10.1056/NEJMoa0804381.PubMedCentralCrossRefPubMed Ding EL, Song Y, Manson JE, Hunter DJ, Lee CC, Rifai N, Buring JE, Gaziano JM, Liu S: Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med. 2009, 361 (12): 1152-1163. 10.1056/NEJMoa0804381.PubMedCentralCrossRefPubMed
3.
go back to reference Goto A, Song Y, Chen BH, Manson JE, Buring JE, Liu S: Coffee and caffeine consumption in relation to sex hormone-binding globulin and risk of type 2 diabetes in postmenopausal women. Diabetes. 2011, 60 (1): 269-275. 10.2337/db10-1193.PubMedCentralCrossRefPubMed Goto A, Song Y, Chen BH, Manson JE, Buring JE, Liu S: Coffee and caffeine consumption in relation to sex hormone-binding globulin and risk of type 2 diabetes in postmenopausal women. Diabetes. 2011, 60 (1): 269-275. 10.2337/db10-1193.PubMedCentralCrossRefPubMed
4.
go back to reference Ohlsson C, Barrett-Connor E, Bhasin S, Orwoll E, Labrie F, Karlsson MK, Ljunggren O, Vandenput L, Mellstrom D, Tivesten A: High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. J Am Coll Cardiol. 2011, 58 (16): 1674-1681. 10.1016/j.jacc.2011.07.019.CrossRefPubMed Ohlsson C, Barrett-Connor E, Bhasin S, Orwoll E, Labrie F, Karlsson MK, Ljunggren O, Vandenput L, Mellstrom D, Tivesten A: High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. J Am Coll Cardiol. 2011, 58 (16): 1674-1681. 10.1016/j.jacc.2011.07.019.CrossRefPubMed
5.
go back to reference Westerink J, Visseren FL: Pharmacological and non-pharmacological interventions to influence adipose tissue function. Cardiovasc Diabetol. 2011, 10 (1): 13-10.1186/1475-2840-10-13.PubMedCentralCrossRefPubMed Westerink J, Visseren FL: Pharmacological and non-pharmacological interventions to influence adipose tissue function. Cardiovasc Diabetol. 2011, 10 (1): 13-10.1186/1475-2840-10-13.PubMedCentralCrossRefPubMed
6.
go back to reference Anderson DC: Sex-hormone-binding globulin. Clin Endocrinol. 1974, 3 (1): 69-96. 10.1111/j.1365-2265.1974.tb03298.x.CrossRef Anderson DC: Sex-hormone-binding globulin. Clin Endocrinol. 1974, 3 (1): 69-96. 10.1111/j.1365-2265.1974.tb03298.x.CrossRef
7.
go back to reference Rosner W, Hryb DJ, Khan MS, Nakhla AM, Romas NA: Sex hormone-binding globulin mediates steroid hormone signal transduction at the plasma membrane. The Journal of steroid biochemistry and molecular biology. 1999, 69 (1–6): 481-485.CrossRefPubMed Rosner W, Hryb DJ, Khan MS, Nakhla AM, Romas NA: Sex hormone-binding globulin mediates steroid hormone signal transduction at the plasma membrane. The Journal of steroid biochemistry and molecular biology. 1999, 69 (1–6): 481-485.CrossRefPubMed
8.
go back to reference Kahn SM, Hryb DJ, Nakhla AM, Romas NA, Rosner W: Sex hormone-binding globulin is synthesized in target cells. J Endocrinol. 2002, 175 (1): 113-120. 10.1677/joe.0.1750113.CrossRefPubMed Kahn SM, Hryb DJ, Nakhla AM, Romas NA, Rosner W: Sex hormone-binding globulin is synthesized in target cells. J Endocrinol. 2002, 175 (1): 113-120. 10.1677/joe.0.1750113.CrossRefPubMed
9.
go back to reference Perry JR, Weedon MN, Langenberg C, Jackson AU, Lyssenko V, Sparso T, Thorleifsson G, Grallert H, Ferrucci L, Maggio M, et al: Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes. Hum Mol Genet. 2010, 19 (3): 535-544. 10.1093/hmg/ddp522.PubMedCentralCrossRefPubMed Perry JR, Weedon MN, Langenberg C, Jackson AU, Lyssenko V, Sparso T, Thorleifsson G, Grallert H, Ferrucci L, Maggio M, et al: Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes. Hum Mol Genet. 2010, 19 (3): 535-544. 10.1093/hmg/ddp522.PubMedCentralCrossRefPubMed
10.
go back to reference Peter A, Kantartzis K, Machann J, Schick F, Staiger H, Machicao F, Schleicher E, Fritsche A, Haring HU, Stefan N: Relationships of circulating sex hormone-binding globulin with metabolic traits in humans. Diabetes. 2010, 59 (12): 3167-3173. 10.2337/db10-0179.PubMedCentralCrossRefPubMed Peter A, Kantartzis K, Machann J, Schick F, Staiger H, Machicao F, Schleicher E, Fritsche A, Haring HU, Stefan N: Relationships of circulating sex hormone-binding globulin with metabolic traits in humans. Diabetes. 2010, 59 (12): 3167-3173. 10.2337/db10-0179.PubMedCentralCrossRefPubMed
11.
go back to reference Stefan N, Kantartzis K, Haring HU: Causes and metabolic consequences of Fatty liver. Endocr Rev. 2008, 29 (7): 939-960. 10.1210/er.2008-0009.CrossRefPubMed Stefan N, Kantartzis K, Haring HU: Causes and metabolic consequences of Fatty liver. Endocr Rev. 2008, 29 (7): 939-960. 10.1210/er.2008-0009.CrossRefPubMed
12.
go back to reference Lin HY, Xu Q, Yeh S, Wang RS, Sparks JD, Chang C: Insulin and leptin resistance with hyperleptinemia in mice lacking androgen receptor. Diabetes. 2005, 54 (6): 1717-1725. 10.2337/diabetes.54.6.1717.CrossRefPubMed Lin HY, Xu Q, Yeh S, Wang RS, Sparks JD, Chang C: Insulin and leptin resistance with hyperleptinemia in mice lacking androgen receptor. Diabetes. 2005, 54 (6): 1717-1725. 10.2337/diabetes.54.6.1717.CrossRefPubMed
13.
go back to reference Fan W, Yanase T, Nomura M, Okabe T, Goto K, Sato T, Kawano H, Kato S, Nawata H: Androgen receptor null male mice develop late-onset obesity caused by decreased energy expenditure and lipolytic activity but show normal insulin sensitivity with high adiponectin secretion. Diabetes. 2005, 54 (4): 1000-1008. 10.2337/diabetes.54.4.1000.CrossRefPubMed Fan W, Yanase T, Nomura M, Okabe T, Goto K, Sato T, Kawano H, Kato S, Nawata H: Androgen receptor null male mice develop late-onset obesity caused by decreased energy expenditure and lipolytic activity but show normal insulin sensitivity with high adiponectin secretion. Diabetes. 2005, 54 (4): 1000-1008. 10.2337/diabetes.54.4.1000.CrossRefPubMed
14.
go back to reference Sato T, Matsumoto T, Yamada T, Watanabe T, Kawano H, Kato S: Late onset of obesity in male androgen receptor-deficient (AR KO) mice. Biochem Biophys Res Commun. 2003, 300 (1): 167-171. 10.1016/S0006-291X(02)02774-2.CrossRefPubMed Sato T, Matsumoto T, Yamada T, Watanabe T, Kawano H, Kato S: Late onset of obesity in male androgen receptor-deficient (AR KO) mice. Biochem Biophys Res Commun. 2003, 300 (1): 167-171. 10.1016/S0006-291X(02)02774-2.CrossRefPubMed
15.
go back to reference World Health Organization: Definition, diagnosis and classification of diabetes mellitus and its complications. World Health Organization. 1999, 31-33. World Health Organization: Definition, diagnosis and classification of diabetes mellitus and its complications. World Health Organization. 1999, 31-33.
16.
go back to reference Sawada N, Iwasaki M, Inoue M, Sasazuki S, Yamaji T, Shimazu T, Tsugane S: Plasma testosterone and sex hormone‐binding globulin concentrations and the risk of prostate cancer among Japanese men: A nested case‐control study. Cancer science. 2010, 101 (12): 2652-2657. 10.1111/j.1349-7006.2010.01721.x.CrossRefPubMed Sawada N, Iwasaki M, Inoue M, Sasazuki S, Yamaji T, Shimazu T, Tsugane S: Plasma testosterone and sex hormone‐binding globulin concentrations and the risk of prostate cancer among Japanese men: A nested case‐control study. Cancer science. 2010, 101 (12): 2652-2657. 10.1111/j.1349-7006.2010.01721.x.CrossRefPubMed
17.
go back to reference Sodergard R, Backstrom T, Shanbhag V, Carstensen H: Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature. J Steroid Biochem. 1982, 16 (6): 801-810. 10.1016/0022-4731(82)90038-3.CrossRefPubMed Sodergard R, Backstrom T, Shanbhag V, Carstensen H: Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature. J Steroid Biochem. 1982, 16 (6): 801-810. 10.1016/0022-4731(82)90038-3.CrossRefPubMed
18.
go back to reference Vermeulen A, Verdonck L, Kaufman JM: A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999, 84 (10): 3666-3672. 10.1210/jc.84.10.3666.CrossRefPubMed Vermeulen A, Verdonck L, Kaufman JM: A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999, 84 (10): 3666-3672. 10.1210/jc.84.10.3666.CrossRefPubMed
19.
go back to reference Kashiwagi A, Kasuga M, Araki E, Oka Y, Hanafusa T, Ito H, Tominaga M, Oikawa S, Noda M, Kawamura T, et al: International clinical harmonization of glycated hemoglobin in Japan: From Japan Diabetes Society to National Glycohemoglobin Standardization Program values. Journal of Diabetes Investigation. 2012, 3 (1): 39-40. 10.1111/j.2040-1124.2012.00207.x.PubMedCentralCrossRefPubMed Kashiwagi A, Kasuga M, Araki E, Oka Y, Hanafusa T, Ito H, Tominaga M, Oikawa S, Noda M, Kawamura T, et al: International clinical harmonization of glycated hemoglobin in Japan: From Japan Diabetes Society to National Glycohemoglobin Standardization Program values. Journal of Diabetes Investigation. 2012, 3 (1): 39-40. 10.1111/j.2040-1124.2012.00207.x.PubMedCentralCrossRefPubMed
20.
go back to reference Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, Tiribelli C: The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006, 6: 33-10.1186/1471-230X-6-33.PubMedCentralCrossRefPubMed Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, Tiribelli C: The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006, 6: 33-10.1186/1471-230X-6-33.PubMedCentralCrossRefPubMed
21.
go back to reference Calori G, Lattuada G, Ragogna F, Garancini MP, Crosignani P, Villa M, Bosi E, Ruotolo G, Piemonti L, Perseghin G: Fatty liver index and mortality: The cremona study in the 15th year of follow-up. Hepatology. 2011, 54 (1): 145-152. 10.1002/hep.24356.CrossRefPubMed Calori G, Lattuada G, Ragogna F, Garancini MP, Crosignani P, Villa M, Bosi E, Ruotolo G, Piemonti L, Perseghin G: Fatty liver index and mortality: The cremona study in the 15th year of follow-up. Hepatology. 2011, 54 (1): 145-152. 10.1002/hep.24356.CrossRefPubMed
22.
go back to reference Balkau B, Lange C, Vol S, Fumeron F, Bonnet F, D.E.S.I.R. GS: Nine-year incident diabetes is predicted by fatty liver indices: the French D.E.S.I.R. study. BMC Gastroenterol. 2010, 10 (1): 56-10.1186/1471-230X-10-56.PubMedCentralCrossRefPubMed Balkau B, Lange C, Vol S, Fumeron F, Bonnet F, D.E.S.I.R. GS: Nine-year incident diabetes is predicted by fatty liver indices: the French D.E.S.I.R. study. BMC Gastroenterol. 2010, 10 (1): 56-10.1186/1471-230X-10-56.PubMedCentralCrossRefPubMed
23.
go back to reference Gastaldelli A, Kozakova M, Hojlund K, Flyvbjerg A, Favuzzi A, Mitrakou A, Balkau B, Investigators R: Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population. Hepatology. 2009, 49 (5): 1537-1544. 10.1002/hep.22845.CrossRefPubMed Gastaldelli A, Kozakova M, Hojlund K, Flyvbjerg A, Favuzzi A, Mitrakou A, Balkau B, Investigators R: Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population. Hepatology. 2009, 49 (5): 1537-1544. 10.1002/hep.22845.CrossRefPubMed
24.
go back to reference Greenland S: Dose–response and trend analysis in epidemiology: alternatives to categorical analysis. Epidemiology. 1995, 6 (4): 356-365. 10.1097/00001648-199507000-00005.CrossRefPubMed Greenland S: Dose–response and trend analysis in epidemiology: alternatives to categorical analysis. Epidemiology. 1995, 6 (4): 356-365. 10.1097/00001648-199507000-00005.CrossRefPubMed
25.
go back to reference Kalyani RR, Franco M, Dobs AS, Ouyang P, Vaidya D, Bertoni A, Gapstur SM, Golden SH: The association of endogenous sex hormones, adiposity, and insulin resistance with incident diabetes in postmenopausal women. J Clin Endocrinol Metab. 2009, 94 (11): 4127-4135. 10.1210/jc.2009-0910.PubMedCentralCrossRefPubMed Kalyani RR, Franco M, Dobs AS, Ouyang P, Vaidya D, Bertoni A, Gapstur SM, Golden SH: The association of endogenous sex hormones, adiposity, and insulin resistance with incident diabetes in postmenopausal women. J Clin Endocrinol Metab. 2009, 94 (11): 4127-4135. 10.1210/jc.2009-0910.PubMedCentralCrossRefPubMed
26.
go back to reference Chen BH, Brennan K, Goto A, Song Y, Aziz N, You NC, Wellons MF, Manson JE, White DL, Butch AW, et al: Sex hormone-binding globulin and risk of clinical diabetes in american black, Hispanic, and asian/pacific islander postmenopausal women. Clin Chem. 2012, 58 (10): 1457-1466. 10.1373/clinchem.2012.193086.PubMedCentralCrossRefPubMed Chen BH, Brennan K, Goto A, Song Y, Aziz N, You NC, Wellons MF, Manson JE, White DL, Butch AW, et al: Sex hormone-binding globulin and risk of clinical diabetes in american black, Hispanic, and asian/pacific islander postmenopausal women. Clin Chem. 2012, 58 (10): 1457-1466. 10.1373/clinchem.2012.193086.PubMedCentralCrossRefPubMed
27.
go back to reference 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 (1): 56-60. 10.1210/jc.77.1.56.PubMed 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 (1): 56-60. 10.1210/jc.77.1.56.PubMed
28.
go back to reference Le TN, Nestler JE, Strauss JF, Wickham EP: Sex hormone-binding globulin and type 2 diabetes mellitus. Trends in endocrinology and metabolism: TEM. 2012, 23 (1): 32-40. 10.1016/j.tem.2011.09.005.PubMedCentralCrossRefPubMed Le TN, Nestler JE, Strauss JF, Wickham EP: Sex hormone-binding globulin and type 2 diabetes mellitus. Trends in endocrinology and metabolism: TEM. 2012, 23 (1): 32-40. 10.1016/j.tem.2011.09.005.PubMedCentralCrossRefPubMed
29.
go back to reference Nestler JE: Sex hormone-binding globulin and risk of type 2 diabetes. N Engl J Med. 2009, 361 (27): 2676-2677.PubMed Nestler JE: Sex hormone-binding globulin and risk of type 2 diabetes. N Engl J Med. 2009, 361 (27): 2676-2677.PubMed
30.
go back to reference Simo R, Barbosa-Desongles A, Lecube A, Hernandez C, Selva DM: Potential Role of Tumor Necrosis Factor-alpha in Downregulating Sex Hormone-Binding Globulin. Diabetes. 2012, 61 (2): 372-382. 10.2337/db11-0727.PubMedCentralCrossRefPubMed Simo R, Barbosa-Desongles A, Lecube A, Hernandez C, Selva DM: Potential Role of Tumor Necrosis Factor-alpha in Downregulating Sex Hormone-Binding Globulin. Diabetes. 2012, 61 (2): 372-382. 10.2337/db11-0727.PubMedCentralCrossRefPubMed
31.
go back to reference Kapoor D, Goodwin E, Channer KS, Jones TH: Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006, 154 (6): 899-906. 10.1530/eje.1.02166.CrossRefPubMed Kapoor D, Goodwin E, Channer KS, Jones TH: Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006, 154 (6): 899-906. 10.1530/eje.1.02166.CrossRefPubMed
32.
go back to reference Grossmann M: Low testosterone in men with type 2 diabetes: significance and treatment. J Clin Endocrinol Metab. 2011, 96 (8): 2341-2353. 10.1210/jc.2011-0118.CrossRefPubMed Grossmann M: Low testosterone in men with type 2 diabetes: significance and treatment. J Clin Endocrinol Metab. 2011, 96 (8): 2341-2353. 10.1210/jc.2011-0118.CrossRefPubMed
Metadata
Title
Associations of sex hormone-binding globulin and testosterone with diabetes among men and women (the Saku Diabetes study): a case control study
Authors
Atsushi Goto
Akemi Morita
Maki Goto
Satoshi Sasaki
Motohiko Miyachi
Naomi Aiba
Yasuo Terauchi
Mitsuhiko Noda
Shaw Watanabe
the Saku Cohort Study Group
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2012
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/1475-2840-11-130

Other articles of this Issue 1/2012

Cardiovascular Diabetology 1/2012 Go to the issue