Correspondence
Sex Hormone–Binding Globulin and Risk of Type 2 Diabetes
N Engl J Med 2009; 361:2675-2678December 31, 2009
- Article
To the Editor:
Ding et al. (Sept. 17 issue)1 found that sex hormone–binding globulin, which is predominantly expressed in hepatocytes, may protect against type 2 diabetes. What variables in the natural history of diabetes determine circulating levels of sex hormone–binding globulin? Recently, monosaccharide-induced hepatic lipogenesis, but not insulin, was shown to suppress hepatic production of sex hormone–binding globulin in animals.2 Because this pathway is involved in the pathogenesis of fatty liver, a major risk factor in type 2 diabetes,3 we hypothesized that levels of sex hormone–binding globulin decrease, particularly under hepatic steatosis. In subjects who underwent precise measurements of liver-fat and body-fat distribution4 we observed that besides sex and age, liver fat, but not visceral fat or total body fat, was an independent predictor of levels of sex hormone–binding globulin (Figure 1AFigure 1
Relationship between Levels of Sex Hormone–Binding Globulin and Liver Fat.). During a lifestyle intervention, an increase in levels of sex hormone–binding globulin was more strongly associated with a decrease in liver fat (Figure 1B) as compared with visceral fat or total body fat. Thus, conditions inducing fatty liver, rather than visceral adiposity or total adiposity, may be logical targets when aiming to increase levels of sex hormone–binding globulin in humans.Norbert Stefan, M.D.
Fritz Schick, M.D., Ph.D.
Hans-Ulrich Häring, M.D.
University of Tübingen,, Tübingen, Germany
norbert.stefan@med. uni-tuebingen. de No potential conflict of interest relevant to this letter was reported.
4 References1
Ding EL ,Song Y ,Manson JE , et al. Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med 2009;361:1152-1163
Full Text | Web of Science | Medline2
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
Web of Science | Medline3
Stefan N ,Kantartzis K ,Haring U . Causes and metabolic consequences of fatty liver. Endocr Rev 2008;29:939-960
CrossRef | Web of Science | Medline4
Kantartzis K ,Thamer C ,Peter A , et al. High cardiorespiratory fitness is an independent predictor of the reduction in liver fat during a lifestyle intervention in non-alcoholic fatty liver disease. Gut 2009;58:1281-1288
CrossRef | Web of Science | Medline
To the Editor:
Ding and colleagues describe the effects of genotypes of the gene encoding sex hormone–binding globulin (SHBG) on plasma levels of sex hormone–binding globulin and the risk of type 2 diabetes. It is likely that the risk of type 2 diabetes associated with a low level of sex hormone–binding globulin is due in part to an inverse correlation between insulin resistance and plasma levels of sex hormone–binding globulin. Insulin decreases hepatic production of sex hormone–binding globulin in vitro,1 and inhibition of insulin release increases plasma levels of sex hormone–binding globulin in humans.2 Hyperinsulinemia induced by insulin resistance probably causes low levels of sex hormone–binding globulin in insulin-resistant conditions such as obesity, type 2 diabetes, and the polycystic ovary syndrome. Neither insulin sensitivity nor circulating insulin was measured in the present study, and insulin resistance may be present even when the body-mass index and glycated hemoglobin value are normal. Within the subgroups of persons with the rs6259 or rs6257 SHBG genotypes, was the risk of the development of type 2 diabetes higher among persons with lower levels of sex hormone–binding globulin? If so, that would suggest that hyperinsulinemic insulin resistance decreases levels of sex hormone–binding globulin regardless of genotype and may independently contribute to the risk of type 2 diabetes.
John E. Nestler, M.D.
Virginia Commonwealth University, Richmond, VA
jnestler@mcvh-vcu.edu No potential conflict of interest relevant to this letter was reported.
2 References1
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
CrossRef | Web of Science | Medline2
Nestler JE ,Powers LP ,Matt DW , et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 1991;72:83-89
CrossRef | Web of Science | Medline
To the Editor:
Ding and colleagues report a strong association between a low serum level of sex hormone–binding globulin and the development of type 2 diabetes mellitus, and using mendelian randomization, they implicate a low level of sex hormone–binding globulin as a causative factor in the pathogenesis of type 2 diabetes. The authors' conclusions should be viewed in the light of a substantial body of data (very little of which is discussed) indicating that insulin physiologically suppresses serum levels of sex hormone–binding globulin. Levels of sex hormone–binding globulin are elevated both in type 1 diabetes,1 a state of relative portal hypoinsulinism, and in insulin-receptor dysfunction.2 Other forms of insulin resistance and hyperinsulinemia are associated with low serum levels of sex hormone–binding globulin,2,3 consistent with preservation of some hepatic insulin responsiveness in these settings.4 Thus, low serum levels of sex hormone–binding globulin commonly result from hyperinsulinemia related to insulin resistance. It is possible that low levels of sex hormone–binding globulin could be both a consequence of hyperinsulinemia and contribute directly (by an unknown mechanism) to the pathogenesis of type 2 diabetes. However, full understanding of the relationship between sex hormone–binding globulin and metabolic disease will require balanced consideration of all available data, avoiding overreliance on a single, albeit powerful, genetic epidemiologic tool.
Robert Semple, M.B., Ph.D.
David B. Savage, M.D.
Steven O'Rahilly, M.D.
University of Cambridge, Cambridge, United Kingdom
rks16@cam.ac. uk No potential conflict of interest relevant to this letter was reported.
4 References1
Danielson KK ,Drum ML ,Lipton RB . Sex hormone-binding globulin and testosterone in individuals with childhood diabetes. Diabetes Care 2008;31:1207-1213
CrossRef | Web of Science | Medline2
Semple RK ,Cochran EK ,Soos MA , et al. Plasma adiponectin as a marker of insulin receptor dysfunction: clinical utility in severe insulin resistance. Diabetes Care 2008;31:977-979
CrossRef | Web of Science | Medline3
Jayagopal V ,Kilpatrick ES ,Jennings PE ,Hepburn DA ,Atkin SL . The biological variation of testosterone and sex hormone-binding globulin (SHBG) in polycystic ovarian syndrome: implications for SHBG as a surrogate marker of insulin resistance. J Clin Endocrinol Metab 2003;88:1528-1533
CrossRef | Web of Science | Medline4
Semple RK ,Sleigh A ,Murgatroyd PR , et al. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J Clin Invest 2009;119:315-322
Web of Science | Medline
Author/Editor Response
We appreciate the comments by Stefan et al. suggesting that lipogenesis and hepatic steatosis may be determinants of circulating sex hormone–binding globulin. Their data relating levels of sex hormone–binding globulin to liver fat as measured by means of magnetic resonance spectroscopy are indeed consistent with our own observation that elevated levels of fasting triglycerides were inversely related to levels of sex hormone–binding globulin. In addition, postmenopausal women who consumed a diet with a high glycemic load had elevated levels of fasting triglycerides1 and inflammatory markers2; this provides further support for the potential role that lipogenesis may play in suppressing levels of sex hormone–binding globulin and the development of insulin resistance.
Nestler and Semple et al. point out that compensatory hyperinsulinemia associated with insulin resistance could reduce levels of sex hormone–binding globulin and also increase the risk of type 2 diabetes. Although such confounding by insulin resistance is difficult to rule out, it is unlikely that the shared variance between insulin and sex hormone–binding globulin would explain the strong magnitude of association observed between the risk of type 2 diabetes and levels of sex hormone–binding globulin (an association that is far stronger than that with insulin levels).3,4 Further, the identification of germ-line variants in the SHBG gene that are directly predictive of the risk of type 2 diabetes is indicative of heritable SHBG-dependent pathways leading to type 2 diabetes. For example, the effects of rs6257 and rs6259 were each independent and additive, jointly contributing to an approximately 57% lower risk of type 2 diabetes (Fig. 1 of our article). Because the plasma phenotype of sex hormone–binding globulin seems to best capture the cumulative effects of both the genetic and environmental factors on the risk of type 2 diabetes in our prospective data, identification of the major drivers that regulate SHBG gene expression and protein levels in the causal pathways leading to diabetes (via impaired insulin action or secretion or even other as-yet unrecognized mechanisms) would be of interest.
Indeed, the elegant experiments by Selva et al.5 were the first to show that expression of sex hormone–binding globulin in hepatocytes could be directly suppressed by either fructose or glucose, independent of insulin, via a down-regulation of the hepatocyte nuclear factor 4α, a transcriptional factor that has been associated with a form of maturity-onset diabetes of the young. Taken together, these recent data provide further molecular insights in support of targeting sex hormone–binding globulin in clinical risk stratification and intervention for the maintenance of glucose homeostasis.
Simin Liu, M.D., Sc.D.
University of California, Los Angeles, Los Angeles, CA
siminliu@ucla.edu Eric Ding, Sc.D.
Harvard School of Public Health, Boston, MAYiqing Song, M.D., Sc.D.
Brigham and Women's Hospital, Boston, MASince publication of their article, the authors report no further potential conflict of interest.
5 References1
Liu S ,Manson JE ,Stampfer MJ , et al. Dietary glycemic load assessed by food-frequency questionnaire in relation to plasma high-density-lipoprotein cholesterol and fasting plasma triacylglycerols in postmenopausal women. Am J Clin Nutr 2001;73:560-566
Web of Science | Medline2
Liu S ,Manson J ,Buring J ,Stampfer M ,Willett WC ,Ridker PM . Relation between a diet with a high glycemic load and plasma concentrations of high-sensitivity C-reactive protein in middle-aged women. Am J Clin Nutr 2002;75:492-498
Web of Science | Medline3
Song Y ,Manson JE ,Tinker L , et al. Insulin sensitivity and insulin secretion determined by homeostasis model assessment and risk of diabetes in a multiethnic cohort of women: the Women's Health Initiative Observational Study. Diabetes Care 2007;30:1747-1752
CrossRef | Web of Science | Medline4
Ding EL ,Song Y ,Manson JE ,Rifai N ,Buring JE ,Liu S . Plasma sex steroid hormones and risk of developing type 2 diabetes in women: a prospective study. Diabetologia 2007;50:2076-2084
CrossRef | Web of Science | Medline5
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
Web of Science | Medline
- Citing Articles (4)
Citing Articles
1
Lei Sun, Zhen Jin, Weiping Teng, Xinshu Chi, Yanan Zhang, Wanting Ai, Pinting Wang. (2011) Expression changes of sex hormone binding globulin in GDM placental tissues. Journal of Perinatal Medicine---
CrossRef2
Jang Yel Shin, Soo-Ki Kim, Mi Young Lee, Hyun Soo Kim, Byung Il Ye, Young Goo Shin, Soon Koo Baik, Choon Hee Chung. (2011) Serum sex hormone-binding globulin levels are independently associated with nonalcoholic fatty liver disease in people with type 2 diabetes. Diabetes Research and Clinical Practice 94:1, 156-162
CrossRef3
A Peter, K Kantartzis, F Machicao, J Machann, S Wagner, S Templin, I Königsrainer, A Königsrainer, F Schick, A Fritsche, H-U Häring, N Stefan. (2011) Visceral obesity modulates the impact of apolipoprotein C3 gene variants on liver fat content. International Journal of Obesity
CrossRef4
N. Stefan, H. Staiger, H.-U. Häring. (2011) Dissociation between fatty liver and insulin resistance: the role of adipose triacylglycerol lipase. Diabetologia 54:1, 7-9
CrossRef
