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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 3 1550-1556
Copyright © 2005 by The Endocrine Society

Sex Hormone-Binding Globulin and Insulin-Like Growth Factor-Binding Protein-1 as Indicators of Metabolic Syndrome, Cardiovascular Risk, and Mortality in Elderly Men

Tarja Kalme, Markku Seppälä, Qing Qiao, Riitta Koistinen, Aulikki Nissinen, Maija Harrela, Mikko Loukovaara, Pekka Leinonen and Jaakko Tuomilehto

Departments of Obstetrics and Gynecology (T.K., R.K., M.H., M.L., P.L.) and Clinical Chemistry (M.S.), Helsinki University Central Hospital, FIN-00029 Helsinki, Finland; Jorvi Hospital (T.K.), FIN-02740 Espoo, Finland; Department of Epidemiology and Health Promotion, National Public Health Institute (Q.Q., A.N., J.T.), FIN-00300 Helsinki, Finland; Department of Neuroscience, Kuopio University Hospital (A.N.), FIN-70211 Kuopio, Finland; Department of Public Health, University of Helsinki (Q.Q., J.T.), FIN-00300 Helsinki, Finland; and South Ostrobotnia Central Hospital (J.T.), FIN-60220 Seinäjoki, Finland

Address all correspondence and requests for reprints to: Dr. Jaakko Tuomilehto, Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland. E-mail: jaakko.tuomilehto{at}ktl.fi.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Two binding proteins, SHBG and IGF-binding protein-1 (IGFBP-1), are both down-regulated by insulin and therefore could serve as potential indicators of the metabolic syndrome and hyperinsulinemia-related cardiovascular risk. We compared serum SHBG and IGFBP-1 as potential markers of abnormal glucose tolerance, the metabolic syndrome, diabetes mellitus, cardiovascular risk factors, and total, cardiovascular, and coronary heart disease mortality in elderly men. Of the original cohort of 1711 men, 524 were alive on January 1, 1989, and 413 participated in the 30-yr examination, of whom 335 men, aged 70–89 yr, formed the study group for the present analysis. Low SHBG and IGFBP-1 were both associated with an increased prevalence of abnormal glucose tolerance and the metabolic syndrome, but only SHBG was associated with diabetes mellitus. SHBG was less influenced by body mass index than IGFBP-1. Low SHBG indicated increased cardiovascular and coronary disease mortality; the association remained after adjustment for abnormal glucose tolerance, but not after adjustment for prevalent cardiovascular disease. IGFBP-1 had no association with mortality. It is concluded that low SHBG is a better indicator of increased cardiovascular mortality than low or high IGFBP-1.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE METABOLIC SYNDROME comprises disturbances in glucose metabolism and insulin secretion, overweight and abdominal fat distribution, dyslipidemia, and hypertension. It has a close association with subsequent development of type 2 diabetes mellitus and cardiovascular disease (CVD) (1, 2). Recently, new definitions of the syndrome have been introduced (3, 4). Diagnosis of the metabolic syndrome requires multiple laboratory tests. Because the metabolic syndrome is becoming increasingly common in the western world, practical tools for mass screening for it should be helpful.

SHBG and IGF-binding protein-1 (IGFBP-1) are both produced in the liver (5, 6) and are down-regulated by insulin (7, 8). Therefore, they could serve as potential indicators of the metabolic syndrome and hyperinsulinemia-related cardiovascular risk (9). Association between low SHBG and the development of type 2 diabetes has also been reported (10, 11, 12, 13, 14, 15). In insulin clamp studies, the relative insulin-induced decline in the IGFBP-1 concentration is 18 times greater than that in SHBG (15). Therefore, IGFBP-1 might correlate better than SHBG with hyperinsulinemia and its related cardiovascular risk factors. Moreover, IGFBP-1 might be devoid of the effects of confounding factors, such as estrogens and testosterone, that affect SHBG only (16). Testosterone has been found to decrease both the SHBG level and insulin sensitivity (17).

Thyroid hormones also have an influence on cardiovascular risk factors. Serum cholesterol is increased in hypothyroid patients, and there is a relationship between TSH and low density lipoprotein cholesterol that is modified by insulin sensitivity in euthyroid subjects (18, 19). Thyroid hormones have been shown to affect both SHBG and IGFBP-1 in vivo and in vitro (20, 21, 22).

We compared serum SHBG with IGFBP-1 as potential indicators of abnormal glucose tolerance, the metabolic syndrome, diabetes mellitus, cardiovascular risk factors, and total, cardiovascular (CVD), and coronary heart disease (CHD) mortality in elderly men. Because the prevalent disease is probably the strongest factor predicting cardiovascular death, mortality analysis was also performed after adjustment for prevalent cardiovascular disease as well as for abnormal glucose tolerance and the metabolic syndrome. Testosterone and TSH were also analyzed from the same material.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study subjects

The study subjects came from the Seven Countries Study, initiated as a cardiovascular risk survey among 16 cohorts of men in seven countries in 1959 (23). The original cohorts of the Finnish part of the study consisted of men born between 1900 and 1919 in two geographically defined rural areas in eastern (n = 823) and southwestern (n = 888) Finland (24). Of the original cohort of 1711 men, 524 were alive on January 1, 1989, and 413 participated in the 30-yr examination, of whom 335 men, aged 70–89 yr, formed the study group for the present analysis. The reasons for nonparticipation of the 70- to 89-yr-old men included long distance travel, poor health, inadequate fasting, and refusal to participate. Prevalent diseases in the study population are given in Table 1Go. All subjects had given their informed consent, and the ethics committee of the National Public Health Institute approved the study design.


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  		TABLE 1. Prevalent diseases in the study population

 
Study protocol and laboratory analyses

In 1989, the examinations included questionnaires, clinical investigations, physical performance measurements, and laboratory investigations (24). Briefly, body weight was measured in light clothing to the nearest 100 g. Two measurements of blood pressure were performed by a trained nurse on the right arm of men who were in sitting position after 5 min of rest. The mean of two measurements was used.

Glucose tolerance was tested using a 75-g oral glucose load (25). The participants were asked to fast over at least 12 h, and the tests were carried out between 0800 and 1200 h. Blood glucose was measured from venous plasma using the glucose dehydrogenase method (Glucose Analyzer II, Beckman Coulter, Fullerton, CA). Insulin analyses at fasting and 2 h after the glucose load were performed using Pharmacia Diagnostica Phadeseph Insulin RIA kit (Pharmacia Biotech, Uppsala, Sweden).

Total and high density lipoprotein (HDL) cholesterol concentrations were analyzed from fresh sera by an enzymatic method (Monotest, Roche, Mannheim, Germany) using Olli C 3000 photometer (Kone Ltd., Espoo, Finland). HDL cholesterol was measured after precipitation of very low density lipoprotein and low density lipoprotein cholesterol by the dextran-magnesium-chloride method (26), and serum triglycerides were determined after enzymatic hydroxylation and determination of the liberated glycerol by colorimetry with commercial agents (GPOPAP method, Roche) using the KONE C automatic discrete analyzer.

The serum samples were kept frozen at –20 C until tested. IGFBP-1 was measured in 1995, SHBG in 1997, and testosterone and TSH in 2001. An immunofluorometric assay (Delfia SHBG assay, Wallac Oy, Turku, Finland) was used, based on the direct sandwich technique with polyclonal rabbit anti-SHBG antibodies and monoclonal mouse anti-SHBG antibodies. The sensitivity of the assay was 0.01 µg/dl (0.5 nmol/liter), intra- and interassay coefficients were 7.8% and 9.1%, respectively, and the measurement range was 0.01–5 µg/dl (0.5–200 nmol/liter). The IGFBP-1 concentration was determined by immunofluorometric assay using two monoclonal antibodies, F34-15C9 and F36-9G3 as previously described (27). The sensitivity of the assay was 0.1 µg/liter, the intraassay variation was 3–11%, and the linear measurement range was 0.1–100 µg/liter. Serum testosterone concentrations were measured with an immunofluorometric assay (AutoDelfia testosterone assay, Wallac Oy) with sensitivity of 0.3 nmol/liter and intra- and interassay variations of 2.6–3.3% and 6.1–7.3%, respectively. TSH was measured with an immunofluorometric assay (AutoDelfia hTSH Ultra assay, Wallac Oy).

Definitions

Impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetes mellitus were all defined according to the 1999 WHO definition (3). The IFG and IGT groups were alone too small for reliable analysis. Therefore, they were combined as an IFG/IGT group. In this study IFG/IGT was defined as venous plasma fasting glucose between 110–125 mg/dl (6.1–6.9 mmol/liter) and/or two 2-h postload glucose measurements between 140–199 mg/dl (7.8–11.0 mmol/liter). In diabetes mellitus, venous plasma fasting glucose was greater than 126 mg/dl (7.0 mmol/liter) and/or greater than 200 mg/dl 2 h postglucose load (11.1 mmol/liter), or clinical diagnosis of diabetes was assessed with dietary, oral, or insulin treatment. Abnormal glucose tolerance comprised IFG, IGT, and diabetes.

The metabolic syndrome was defined according to the European Group for the Study of Insulin Resistance (28). Hypertension was defined according to the definition agreed upon by the International Society of Hypertension and Sixth Joint National Committee recommendations (29). Thus, the metabolic syndrome was defined as hyperinsulinemia, elevated fasting glycemia or diabetes (fasting serum glucose, >110 mg/dl or 6.1 mmol/liter) and at least two of the following: obesity [body mass index (BMI), ≥30], dyslipidemia [serum triglycerides, ≥150 mg/dl (1.7 mmol/liter)], serum HDL cholesterol less than 40 mg/dl (0.9 mmol/liter), or hypertension (blood pressure, 140/90 mm Hg or greater or blood pressure medication use). Hyperinsulinemia was estimated on the basis of fasting insulin levels in the upper fourth quartile of the nondiabetic population.

Mortality data

Mortality data were systemically collected from the Finnish Death Register. Death certificates and hospital records were collected for all men who died between 1989 and 1997. A single reviewer recorded the cause of death to minimize variability. In 1997, the vital status of all subjects was ascertained through the Finnish Population Registry. In addition, for the study population all hospital discharge diagnoses with the ninth revision of International Classification of Disease (IDC-9) (30) codes 410–414, 426–438, and 440–448 were identified from the National Hospital Discharge Register, and hospital records were collected and reviewed. The coder of the causes of death was blind to the risk factor status of the subject. Where multiple causes of death were recorded, priority was given to accidents, advance stage cancer, CHD, and stroke. Total, CVD, and CHD mortality were used as outcome parameters.

Study serial number only, without identification of the person’s name, was used to examine the results. The research staff performing IGFBP-1, SHBG, testosterone, and TSH measurements were blind to the other risk factors or outcome parameters.

Statistical analyses

Statistical analyses were performed using SPSS for Windows version 11.0. The Pearson correlation coefficients were calculated for IGFBP-l, SHBG, testosterone, TSH, and a number of cardiovascular risk factors and components of the metabolic syndrome (Table 2Go). Age- and BMI-adjusted mean values of IGFBP-1 and SHBG in the metabolic syndrome, abnormal glucose tolerance, and diabetes mellitus were estimated using general linear models. Relative risks (95% confidence intervals) of death from all causes, CVD causes, and CHD causes were estimated using Cox regression analyses. The {chi}2 test was used to test the difference for the categorical variables.


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  		TABLE 2. Mean SHBG and IGFBP-1 in the metabolic syndrome, different glucose tolerance categories, and subjects with or without prevalent CVD

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
In age-adjusted analysis, men with the metabolic syndrome, abnormal glucose tolerance or diabetes had significantly (9–27%) lower mean values of SHBG compared with the rest of the men (mean, 1.80–1.86 µg/dl or 72.1–74.5 nmol/liter; Table 2Go). The association between low SHBG and abnormal glucose tolerance or diabetes remained significant also after adjusting for BMI. The mean concentration of IGFBP-1 for men without the metabolic syndrome, abnormal glucose tolerance, or diabetes was 114.4–122.1 µg/liter (4.6–4.8 nmol/liter). IGFBP-1 had a significant inverse association with the metabolic syndrome, IGF/IGT, and abnormal glucose tolerance in the age-adjusted analysis, but none of the associations remained significant after adjusting for BMI (Table 2Go).

The results of the Pearson correlation analyses for fasting serum SHBG and IGFBP-1 concentrations against various cardiovascular risk factors are presented in Table 3Go. SHBG had more frequent and stronger inverse correlations than IGFBP-1. SHBG correlated with fasting and 2-h glucose in the oral glucose tolerance test (OGTT), whereas IGFBP-1 showed no correlation. Both SHBG and IGFBP-1 correlated with fasting and 2-h insulin in the OGTT (Table 3Go).


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  		TABLE 3. Pearson correlation coefficients for CVD risk factors and studied factors

 
In the Cox regression analysis, the lowest quartile of SHBG was related to an increased risk of CVD and CHD mortality, and the association remained significant after adjustment for abnormal glucose tolerance, and for CVD after adjustment for the metabolic syndrome. However, the association between SHBG and mortality did not remain significant after adjustment for prevalent cardiovascular disease (Table 4Go). In the ANOVA, baseline SHBG values were somewhat lower, but not significantly so, in the men with prevalent CVD (Table 2Go). The lowest quartile of IGFBP-1 showed no excess risk of either CVD or CHD mortality (Table 4Go). The highest quartile values of neither SHBG nor IGFBP-1 showed any correlation with increased mortality (data not shown).


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  		TABLE 4. Relative risks for 8-yr total all-cause, CVD, and CHD mortality

 
The number of CVD and CHD deaths in subjects with or without the metabolic syndrome and in the different glucose tolerance categories did not differ significantly among the various groups (Table 5Go).


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  		TABLE 5. The number of CVD and CHD deaths in metabolic syndrome and glucose tolerance categories

 
Testosterone had correlations with cardiovascular risk factors similar to those of SHBG, but it did not correlate with systolic blood pressure (Table 2Go). Serum testosterone had a strong inverse association with abnormal glucose tolerance, the metabolic syndrome, and diabetes (Table 6Go). The mean values of testosterone for men without the metabolic syndrome or abnormal glucose tolerance were 634.0–668.6 ng/dl (22.0–23.2 nmol/liter).


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  		TABLE 6. Mean testosterone and TSH values in metabolic syndrome, IFG/IGT, abnormal glucose tolerance, and diabetes

 
Thyroid hormones had few correlations with cardiovascular risk factors (Table 2Go). TSH had no association with abnormal glucose tolerance or diabetes, but was associated with the metabolic syndrome (Table 6Go). The mean TSH values for men without the metabolic syndrome or abnormal glucose tolerance were 1.7–1.8 µU/ml.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This is the first study comparing in the same cohort SHBG with IGFBP-1 as surrogate markers of IFG/IGT, the metabolic syndrome, diabetes mellitus, cardiovascular risk, and cardiovascular mortality.

Both SHBG and IGFBP-1 were found to correlate inversely with the metabolic syndrome in the same fashion, but the main difference was that low SHBG was also associated with diabetes, whereas IGFBP-1 was not. Moreover, this association with SHBG was less influenced by the adjustment for BMI, suggesting that the effect of SHBG on glycemia was less dependent on obesity. Because this study addressed elderly men, our results point to a need for additional studies including both genders and with a broader age scale to assess whether serum SHBG and IGFBP-1 measurements are valuable in the characterization and management of abnormal glucose tolerance, the metabolic syndrome, and diabetes. Hyperinsulinemia alone does not appear to increase the risk of fatal cardiovascular disease in elderly men without diabetes (31), whereas older men with isolated postchallenge hyperglycemia have been reported to have an increased risk of mortality similar to that in other diabetic patients (32). These patients cannot be identified without an OGTT, which is time-consuming and therefore not suitable for mass screening. Because SHBG correlates with 2-h glucose and insulin in OGTT, it might provide useful information when postchallenge hyperglycemia cannot be determined.

There was a strong association between SHBG and lipids, making SHBG likely to be useful in predicting the metabolic syndrome defined by the National Cholesterol Education Program Adult Treatment Panel (4). This definition does not include insulin resistance as a component of the syndrome, and therefore, it tends to be more weighted toward abdominal obesity and lipid components compared with the WHO definition of the metabolic syndrome. Because IGFBP-1 lacks an association with either fasting or post-OGTT glucose, and its association with lipids is weaker than for SHBG, IGFBP-1 is probably less valuable in predicting the metabolic syndrome defined by the National Cholesterol Education Program.

This is the first study to show an association between CHD mortality and low SHBG levels in men, even if the association between low SHBG and abnormal glucose tolerance, the metabolic syndrome, or diabetes, conditions known to increase the risk of CVD (33), has been observed in previous prospective studies (34, 35). The main difference between our study and a previous study showing no association between SHBG and CVD deaths (35) is that our study group is older and has more prevalent diseases at the baseline. After adjustment for abnormal glucose tolerance, the association between low SHBG and CVD or CHD mortality remained significant, indicating that glucose tolerance does not explain this association. Prevalent CVD is the strongest predictor of CVD mortality. In the present study the association between low SHBG and CHD or CHD mortality was no longer significant after adjustment for prevalent CVD. This is logical, because our study population consists of elderly men, and the prevalence of CVD at baseline was high at the outset. Nevertheless, SHBG levels did not differ between men with or without prevalent CVD at baseline.

Low IGFBP-1 did not have the same association with CHD as did low SHBG, so we were not able to confirm the findings of a recent investigation that concluded that low baseline IGFBP-1 increases the risk of fatal ischemic heart disease among elderly, predominantly nondiabetic, men and women (36). Interestingly, in that study the association between low IGFBP-1 and CHD mortality was found only in subjects without prevalent disease. In our study group there were more diabetics (32% vs. 14%), the number of subjects with existing CHD was larger (50% vs. 32%), and more CVD deaths were due to CHD (72% vs. 51%), which could explain the difference. Our follow-up time was also longer (8 vs. 5 yr). The association between low IGFBP-1 and unfavorable cardiovascular risk profile (37) is concordant with the results of this study, whereas the unexplained association between high IGFBP-1 and mortality observed in the same population as ours at a younger age or with a shorter follow-up period (38) was no longer evident. This might reflect changes in the aging population, because the sensitivity of the population to risk factors is likely to change.

The survivor bias may influence the findings of this study, because the subjects most sensitive to cardiovascular risk factors may already be ill or dead. This is obviously the case in all studies of elderly people. The absence of any significant difference in the number of deaths between different glucose tolerance categories may reflect this, because diabetes, abnormal glucose tolerance, and the metabolic syndrome should be important risk factors for death. The reason for our observation may be that, unlike in the proportional hazard analysis, time is not accounted for. The high prevalence of CVD in the study group indicates that there are still enough risk-sensitive subjects alive. At the baseline, the SHBG values in subjects with or without prevalent CVD were not statistically different from each other, so SHBG seems to be associated more with future risk than existing disease.

The reasons for discordance between low SHBG and low IGFBP-1 with respect to CVD and CHD death, despite their similar associations with cardiovascular risk factors, are unclear. Because insulin is the major regulator of both of these binding proteins, it is possible that glucose metabolism does not explain the observed discordance. Because sex hormones are also important regulators of SHBG, they may play a role here.

Insulin has been shown to increase ovarian androgen secretion in women (39), whereas in men the association between testosterone and insulin is inverse, independent of age (40). In keeping with this, the observed strong associations of low SHBG and low testosterone with abnormal glucose tolerance, the metabolic syndrome, and diabetes are concordant with somewhat higher insulin levels, also observed by other investigators (17, 40). Prospective studies have shown that low levels of SHBG and testosterone may predict the development of type 2 diabetes (34). Whether the relationship between low testosterone and abnormal glucose metabolism is direct or indirect is not known, because the relationship between testosterone and insulin is complex (41). However, previous studies show no consistent association between testosterone values and CHD or mortality (41, 42).

It is somewhat surprising that in this study, both low SHBG and low testosterone levels were correlated to abnormal glucose tolerance and cardiovascular risk factors, because SHBG usually rises with age, whereas testosterone tends to fall. However, similar findings have been reported by other investigators (35, 36). In elderly men, total testosterone, but not free bioavailable testosterone, has been associated with the development of type 2 diabetes (43). The effect of androgen therapy could be either beneficial or harmful, because both high and low testosterone levels have been associated with a higher risk (14), and in animal studies, high dose testosterone worsened insulin resistance (44). Studies of elderly men with androgen therapy would be needed to clarify this issue.

Thyroid hormones regulate both SHBG and IGFBP-1 (20, 21, 22). Manifest or subclinical hypothyroidism, with normal T4 and slightly elevated TSH levels are associated with an increased risk of CVD and an adverse blood lipid profile (45). In old men, as in this study, no connection was found between thyroid hormones and abnormal glucose tolerance or diabetes. The correlations with other cardiovascular risk factors were few. However, men with the metabolic syndrome had higher TSH values than those without it.

The time between venipuncture and the measurement of hormones ranged between 6–12 yr. This raises legitimate concern over the reliability of the results. Importantly, SHBG measurements from old samples have been shown to be reliable (46), and serum IGFBP-1 values have not been found to change after freezing and thawing or because of the duration of storage of the samples (47). Previous studies have also demonstrated no deterioration of total testosterone when samples were frozen for more than 10 yr (48). Studies of the effects of long-term storage on TSH were not found, but one study concerning freezing and thawing reported no change in the results (49). The values in the present study were also within the normal range for adult men.

We conclude that low serum SHBG and IGFBP-1 levels may indicate abnormal glucose tolerance and the metabolic syndrome, and they may also correlate with other known risk factors or surrogate markers of cardiovascular risk. In fact, they may serve as surrogate markers themselves. Whereas IGFBP-1 shows no association with cardiovascular morbidity or mortality, low SHBG levels are associated with increased cardiovascular mortality.


   Acknowledgments
 
We thank Ms. Anu Harju and Ms. Annikki Löfhjelm for technical assistance.


   Footnotes
 
This work was supported by the Academy of Finland [Grants 38387 and 46558 (to J.T.) and 52342 (to Q.Q.)], Research Foundation of Orion Corp., the Helsinki University Central Hospital Research Fund, NIH (Bethesda, MD) Grant AG-O8762, the Finnish Cancer Foundation, the Sandoz Gerontological Foundation, and the University of Helsinki.

First Published Online December 21, 2004

Abbreviations: BMI, Body mass index; CHD, coronary heart disease; CVD, cardiovascular disease; HDL, high-density lipoprotein; IFG, impaired fasting glucose; IGFBP-1, IGF-binding protein-1; IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test.

Received April 26, 2004.

Accepted December 6, 2004.


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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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