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Original Article |
Center for Human Nutrition (N.A., A.G., S.M.G.), Department of Internal Medicine (N.A., A.G., S.M.G.), Division of Endocrinology and Metabolism (N.A., A.G., S.M.G.), and Division of Radiology (R.M.P.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Internal Medicine, University of Texas Health Science Center (S.M.H.), San Antonio, Texas 78229
Address all correspondence and requests for reprints to: Nicola Abate, M.D., Center for Human Nutrition, University of Texas Southwestern Medical Center, 6011 Harry Hines Boulevard, Dallas, Texas 75390-9169. E-mail: nicola.abate{at}utsouthwestern.edu.
Abstract
Low plasma levels of SHBG and free testosterone have been associated with increased insulin resistance and risk for type 2 diabetes in males. As truncal obesity, a condition accompanied by increased insulin resistance, is also associated with low SHBG and testosterone levels, the independent association of low free testosterone and SHBG with excessive insulin resistance remains to be determined. In this study we evaluated whether in normogonadic men, plasma levels of SHBG and free testosterone are primarily related to insulin resistance or to generalized and regional adiposity. Hyperinsulinemic-euglycemic clamps and iv glucose tolerance tests were performed in 24 healthy volunteer and 33 patients with mild type 2 diabetes. The 2 groups were chosen to have similar body mass index and were found to have similar body composition and fat distribution, assessed by underwater weighing, skinfold thickness, and magnetic resonance imaging of the abdomen. In the 2 groups combined, plasma levels of SHBG correlated inversely with fat accumulation in both sc and intraabdominal areas. Plasma levels of free testosterone correlated inversely with both truncal and peripheral skinfold thickness only in the nondiabetic men. No associations between plasma levels of sex steroid hormones and insulin resistance, hepatic glucose output, or insulin secretion were found to be independent of adiposity. Furthermore, although patients with diabetes were more insulin resistant than those without diabetes, the 2 groups had similar plasma concentrations of free testosterone (55 ± 14 and 67 ± 27 pmol/liter, respectively), SHBG (19 ± 13 and 19 ± 13 nmol/liter), estradiol (83 ± 5 and 81 ± 21 pmol/liter), and dehydroepiandrosterone sulfate (3.6 ± 2.2 and 2.8 ± 1.7 nmol/liter). We conclude that in normogonadal nondiabetic males, the variability in plasma bioavailable testosterone concentrations is predictive of the variability in fat deposition in the sc adipose tissue compartments of both truncal and peripheral areas. Low plasma levels of bioavailable testosterone do not independently predict excessive insulin resistance, ß-cell dysfunction, or hepatic glucose output in normogonadal men.
EPIDEMIOLOGICAL OBSERVATIONS suggest that low plasma levels of SHBG and free testosterone are associated with increased risk for type 2 diabetes in men (1). Furthermore, the plasma concentrations of these hormones have been reported to be lower in men with type 2 diabetes than in nondiabetic subjects (2, 3). Although the mechanisms underlying the association between plasma levels of sex steroid hormones and type 2 diabetes are not entirely understood, it has been postulated that low plasma levels of both SHBG and bioavailable testosterone contribute to the development of insulin resistance (4, 5, 6, 7, 8, 9, 10) and, through this effect, to the complex metabolic abnormalities that lead to type 2 diabetes in men. However, low plasma levels of free testosterone are also observed in obesity, particularly in abdominal/truncal obesity, a condition that is itself independently accompanied by insulin resistance and heightened risk for type 2 diabetes (11, 12). Furthermore, administration of testosterone to hypogonadal rats (13) or humans (14) has resulted in reductions of both abdominal obesity and insulin resistance. Therefore, the reported relationship between low plasma levels of free testosterone and insulin resistance and/or type 2 diabetes may be the result of two different mechanistic scenarios: 1) plasma testosterone levels may directly promote insulin resistance, in parallel to other established factors, such as abdominal obesity, lack of exercise, and genetic predisposition; and 2) low plasma levels of free testosterone and SHBG may be primarily associated with obesity, which, in turn, predisposes to insulin resistance and type 2 diabetes.
We have previously reported that for any given level of generalized or regional adiposity, men with type 2 diabetes have a significantly higher degree of insulin resistance than nondiabetics (15). Therefore, if low plasma concentrations of testosterone and SHBG have an independent role in the pathogenesis of insulin resistance and predisposition to type 2 diabetes, the reported excessive insulin resistance of diabetic males could be related at least in part to decreased plasma levels of testosterone and SHBG.
This study was designed to evaluate whether plasma levels of free testosterone and SHBG are primarily related to obesity or whether low plasma levels of free testosterone and SHBG may predict excessive insulin resistance in men with and without diabetes, independently of body fat content and body fat distribution. As ß-cell dysfunction and excessive hepatic glucose output are two other major abnormalities involved in the pathophysiology of type 2 diabetes besides insulin resistance, this study also examined the relationships that free testosterone and SHBG might have with ß-cell function and hepatic glucose output.
Experimental Subjects
Two groups of men participated in this study: 33 patients with type 2 diabetes and 24 healthy control subjects. The study was approved by the institutional review board of University of Texas Southwestern Medical Center (Dallas, TX), and all subjects gave written informed consent. All patients met the criteria for type 2 diabetes as defined by the National Diabetes Data Group (16). In all patients, diabetes mellitus was diagnosed after age 39 yr, and all had a positive family history of diabetes. The ethnic composition of the study subjects included 2 subjects of Hispanic ancestry and 22 of European ancestry for the control group, and 8 subjects of Hispanic ancestry and 25 of European ancestry for the diabetic group. None of the patients had a history of ketosis. No patient with type 2 diabetes was taking oral hypoglycemic agents or insulin therapy. They were instructed to follow the dietary recommendations of the American Diabetes Association (17) for glycemic control. On entry into the study, the fasting plasma glucose levels of diabetic patients ranged from 4.4–17.3 mmol/liter. Patients with abnormal hepatic or renal functions and proteinuria were excluded from the study.
None of the healthy control subjects had elevations of fasting plasma glucose levels or a history of hyperglycemia. The healthy control subjects were selected to have the same range of body mass index (BMI) as did the patient group with type 2 diabetes. None of the control subjects had any metabolic or endocrine disorder. All participants were weight stable before entering the study.
After obtaining written informed consent, the study subjects were admitted for 3 d to the General Clinical Research Center at University of Texas Southwestern Medical Center for 3 d. All subjects were provided with an isocaloric diet (calculated from height, weight, and age) during the admission in General Clinical Research Center. Oral glucose tolerance tests (OGTT), iv glucose tolerance tests (IVGT), and hyperinsulinemic-euglycemic clamps were performed on d 1, 2, and 3 of admission, respectively. Anthropometric measurements were made on the second day. Magnetic resonance imaging (MRI) of the abdomen was performed on last day of admission, after completion of hyperinsulinemic-euglycemic clamp studies.
Materials and Methods
OGTT
A standard OGTT with 75 g glucose (Tru-Glu 100, Fisher Scientific, Pittsburgh, PA) was conducted after 12 h of overnight fasting on the first day of admission. An iv catheter was placed in a forearm vein, and blood was collected for determination of glucose and insulin concentrations at 30, 15, and 0 min before glucose administration and at 30-min intervals thereafter for 180 min.
IVGTT
A standard IVGTT was conducted after 12-h overnight fasting on the second day of admission to the General Clinical Research Center. The dose of glucose administered was 0.5 g/kg body weight. An iv catheter was placed in a forearm vein, and blood was collected for determination of glucose and insulin concentrations at 30, 15, and 0 min before glucose administration and every minute for the first 10 min of the test.
Anthropometric measurements
Height and weight were measured by standard procedures. Waist and hip circumferences were measured using a flexible measuring tape with a tension caliper at the extremity (Gulick-Creative Health Product, Inc., Plymouth, MI), midway between the xyphoid and the umbilicus during the midinspiratory phase and at the maximum circumference in the hip area, respectively. Skinfold thickness was measured at nine different anatomical sites [subscapular (diagonal and vertical), chest, midaxillary, abdominal (horizontal and vertical), suprailiac (diagonal and vertical), triceps, biceps, thigh, and calf] using a Lange skinfold caliper (Cambridge Scientific Industries, Inc., Cambridge, MD). The means of three repeat measurements at each site were used for calculations. The sum of truncal skinfold thickness was calculated by adding the skinfold thickness of subscapular, midaxillary, chest, abdomen, and suprailiac sites, and the sum of peripheral skinfold thickness was calculated by adding skinfold thickness of triceps, biceps, thigh, and calf regions.
Body composition was studied by determination of body density using a Volumeter (Whitmore Enterprises, San Antonio, TX), as previously described (11).
Abdominal MRI
The MRI studies were performed using a 0.35 T imaging device (Toshiba America MRI, Inc., South San Francisco, CA) with a quadrature body coil, as previously described (18).
Euglycemic hyperinsulinemic glucose clamp study
Clamp studies were conducted on the last day of admission after an overnight fast. A primed continuous infusion of regular insulin (Humulin, Squibb-Novo, Princeton, NJ) was given iv at a rate of 20 mU/m2·min from 0–120 min (low dose insulin infusion). The insulin infusion rate was increased to 40 mU/m2·min from 120–210 min (high dose insulin infusion). The details of this method have been previously described (11). The data for hepatic glucose output and glucose disposal rate are presented as milligrams per minute per kilogram of lean body mass during the higher insulin infusion rate.
Biochemical analyses
Plasma glucose concentrations were assayed by a glucose oxidase method (glucose analyzer, Beckman, Fullerton, CA). The specific activity of glucose was determined from the plasma samples deproteinized by barium hydroxide and zinc sulfate precipitation according to the method of Meneilly et al. (19). Plasma insulin levels were determined by modification (20) of the RIA described by Yalow and Berson (21).
Aliquots of fasting serum specimens were frozen at -70 C. Analyses for sex hormones and SHBG levels were performed in Dr. Haffner’s laboratory. Estradiol, total testosterone, and dehydroepiandrosterone sulfate (DHEA-SO4) levels were measured with solid phase commercial RIAs (Diagnostic Products, Los Angeles, CA). Free testosterone was measured with a commercial double antibody system (Diagnostic Products). SHBG was measured with a commercial double antibody system (Diagnostic Systems Laboratory, Inc., Webster, TX). The intra- and interassay coefficients of variation for SHBG were 6.0% and 9.0%, respectively.
Calculations and statistical analyses
Comparisons of baseline characteristics, body composition, fat distribution, and euglycemic hyperinsulinemic glucose clamp study data between diabetic patients and control subjects were made using the two-sample t test. Because of skewed distribution of skinfold thickness in both groups, loge-transformed values were compared with the two-sample t test. For each group, Spearman correlation coefficients (r) and partial correlations adjusting for age were computed to assess associations between plasma concentrations of steroid hormones and either measures of generalized and regional adiposity or measures of peripheral glucose disposal, insulin secretion, and hepatic glucose output. Results were presented as the mean ± SD unless otherwise stated. The level of significance was P = 0.05. Statistical analyses were performed with BMDP (BMDP Statistical Software, Los Angeles, CA).
Results
In Table 1
, the general characteristics of the nondiabetic volunteers are compared with those of the patients with type 2 diabetes. Because of the selection criteria, BMIs were comparable in the two study groups. Fasting plasma glucose concentrations, age, and systolic blood pressure were significantly higher in the diabetics. The results of the hyperinsulinemic-euglycemic clamp studies are reported as peripheral glucose disposal and hepatic glucose output during the higher insulin infusion rate (40 mU/m2·min). The peripheral glucose disposal rate and the insulin area under the curve during the first 10 min of IVGTT were significantly lower in the diabetics than in the nondiabetics.
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, the results for body composition and fat distribution in the diabetic and nondiabetic groups are compared. No differences in generalized adiposity, measured by underwater weighing, were detected. Neither anthropometric measurements (waist and hip circumference or skinfold thickness) nor MRI measurements of abdominal adiposity revealed differences in fat distribution between the patients with and without diabetes.
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compares plasma levels of steroid hormones in the two groups of patients. Plasma levels of free testosterone and DHEA-SO4 tended to be lower in the group with diabetes, but no significant differences were found for any of the plasma sex steroid hormone concentrations between the two study groups. The range for free testosterone levels was 31–90 pmol/liter for the nondiabetics and 35–94 pmol/liter for patients with diabetes.
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summarizes the age-adjusted Pearson correlation coefficients between each plasma hormone level measured and various parameters of body composition and fat distribution. The analysis is reported both with the inclusion of all study subjects and with diabetic group and nondiabetic group separately. Total body fat, truncal skinfold thickness, peripheral skinfold thickness, and intraabdominal fat variables were all inversely correlated with plasma concentrations of SHBG. In the nondiabetic group, plasma free testosterone concentrations were inversely correlated with total body fat and truncal and peripheral fat. However, none of the abdominal fat compartments was associated with the plasma free testosterone level. Furthermore, the correlation analysis for the two separate groups revealed no correlation between free testosterone and any of the studied body fat compartments for the group with diabetes.
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is the summary of the correlation analysis between plasma levels of sex steroid hormones and metabolic parameters. SHBG was the only variable significantly correlated with peripheral glucose disposal rate (r = 0.36; P < 0.05). Age-adjusted Spearman correlation coefficients between the plasma levels of the other studied sex hormones and insulin resistance were not significant. None of the measured plasma hormone concentrations was correlated with baseline hepatic glucose output or plasma insulin levels during the initial 10 min of the IVGT.
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show that the relationship between SHBG and peripheral glucose disposal rate became nonsignificant after adjustment for both age and variables representing regional adiposity in the ip and sc truncal areas.
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The primary finding of this study was that plasma levels of free testosterone are inversely related to generalized and truncal sc adiposity in men without diabetes, but have no direct role in predicting excessive insulin resistance in men with or without diabetes. This conclusion is supported by two main observations: first, free testosterone and insulin resistance were found not to be correlated in either the group with diabetes or the group without diabetes, and second, despite the excessive insulin resistance in the patients with diabetes in this study, there was no difference in plasma concentrations of free testosterone between the two study groups. The patients of this study were selected to have similar BMIs and also had similar total body fat contents and body fat distributions. Therefore, although it is possible that the average male patient with diabetes in the general population has a tendency to have lower plasma levels of free testosterone in association with a higher degree of generalized and truncal obesity (22, 23, 24, 25), our study shows that lower plasma free testosterone levels probably do not account for the excessive insulin resistance of these patients independently of obesity. The methods and the selection criteria used in this study may explain the apparent discrepancy between our results and previous observations. The double antibody system used in our study and many others to measure free testosterone was recently shown to measure 20–60% of the free testosterone measured with the more complex equilibrium dialysis technique (26). This methodological limitation may account for discrepancies in correlation analysis among different studies and may also have weakened the relationships between free cholesterol and adiposity or insulin sensitivity. In the Telecom study (9), 1292 Caucasian men, aged 20–60 yr, were found to have decreased plasma levels of testosterone associated with increased insulin levels, age, and BMI. Although insulin levels are related to insulin resistance, they are not a precise method to measure insulin resistance. Of interest is that the same study revealed that statistical adjustments for BMI and subscapular skinfold thickness reduced the significance of the association between plasma testosterone levels and insulin resistance. That study did not include more detailed evaluation of body composition and fat distribution. Furthermore, free testosterone was not measured. In another study by Haffner et al. (4), variability in plasma levels of free testosterone did not explain the variability in whole body glucose disposal rate in a group of nondiabetic males. Bierkland et al. (6) also failed to find a relationship between free testosterone and insulin resistance in nondiabetic men. Tchernof et al. (27) found that the relationship between total testosterone and insulin resistance is mediated by obesity and visceral adiposity in nondiabetic men. More recently, Oh et al. (28) failed to find that bioavailable testosterone predicted the development of diabetes in males participating in the Rancho-Bernardo study.
Of interest is the additional finding that neither ß-cell function nor hepatic glucose output, the two other metabolic determinants of type 2 diabetes, correlated with plasma levels of free testosterone. It is therefore possible that previous findings, showing that low plasma testosterone concentrations are associated with increased risk for type 2 diabetes, are the result of an association between low plasma testosterone levels and obesity, an established risk factor for type 2 diabetes. Our study confirmed that nondiabetics tend to have lower plasma levels of free testosterone when their body fat content increases. Interestingly, the fat distribution data showed that sc fat accumulation in the truncal area is highly predictive of low plasma concentrations of free testosterone, whereas relative excess of fat in the ip region did not predict low testosterone concentrations. Haffner et al. (4) had previously reported an association between increasing body mass index and waist to hip ratio with lower plasma levels of testosterone in nondiabetic men, randomly selected from a population-based study in Finland. In another study conducted in 25 nondiabetic males (25), increasing BMI, visceral adiposity, and sc abdominal adiposity (both measured by single slice computed tomography scan) was reported to be inversely related to plasma free testosterone. On the other hand, Couillard et al. (29) reported lack of correlation between visceral adiposity and plasma testosterone levels. Of note is their finding that sc adipose tissue and both waist and hip circumferences were strongly and inversely related to testosterone levels. Our study used a precise method to assess body fat distribution in the abdominal areas of the intraperitoneum, retroperitoneum and sc abdominal regions (18). Our findings reveal a strong and inverse relationship between skinfold thickness and plasma free testosterone levels in nondiabetics, while excluding a direct relationship between plasma testosterone levels and abdominal adiposity in both diabetic and nondiabetic men. We need to underscore the fact that the subjects selected for this study were not hypogonadal. Therefore, previous reports that administration of testosterone results in loss of visceral fat, suggesting a causative role of low plasma testosterone levels in accumulation of visceral adiposity, may exclusively apply to hypogonadal men. The data of our study do not support a role of bioavailable testosterone in the regulation of visceral adiposity when plasma levels of free testosterone are in the normal range.
Another major finding of this study is the strong association between plasma levels of SHBG with obesity. In a previous large epidemiological study (29) that included evaluation of sc and visceral adipose tissue by computed tomograhy scan, increasing total body fat content and both sc and visceral adiposity were associated with decreased plasma levels of SHBG. Our study demonstrates a correlation between SHBG and all abdominal adipose tissue compartments, including sc, ip, and retroperitoneal. Although plasma concentrations of SHBG were found to be correlated with insulin resistance (Table 4
), there was no association between SHBG and ß-cell function or hepatic glucose output. Furthermore, after adjustment for regional adiposity even plasma levels of SHBG were no longer correlated with insulin resistance, suggesting that adiposity is the real determinant of the reported relationships between SHBG and insulin resistance. Lower levels of SHBG in obesity have been proposed to be the consequence of reduced production of SHBG, secondary to hyperinsulinemia (30). This effect may improve the availability of free testosterone in the early stage of obesity development when hyperinsulinemia/insulin resistance develops. However, once obesity develops, besides insulin resistance, adiposity has been reported to have an impact on the hypothalamus-pituitary-gonadal axis, which may directly influence testosterone and SHBG production. In fact, low GH levels have been associated with reduced SHBG (31), and changes in LH pulse amplitude and reduced plasma LH levels may induce a reduction of plasma testosterone concentrations (32). Reduced plasma concentrations of testosterone may also directly follow increased conversion of testosterone to estradiol occurring in the adipose tissue (33, 34). Lower bioavailable testosterone may, in turn, affect body composition and fat distribution by reducing adipose tissue lipolysis (35) and promoting storage of fat. It is of interest that administration of testosterone, but not of its aromatized metabolite, dihydrotestosterone, induces a reduction in truncal adiposity (36), It is therefore possible that aromatization of testosterone or the formation of other testosterone metabolites is required for its lipolytic effect on adipose tissue. As sc truncal adipose tissues have been found to be more responsive to the effects of testosterone, the net result of reduced plasma testosterone concentrations initiated by obesity will be preferential accumulation of fat in the sc truncal adipose tissue areas. According to this view, the relationship between obesity and testosterone are of reciprocal cause and effect, causing a chain of events ultimately favoring preferential accumulation of fat in the truncal area of increasingly obese males. Regardless of the initial mechanism leading to reduced plasma concentrations of testosterone and SHBG, the reciprocal cause of effect relationship between testosterone and obesity will favor truncal obesity and constitute a metabolic risk for the development of type 2 diabetes.
We conclude that in normogonadal nondiabetic males, variability of plasma bio-available testosterone concentrations is predictive of the variability of fat deposition in the sc adipose tissue compartments of both the truncal and peripheral areas. In these circumstances, low plasma levels of bioavailable testosterone do not independently predict insulin resistance, ß-cell dysfunction, or excessive hepatic glucose output. However, through its effect on body composition and fat distribution, it is conceivable that testosterone may play a role in the pathogenesis of insulin resistance and development of the metabolic syndrome and type 2 diabetes. Although plasma levels of bioavailable testosterone do not appear to contribute to the excessive insulin resistance of patients with mild diabetes, it would be of interest to further evaluate the mechanistic bases of the reported associations in nondiabetics and the possible role of testosterone replacement therapy in the amelioration of body composition and fat distribution of patients at risk to become diabetic.
Acknowledgments
We express appreciation for the assistance of Beverley Huet-Adams with statistical analysis of the data. The assistance of Mary Tenyson, Marjorie Whelan, and the nursing and dietetic services of the General Clinical Research Center are greatly appreciated. Kay McKorkle, Lovie Peace, and Margaret Haney in the laboratory of Dr. Unger assisted with the insulin assays.
Footnotes
This work was supported by Grant MOl-RR-00633.
Abbreviations: BMI, Body mass index; DHEA-SO4, dehydroepiandrosterone sulfate; IVGTT, iv glucose tolerance test; MRI, magnetic resonance imaging; OGTT, oral glucose tolerance test.
Received April 9, 2002.
Accepted July 19, 2002.
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) and diabetic males (
).