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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 5 1540-1543
Copyright © 1999 by The Endocrine Society

Original Studies

Serum Dioxin, Insulin, Fasting Glucose, and Sex Hormone-Binding Globulin in Veterans of Operation Ranch Hand

Joel E. Michalek, Fatema Z. Akhtar and Johnathan L. Kiel

Air Force Research Laboratory, Brooks Air Force Base (J.E.M., J.L.K.), Texas 78235; and Vista Technologies, Inc. (F.Z.A.), San Antonio, Texas 78218

Address all correspondence and requests for reprints to: Joel E. Michalek, Ph.D., AFRL/HEDB, 2606 Doolittle Road, Building 807, Brooks Air Force Base, Texas 78235-5250.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We studied insulin, fasting glucose, and sex hormone-binding globulin (SHBG) in Air Force veterans exposed to Agent Orange and its contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), during the Vietnam War. The index subjects were veterans of Operation Ranch Hand, the unit responsible for aerial herbicide spraying in Vietnam from 1962–1971. Other Air Force veterans who served in Southeast Asia during the same period but were not involved with spraying herbicides served as comparisons. We assigned each Ranch Hand veteran based on his dioxin level to one of three exposure categories, named background, low, and high. Among nondiabetic veterans, we found the mean of the logarithm of insulin significantly increased in the high dioxin category. Additionally, in nondiabetic veterans the relation between SHBG and insulin interacted significantly with dioxin category on the log scale within strata defined by age and percent body fat. Among young (age, <=53 yr), lean (percent body fat, <=25%) nondiabetic veterans in the high category, the slope relating the logarithm of SHBG and the logarithm of insulin was significantly decreased. These findings suggest a compensatory metabolic relationship between dioxin and insulin regulation.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SERUM concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) in veterans of Operation Ranch Hand, the unit responsible for the aerial spraying of Agent Orange and other herbicides during the Vietnam War, have been found to be associated with the occurrence and severity of diabetes mellitus (1). Other studies of the same veterans found no relation between dioxin and abnormal values of total testosterone, LH, or FSH (2). Risk factors for the development of noninsulin-dependent diabetes mellitus include obesity, an unfavorable body fat distribution, glucose and insulin concentrations, and insulin resistance (3). Sex hormone-binding globulin (SHBG) is a circulating steroid-binding protein produced by the liver that binds testosterone with high affinity and estrogens with lower affinity and functions as a modulator of androgen delivery to tissues (4). Low levels of SHBG and testosterone may be related to hyperinsulinemia and the development of type 2 (insulin-resistant) diabetes (4). These previous data suggest a possible mechanistic relationship among sex hormones, dioxin, and insulin-related metabolism.

To further elucidate the relation between dioxin and diabetes mellitus we studied the effect of dioxin body burden on the relation between SHBG and insulin and fasting glucose in Ranch Hand veterans. These data were gathered during 10 yr of follow-up in the ongoing Air Force Health Study from veterans whose exposure to dioxin and herbicides in Vietnam occurred from 24–35 yr ago.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subject selection and definition of study groups

The details of study design and subject selection were published previously (5). The study seeks to determine whether veterans of Operation Ranch Hand (the personnel tasked with spraying operations during the Vietnam conflict) have experienced adverse health that can be attributed to exposure to herbicides or their dioxin contaminant. Ranch Hand veterans were exposed to herbicides during flight operations and maintenance of the aircraft and herbicide spray equipment. The study compares the current health and cumulative mortality experience of Ranch Hand veterans with those of a comparison group of other Air Force veterans who served in Southeast Asia during the same period (1962–1971) that the Ranch Hand unit was active and who were not involved with spraying herbicides. Comparison veterans were matched to Ranch Hands for age, race, and military occupation. The study includes periodic analyses of noncombat mortality, in-person interviews, and physical examinations. Physical examinations were conducted in 1982, 1985, 1987, 1992, and 1997. An additional examination is planned for 2002. All Ranch Hand and comparison veterans are male.

In 1987, blood from willing participants was collected and assayed for dioxin (5). Participation was voluntary and consent forms were signed at the examination site. Veterans with no quantifiable dioxin result in 1987, those who refused in 1987, and subjects new to the study were also asked to give blood for the assay at the 1992 examination.

We reviewed medical records and laboratory results to determine diabetic status. Veterans who had a verified history of diabetes by medical diagnosis or exhibited a 2-h postprandial glucose laboratory value of 200 mg/dL or greater before July 1995 were classified as diabetic. Veterans not meeting these criteria were defined as nondiabetic.

Every veteran who attended the 1992 physical examination regardless of his current vital status was considered for inclusion in the analysis. We excluded from all statistical analyses veterans taking hormone medications; those who had prostatic cancer, cancer of the testes or other genital organ, or surgery of the testes; and those with a history of diabetes before their service in Southeast Asia. Additionally, we excluded those with no dioxin measurement or with a nonquantifiable dioxin result and comparison veterans with a dioxin result greater than 10 parts/trillion (ppt), the value we regard as the threshold for background dioxin exposure. Table 1Go shows sample size reductions by group (Ranch Hand and comparison).


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  		Table 1. Sample size reduction by group

 
We estimated the initial dioxin dose at the end of the tour of duty in Vietnam in Ranch Hands having current dioxin levels above background using a constant half-life of 8.7 yr (6) and assigned each veteran to one of four exposure categories, named comparison, background, low, and high, according to his group, current dioxin level, and initial dioxin level. The comparison category was comprised of comparison veterans with current dioxin less than or equal to 10 ppt. The background category was comprised of Ranch Hand veterans with current dioxin level less than or equal to 10 ppt. The low and high categories were comprised of Ranch Hand veterans with current dioxin levels greater than 10 ppt. The cut point separating the low and high categories (95 ppt) was the median initial dioxin level among all Ranch Hands having current dioxin levels greater than 10 ppt. Table 2Go shows sample sizes by dioxin category and diabetic status.


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  		Table 2. Sample sizes by dioxin exposure category and diabetic status

 
Hormone tests

We report SHBG, insulin, and fasting glucose levels. SHBG (nanomoles per L) and serum insulin (microinternational units per mL) were measured by RIA. Fasting glucose (milligrams per dL) was determined with Paramax equipment. SHBG was measured after an overnight fast. Among veterans not known to have diabetes, insulin was measured 2 h after a 100-g glucose load standardized by the use of Glucola. Among known diabetics, insulin was measured after an overnight fast. All measurements were determined at the 1992 physical examination (7).

Statistical analysis

We defined percent body fat (PBF) (8) as PBF = 1.26 x BMI - 13.305, where BMI was the body mass index [weight (kilograms) divided by the square of height (meters)] measured at the time of blood drawing for dioxin measurement. We defined age as the age in years at the time of the 1992 physical examination. We dichotomized age at the median (53 yr) and PBF at 25% for the purpose of stratifying by age and PBF.

We applied a logarithmic transformation to insulin, fasting glucose, and SHBG. We analyzed data with analysis of covariance, partial correlations, linear models, and graphs and adjusted all analyses for age and PBF. We used analysis of covariance to contrast the high, low, and background dioxin exposure categories with the comparison category with regard to insulin, fasting glucose, and SHBG. We report the P value for each contrast and the geometric mean of the dependent variable within each exposure category. We assessed the significance of the interaction of SHBG, insulin, fasting glucose, and dioxin category using linear models with SHBG and dioxin category as independent variables and insulin and fasting glucose as dependent variables. Each analysis proceeded in two steps. In the first step, the model included SHBG, age, PBF, dioxin category, all second order interactions, all third order interactions, and a fourth order interaction involving age, PBF, SHBG, and dioxin. In the second step, we stratified by age and PBF and analyzed within each strata with a reduced model containing only SHBG, dioxin category, and the interaction of SHBG and dioxin category. We present the results of full and reduced models and describe interactions with scatter plots and least square lines. We adjusted all analyses for diabetic status by stratification.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Demographic characteristics of all veterans are presented in Table 3Go. Ranch Hand veterans in the high dioxin category were younger and heavier than those in the low and background categories. Most of the veterans in the high dioxin category were enlisted ground crew, and those in the background category were predominantly officers.


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  		Table 3. Distribution of dioxin and demographic characteristics by dioxin exposure category

 
Table 4Go summarizes the three biochemical measurements by dioxin category and diabetic status. Among nondiabetic veterans, the mean of the logarithm of insulin in the high category was significantly increased relative to the mean in the comparison category (P = 0.004). The geometric mean of insulin increased with dioxin exposure category among nondiabetic Ranch Hand veterans (background, 62.6 µIU/mL; low, 64.2 µIU/mL; high, 81.1 µIU/mL); the geometric mean in the comparison category was 67.7 µIU/mL. There were no significant differences from the comparison category with regard to the mean of the logarithm of fasting glucose or SHBG among nondiabetic veterans. Among diabetic veterans, the mean of the logarithm of fasting glucose was significantly increased in the high category relative to the mean in the comparison category (P = 0.03). There were no significant differences with the comparison category among diabetic veterans with regard to the mean of the logarithm of insulin or the logarithm of SHBG.


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  		Table 4. Geometric mean of insulin, fasting glucose, and SHBG by dioxin category and diabetic status

 
Partial correlations ({rho}) with the logarithm of SHBG adjusted for age and PBF by dioxin category and diabetic status are given in Table 5Go. Among nondiabetic veterans, the correlations between the logarithm of SHBG and the logarithm of insulin were significantly different from zero in every dioxin category (comparison: {rho} = -0.07, P = 0.03; background: {rho} = -0.14, P = 0.01; Low: {rho} = -0.15, P = 0.03; High: {rho} = -0.27, P < 0.001). The correlation between the logarithm of SHBG and the logarithm of fasting glucose was significantly different from zero in the high dioxin category ({rho} = -0.19, P = 0.007). There were no significant partial correlations with the logarithm of SHBG among diabetic veterans.


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  		Table 5. Partial correlations between log(insulin) and log(fasting glucose) with log(SHBG) adjusted for age and percent body fat

 
Among nondiabetic veterans, the fourth order interaction term (age by PBF by SHBG by dioxin) was significant at the 0.2 level of significance for both insulin (P = 0.23) and fasting glucose (P = 0.13). Among diabetic veterans, the fourth order interaction term was not significant at the 0.2 level for either variable (insulin, P = 0.59; fasting glucose, P = 0.29). These full model results motivated us to stratify by age and PBF category among nondiabetics and fit reduced models within each stratum.

Insulin interacted significantly (P = 0.01) with SHBG and dioxin category (Fig. 1Go) among young (age, <=53 yr), lean (PBF, <=25%), nondiabetic veterans (comparison: slope = -0.06; background: slope = -0.10; low: slope = -0.26; high: slope = -0.36), reflecting a decrease in the slope with dioxin category. The slope in the high category was significantly different from 0 (P < 0.001) and significantly different from the comparison slope (P = 0.003). The slope in the low category was significantly different from 0 (P = 0.02) and was borderline significantly different from the comparison slope (P = 0.07). The sample sizes in this stratum were: comparison, n = 450; background, n = 158; low, n = 80; and high, n = 105. The patterns in the other three nondiabetic strata were dissimilar and did not exhibit significant interactions with dioxin.



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  		Figure 1. Log(insulin) vs. log(SHBG) by dioxin category among nondiabetic veterans aged less than or equal to 53 yr and with PBF of 25% or less.

 
Fasting glucose interacted significantly with SHBG and dioxin category among old (age, >53 yr), lean (PBF, <=25%), nondiabetic veterans (comparison, slope = 0.00; background, slope = 0.00; low, slope = 0.01; high, slope, -0.03), reflecting a decreased slope in the high category. The slope in the high category was significantly different from 0 (P = 0.05) and borderline significantly different from the comparison slope (P = 0.09). The sample sizes in this stratum were: comparison, n = 364; background, n = 152; low, n = 90; and high, n = 45. The patterns in the other three nondiabetic strata were dissimilar and did not exhibit significant interactions with dioxin.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
A possible, but speculative, mechanism consistent with this study and previous studies on the mechanisms of type 2 diabetes is that dioxin affects the activity of pancreatic nitric oxide synthase (NOS). The release of insulin from the ß-cells of the pancreas is regulated by type I nitric oxide synthase (9). Estrogens and, to a lesser extent, testosterone inhibit the production of interleukin-1, which is a stimulator of NOS activity in pancreatic ß-cells (10, 11). Estrogens have also been shown to increase the production of nitric oxide by macrophages in male rats at physiological levels but inhibit production at pharmacological levels (12). The regulation of insulin release by arginine (mediated through NOS) is deficient in patients with noninsulin-dependent (type 2) diabetes mellitus (13). Dioxin could modify the induction of NOS or its activity directly, like many other polyaromatic compounds that react strongly with the type b cytochrome oxidases (such as NOS) (14, 15, 16, 17).

Dioxin’s estrogen-like activity has been implicated in a 15-yr study of primates that revealed an incidence of endometriosis that directly correlated with dioxin exposure and in which the severity of disease depended on the dose administered (18). The rate of conversion of testosterone to estradiol in males could be stimulated by dioxin, leading to an increased level of SHBG to compensate for the increased rate of conversion. In young lean nondiabetic veterans exposed to dioxin, the negative correlation of SHGB levels to insulin levels suggests that the transported sex hormones are down-regulating insulin release. In other words, the increase in testosterone metabolism could lead to a rise in SHBG to maintain the steady state levels of testosterone within normal limits, a compensatory effect. Dioxin, like estrogen, may have initially increased the induction of NOS activity, leading to a negative feedback, that is, decreased sensitivity to arginine, or decreased NOS activity and deregulation of insulin release. If correct, this speculative mechanism would lead to hyperinsulinemia and compensatory desensitization to insulin and eventually type 2 diabetes. This hypothesis is consistent with an association among dioxin body burden and type 2 diabetes mellitus in Ranch Hand veterans (1). It is unknown why this hypothetical mechanism should operate specifically in young lean nondiabetic veterans, although it seems plausible that other stronger factors, such as age, body fat, and diabetes, may overwhelm the effects in the other strata.

Our results were consistent with those of a recent study of men participating in the Multiple Risk Factor Intervention Trial (MRFIT) (3). Among comparison veterans, we found that SHBG was lower in nondiabetics than in diabetics, and among nondiabetic veterans, insulin and SHBG were negatively correlated. Our finding of increased insulin levels in the high dioxin exposure category, and the association between dioxin and diabetes (1) appeared consistent with the noted positive relation between hyperinsulinemia and diabetes in the MRFIT cohort. Our insulin results were higher than those in the MRFIT cohort, most likely because for veterans not known to be diabetic, our measurements were made after a glucose tolerance test, whereas the MRFIT subjects were measured after an overnight fast (Haffner, S. M., personal communication).

In conclusion, we found a significantly increased mean of the logarithm of insulin, among nondiabetic Ranch Hand veterans in the high dioxin category. We also found significant interactions among dioxin category, SHBG, and insulin and among dioxin category, SHBG, and fasting glucose among lean nondiabetic Ranch Hand veterans on the log scale. These findings suggest a compensatory metabolic relation between dioxin and insulin regulation.

Received August 12, 1998.

Revised January 4, 1999.

Revised February 3, 1999.

Accepted February 3, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Henriksen GL, Ketchum NS, Michalek JE, Swaby JA. 1997 Serum dioxin and diabetes in veterans of Operation Ranch Hand. Epidemiology. 8:252–258.[CrossRef][Medline]
  2. Henriksen GL, Michalek JE, Swaby JA, Rahe AJ. 1996 Serum dioxin, testosterone and gonadotropins in veterans of Operation Ranch Hand. Epidemiology. 7:352–357.[Medline]
  3. Haffner SM, Shaten J, Michael PS, Smith GD, Kuller L. 1996 Low levels of sex hormone-binding globulin and testosterone predict the development of non-insulin-dependent diabetes mellitus in men. Am J Epidemiol. 143:889–897.[Abstract/Free Full Text]
  4. Nestler JE. 1993 Sex hormone-binding globulin: a marker for hyperinsulinemia and/or insulin resistance? J Clin Endocrinol Metab. 76:273–274.[CrossRef][Medline]
  5. Wolfe WH, Michalek JE, Miner JC, et al. 1990 Health status of Air Force veterans occupationally exposed to herbicides in Vietnam. I. Physical health. JAMA. 264:1824–1831.[Abstract]
  6. Michalek JE, Pirkle JL, Caudill SP, Tripathi RC, Patterson Jr DG, Needham LL. 1996 Pharmacokinetics of TCDD in veterans of Operation Ranch Hand: 10 year follow-up. J Toxicol Environ Health. 47:209–220.[CrossRef][Medline]
  7. Grubbs WD, Lustik MB, Brockman AS, et al. 1995 The Air Force Health Study: n epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides: 1992 follow-up examination results. AD A 304 306 through AD A 304 316. Springfield: National Technical Information Service.
  8. Knapik JJ, Burse RL, Vogel JA. 1983 Height, weight, percent body fat, and indices of adiposity for young men and women entering the U.S. Army. Aviat Space Environ Med. 54:223–231.[Medline]
  9. Schmidt HHHW, Warner TD, Ishii K, Sheng H, Murad F. 1992 Insulin secretion from pancreatic B cells caused by L-arginine-derived nitrogen oxides. Science. 255:721–723.[Abstract/Free Full Text]
  10. Horowitz MC. 1993 Cytokines and estrogen in bone: anti-osteoporotic effects. Science. 260:626–627.[Free Full Text]
  11. Kaneto H, Fujii J, Seo HG, et al. 1995 Apoptotic cell death triggered by nitric oxide in pancreatic ß-cells. Diabetes. 44:733–738.[Abstract]
  12. Robert R, Spitzer JA. 1997 Effects of female hormones (17-ß-estradiol and progesterone) on nitric oxide production by alveolar macrophages in rats. Nitric Oxide Biol Chem. 1:453–462.[CrossRef][Medline]
  13. Ward WK, Bolgiano DC, McKnight B, et al. 1984 Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Invest. 74:1318–1328.
  14. Reed KC, Ohno S. 1976 Kinetic properties of human placental aromatase: application of an assay measuring 3H2O release from 1ß,2ß-3H-androgens. J Biol Chem. 251:1625–1631.[Abstract/Free Full Text]
  15. Kiel JL. 1995 Type-B cytochromes: sensors and switches. Boca Raton: CRC Press; 8–9, 98–99.
  16. Lyttle CR, DeSombre ER. 1977 Uterine peroxidase as a marker for estrogen action. Proc Natl Acad Sci USA. 74:3162–3166.[Abstract/Free Full Text]
  17. DeVito MJ, Ma X, Babish JG, Menache M, Birnbaum LS. 1994 Dose-response relationships in mice following subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin: CYP1A1, CYP1A2, estrogen receptor, and protein tyrosine phosphorylation. Toxicol Appl Pharmacol. 124:82–90.[CrossRef][Medline]
  18. Rier SE, Martin DC, Bowman RE, et al. 1993 Endometriosis in rhesus monkeys (Macaca mulatta) following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fund Appl Toxicol. 21:433–441.[CrossRef][Medline]



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