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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 12 6218-6223
Copyright © 2004 by The Endocrine Society

Insulin Resistance and Impaired Insulin Secretion in Prenatally Androgenized Male Rhesus Monkeys

Cristin M. Bruns, Scott T. Baum, Ricki J. Colman, Joel R. Eisner, Joseph W. Kemnitz, Richard Weindruch and David H. Abbott

Departments of Medicine (C.M.B., R.W.), Physiology (J.W.K.), and Obstetrics and Gynecology (D.H.A), National Primate Research Center (S.T.B., R.J.C., J.R.E., J.W.K., D.H.A.), and Institute on Aging (R.J.C., J.W.K., R.W.), University of Wisconsin, Madison, Wisconsin 53792; Cato Research (J.R.E.), Durham, North Carolina 27713; and Geriatric Research, Education, and Clinical Center, Veterans Administration Hospital (R.W.), Madison, Wisconsin 53705

Address all correspondence and requests for reprints to: Dr. Cristin M. Bruns, 600 Highland Avenue, H4/568 CSC (5148), Madison, Wisconsin 53792. E-mail: cb2{at}medicine.wisc.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Polycystic ovary syndrome (PCOS) is a familial disease. Affected males harbor some of the metabolic deficits seen in affected females. The prenatally androgenized (PA) female rhesus monkey, an animal model for PCOS, manifests glucoregulatory and reproductive abnormalities similar to those seen in PCOS women. The purpose of this study was to determine whether exposure of fetal male rhesus monkeys to testosterone excess would induce glucoregulatory and reproductive deficits. Seven adult PA males and seven matched controls underwent somatometric measurements, sex steroid analysis, and a frequently sampled iv glucose tolerance test. Body measurements were similar in the two groups, although arm circumference was greater in control compared with PA males (P < 0.01). There were no differences in neonatal weight or serum levels of sex steroids between the two male groups. Measures of insulin sensitivity and pancreatic ß-cell compensation (disposition index) were clearly diminished in PA compared with control males [insulin sensitivity: PA, mean 0.8 (95% confidence interval, 0.11, 5.82); controls, 3.06 (1.51, 6.19) x 10–4/min/µU/ml; P < 0.05; disposition index: PA, 226.38 (69.54, 383.22); controls, 509.21/min (306.52, 711.89); P < 0.02]. PA males do not exhibit elevated androgens during adulthood, suggesting that insulin resistance and impaired pancreatic ß-cell function may result from fetal reprogramming of key metabolic tissues.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
INSULIN RESISTANCE AND impaired pancreatic ß-cell function are two key metabolic defects leading to the premature onset of type 2 diabetes mellitus in women with polycystic ovary syndrome (PCOS) (1, 2, 3). PCOS is a familial disease, and although varying modes of transmission have been described, most suggest an autosomal dominant inheritance with variable penetrance (4, 5). As a result, affected sisters of women with PCOS demonstrate hyperandrogenism and metabolic deficits (6, 7, 8, 9). Given this familial component of impaired insulin action and secretion, it follows that close male relatives of women with PCOS may be similarly affected.

Attempts to identify a male phenotype of PCOS date back several decades. In 1968, Cooper et al. (10) ascertained by questionnaire increased pilosity in PCOS male kin. Cohen et al. (11) subsequently reported oligospermia, elevated LH levels, and Klinefelter syndrome in male members of a large PCOS kindred. Several studies thereafter identified premature balding in male relatives (4, 12, 13, 14). Norman et al. (15) were the first to report hyperinsulinemia in male first-degree relatives of women with PCOS, although only five families were studied. Subsequent larger studies demonstrated a high rate of impaired glucose tolerance and type 2 diabetes mellitus in both mothers and fathers of women with PCOS (8, 16, 17). Moreover, the brothers of women with PCOS (PCOS brothers) manifested hyperinsulinemia despite a young age (mean, 23.8 yr) and normal body mass index (BMI; mean, 22.6 kg/m2) (8). Colilla et al. (6) reported a highly significant correlation between the acute insulin response to glucose and the disposition index (DI) in PCOS brothers and sisters. Additionally, recent evidence suggests that Indian subcontinent PCOS brothers have endothelial dysfunction associated with insulin resistance (18). Such findings indicate that both close female and male relatives of women with PCOS harbor glucoregulatory deficits, suggesting that the metabolic defects of PCOS are not female-specific.

The prenatally androgenized (PA) female rhesus monkey, an animal model for PCOS (19), manifests glucoregulatory deficits similar to those in the human counterpart of the syndrome (20). Glucose-mediated ß-cell secretion of insulin is impaired in PA females exposed to androgen excess during early gestation, when the fetal pancreas is undergoing initial differentiation (21). In contrast, insulin action, but not insulin secretion, is impaired in female monkeys exposed to androgen excess during late gestation, at a fetal age when the pancreas is developing glucoregulatory control (22, 23, 24, 25). Exposed females displayed enhanced male-type behavior, diminished female-like behavior, as well as genital masculinization if exposed early in gestation (26). Androgen excess during late gestation induced only the behavioral traits. In accord, Abbott and colleagues (19, 20, 27) concluded that the associated metabolic changes in exposed females also resulted from fetal masculinization.

The purpose of this study was to determine whether exposure of fetal male rhesus monkeys to the same prenatal androgen excess experienced by fetal female monkeys induced glucoregulatory and reproductive deficits similar to those found in PA females. Any positive outcomes would suggest that the rhesus monkey model of prenatal androgen excess more closely resembles a process of fetal programming than fetal masculinization.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals

Fourteen adult male rhesus monkeys (Macaca mulatta) were used in this study and were maintained at the National Primate Research Center, University of Wisconsin (WNPRC), according to standard protocol (28). Seven prenatally androgenized (PA) males were produced by injecting pregnant rhesus monkeys with 10 mg testosterone propionate (TP) for 14–34 consecutive days, as previously reported for PA females (29). TP was initiated on d 40–55 (early-treated; n = 4), d 60 (mid-treated; n = 2), or d 115 (late-treated; n = 1) of gestation (gestation = 165 d). The seven PA monkeys were pair-matched with seven control (C) monkeys by age [mean (95% confidence interval); PA, 11.85 (6.15, 17.54); C, 9.56 (7.38, 11.74) yr], body weight [PA, 12.20 (9.69, 14.72); C, 12.29 (9.80, 14.77) kg], and BMI [PA, 44.59 (33.95, 55.22); C, 43.70 (38.44, 48.96) kg/m2]. Six PA males and their matched controls were part of a broader study that subsequently investigated the effects of dietary restriction on aging (28, 30) once the current study had been completed. The remaining PA and its pair-matched C monkey were not part of any dietary study. All experimental procedures were performed before any dietary modification. Twelve of these 14 males (six PA and six C) were fed a defined, pelleted diet (no. 85387; Teklad, Madison, WI), comprising 15% lactalbumin, 10% corn oil, and about 65% carbohydrate (28). The remaining two males (one PA and one C) were fed a similar diet (no. 2050, Teklad) comprising 21% crude protein, 5% crude oil, and 45% carbohydrate. All animal diets were supplemented with occasional fresh fruit. The animal care and use committee of the Graduate School of University of Wisconsin (Madison, WI) approved all experiments and animal protocols. Recommendations of the Guide for the Care and Use of Laboratory Animals and the Animal Welfare Act with its subsequent amendments were followed.

Experimental procedures

Somatometrics. Neonatal weights had been measured previously within the first week of life. Adult body measurements were taken while the males were under anesthesia. BMI was calculated as body weight in kilograms divided by the square of the crown rump length (31).

Frequently sampled iv glucose tolerance test (FSIGT). Each animal underwent a single 3-h FSIGT from 0700–0900 h, according to the tolbutamide-modified minimal model of Bergman (20). Animals had not been anesthetized for other procedures within the previous 4 wk. Animals were fasted overnight and were anesthetized with ketamine hydrochloride (15 mg/kg body weight, im) and diazepam (1–1.25 mg/kg body weight, im). Additional ketamine (5–10 mg/kg, im) was given as needed to maintain sedation. Two males (one PA and one C) required acepromazine (2 mg) iv to maintain sedation, a procedure that has no obvious effect on FSIGT outcome measures when used to supplement anesthesia (32). A central iv catheter was placed for blood sampling and administration of 50% dextrose (300 mg/kg body weight) at 0 min and tolbutamide (5 mg/kg body weight; Orinase Diagnostic, Upjohn, Kalamazoo, MI) at 20 min.

Sex steroids. Single determinations of estradiol, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), androstenedione, testosterone, and dihydrotestosterone (DHT) levels were made from the baseline sample of the FSIGT. All plasma and serum samples were stored at –20 C until hormone assays were performed.

Assay procedures. Plasma insulin concentrations were measured by RIA as previously reported (30). Plasma glucose concentrations were measured by the glucose oxidase method (YSI, Inc., Yellow Springs, OH). Serum DHEA-S concentrations were measured by RIA (Diagnostic Products Corp., Los Angeles, CA) (33). Serum concentrations of estradiol, DHEA, androstenedione, testosterone, and DHT were measured by extraction with 5 ml diethyl ether; chromatographic separation was then performed with System II (34). Fraction I was used to measure androstenedione by RIA (Research Diagnostics, Inc., Flanders, NJ). Half of fraction II was used to assay DHEA by RIA (Diagnostic Products Corp.), and the remaining half was evaporated, resuspended in column solvent, and applied to System I (35) to separate testosterone and DHT (36). Fraction III of System II was used to measure estradiol by RIA (Holly Hill Biologicals, Hillsboro, OR) (34). Inter- and intraassay coefficients of variation for insulin were 7.39% and 5.22%, respectively. Intraassay coefficients of variation were: DHEA-S, 3.2%; estradiol, 10.76%; DHEA, 18.2%; androstenedione, 14.32%; testosterone, 18.6%; and DHT, 21.4%.

Data analysis and statistical methods

Summary measures derived from FSIGT. The tolbutamide-modified minimal model [version 3.0, R. N. Bergman (20)] was used to generate estimates of insulin sensitivity (SI) and glucose effectiveness (SG). SI reflects the ability of insulin to promote glucose uptake and inhibit hepatic glucose production. SG reflects insulin-independent glucose uptake and suppression of hepatic glucose production. Additional measures derived from the FSIGT included basal glucose (Gb; mean of the four prechallenge glucose values, –15, –10, –5, and –2 min), basal insulin (Ib; mean of the four prechallenge insulin values), glucose disappearance rate (Kg; slope of log-linear regression of plasma glucose between 10 and 19 min), acute insulin response to glucose (AIRg; average increase in insulin above basal at 2–4 min, postchallenge), acute insulin response to tolbutamide (AIRTOL; average increase in insulin above basal at 22–24 min, postchallenge), and DI (ß-cell compensation index; product of SI and AIRg).

Area under the curve (AUC). The AUCs of insulin and glucose, and the insulin to glucose AUC ratio were calculated using the trapezoidal rule (37).

Statistical analysis

All data were tested for normality using a Lilliefors test (two-sided) and were log-transformed, when appropriate, to achieve homogeneity of variance and increase linearity (38). Data from subgroups of PA males that were early-, mid-, and late-treated with TP during gestation were combined for analysis because the numbers in each subgroup were insufficient for a valid subgroup analysis. All parameters were compared using two-sided paired t tests. P < 0.05 was considered significant. P values were not corrected for multiple comparisons. The Extreme Studentized Deviate outlier test (39) (one-sided) identified one PA male as an outlier for both SI and DI compared with the entire study group and with a population of 37 normal males (30 from a separate population combined with seven C males; study group: SI, P < 0.01; DI, P < 0.00007; normal population: SI, P < 0.05; DI, P < 0.0001). This PA male was early-treated and was fed the no. 85387 Teklad diet. He was the youngest of all of the PA males (8.19 yr of age), and he was more than 2 kg lighter (8.92 kg) than the next lightest PA male. The data from this PA male and his matched control were thus excluded from the analyses. Data from the remaining animals are presented as the mean (95% confidence interval).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Sex steroids

There were no differences between the male groups in serum levels of estradiol, DHEA, DHEA-S, androstenedione, testosterone, or DHT (Table 1Go).


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  		TABLE 1. Serum sex steroid concentrations in prenatally androgenized and control male rhesus monkeys

 
Somatometric measurements

Neonatal weights were available for six PA and five C males. There were no differences in neonatal weight between PA [0.514 (0.412, 0.617) kg] or C [0.523 (0.479, 0.567) kg] males (P < 0.90). BMI and circumferences of the abdomen, chest, and leg were similar between the two groups of males (data not shown). Arm circumference was greater in C compared with PA males [22.00 (20.85, 23.15) vs. 21.08 (19.87, 22.30) cm; P < 0.01].

Measures of SI and glucose regulation

Both SI and DI were derived from the FSIGT by the tolbutamide-modified minimal model of Bergman and were clearly diminished in PA compared with C males (Fig. 1Go). When SI and DI were corrected for BMI, both parameters in PA males remained at approximately 45% of their values in C males (SI/BMI, 0.04 (0.01, 0.07) vs. 0.09 (0.03, 0.14) x 10–4/min/µU/ml/kg/m2; P < 0.05; DI/BMI, 5.52 (1.47, 9.57) vs. 11.91 (6.82, 17.00)/min/kg/m2; P < 0.02]. Measures of Gb, Ib, SG, Kg, AIRg, and AIRTOL were similar in the two male groups (Table 2Go).



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  		FIG. 1. Reduced SI (*, P < 0.05; A) and DI (*, P < 0.02; B) in six PA males compared with six C males. Symbols denote timing of prenatal androgen exposure and pair-matches (circles, early-treated; squares, mid-treated, triangles, late-treated). {oplus} indicates an outlier (see Materials and Methods). The error bar represents the upper 95% confidence interval. a, To convert to 10–5 per minute per picomolar concentration, multiply by 1.44.

 

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  		TABLE 2. Measures of glucose regulation in prenatally androgenized and control male rhesus monkeys

 
AUC measures

There were no differences between the male groups in terms of AUC for insulin from baseline (0 min), before infusion of glucose, and up to administration of tolbutamide (20 min) during the FSIGT [PA, 2,985.38 (1,206.80, 7,385.21); C, 3,580.96 (2,632.13, 4,871.83) µU/ml·19 min; Fig. 2Go]. After the administration of tolbutamide, however, the AUC for insulin (22–180 min) was greater in PA compared with C males [PA, 14,655.48 (8,155.88, 26,334.74); C, 8,491.80 (5,577.75, 12,928.29) µU/ml·158 min; P < 0.03; Fig. 2Go]. When the insulin levels were corrected for glucose, the AUC after the administration of tolbutamide remained significantly elevated in PA compared with C males [PA, 235.50 (135.80, 408.42); C, 160.69 (103.08, 250.51) µU/ml/mg/dl·158 min; P < 0.05].



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  		FIG. 2. Mean plasma insulin (A) and glucose (B) levels (± 95% confidence interval) during the FSIGT with tolbutamide (5 mg/kg, iv) in six PA males and six C males. The AUC for insulin after tolbutamide treatment (22–180 min) is greater in PA than in C males (P < 0.03). a, To convert to picomolar concentrations, multiply by 6.945. b, To convert to millimolar concentrations, multiply by 5.55 x 10–2.

 
The AUCs for glucose from 0–19 min [PA, 3,633.38 (2,930.88, 4,335.89); C, 3,250.02 (2,905.40, 3,594.64) mg/dl·19 min; P < 0.06; Fig. 2Go] and 22–180 min [PA, 9,931.16 (6,640.06, 14,853.47); C, 8,375.29 (7,352.55, 9,540.30) mg/dl·158 min; Fig. 2Go] were similar between the two groups.

Relationships between BMI and FSIGT-derived measures

There were no correlations between BMI and Gb, Ib, SG, Kg, AIRg, AIRTOL, or DI in either PA or C males. There was a significant negative correlation between SI and BMI in PA, but not C, males (Fig. 3Go).



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  		FIG. 3. SI is negatively correlated with BMI in PA males (solid line), but not in C males (X, dashed line). Symbols denote timing of prenatal androgen exposure (circles, early-treated; squares, mid-treated; triangles, late-treated). a, To convert to 10–5 per minute per picomolar concentration, multiply by 1.44.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Adult male rhesus monkeys exposed to exogenous testosterone in utero exhibit insulin resistance and impaired insulin secretion in response to iv glucose administration in adulthood, the major metabolic deficits found in similarly exposed female monkeys (40). Although this study is small and is limited by the presence of an outlier, it provides the first evidence of a detrimental effect of fetal testosterone treatment in male primates. Previously, prenatally exposed male monkeys appeared unaltered by this fetal treatment. They exhibited apparently normal male behavior (26), but demonstrated a slight diminution in preadolescent interactions with male peers (29). In earlier studies, pregnant rhesus monkeys injected with 25 mg TP daily exhibited elevations in circulating levels of testosterone, DHT, and androstenedione compared with controls (41). The exposed male fetuses, however, had normal circulating levels of testosterone and DHT compared with untreated fetal males, but showed marked elevations in circulating androstenedione levels (41), indicating that prenatal testosterone treatment may exert effects on the fetus through either excessive masculinization or fetal programming via excessive generation of a precursor steroid hormone, androstenedione. In adulthood, PA males do not exhibit elevations in androgens, unlike exposed females (42, 43). This suggests that the insulin resistance seen in exposed males is not due to extant hyperandrogenism, but rather suggests that key metabolic tissues are reprogrammed as a result of intrauterine androgen excess. Alternatively, reprogramming of fetal tissues could result from exposure to excess estrogen via placental (44) or fetal (45, 46) aromatization of androgens. In support of this, Napalkov and Anisimov (47) reported persistent estrus and decreased glucose utilization in adult female rats exposed to diethylstilbestrol propionate in utero. The ability of testosterone exposure to generate excess androstenedione and/or estrogen may explain the genesis of similar metabolic abnormalities in the PA male monkeys that we studied.

Perturbations of the maternal environment may play a key role in the development of metabolic disturbances in the exposed offspring. Exogenous testosterone administration in female to male transsexuals modestly reduces insulin sensitivity (48, 49). Testosterone treatment may similarly reduce insulin sensitivity in pregnant rhesus monkeys. The inability of exposed females to compensate for the insulin resistance induced by both pregnancy and testosterone treatment may result in gestational diabetes mellitus. In this condition, transfer of excess glucose and other metabolic fuels to the fetus may induce metabolic abnormalities that become apparent later in life (50).

If testosterone exposure leads to fetal reprogramming through alteration of the intrauterine environment, then specific tissues must be reprogrammed to result in insulin resistance and impaired insulin secretion. Consistent with developing insulin resistance, PA female rhesus monkeys exposed to testosterone excess during early gestation have increased abdominal and visceral adiposity as assessed by combined computed tomography and dual energy absorptiometry (27). Adult female rats exposed to testosterone during the neonatal period also demonstrate insulin resistance associated with an increased amount of mesenteric adipose tissue (51). Thus, it is conceivable that insulin resistance resulting from prenatal testosterone exposure occurs due to permanent alteration of regional fat distribution, and this would be consistent with our finding of adiposity-associated insulin resistance in prenatally androgenized males, alone. Although there were no differences in BMI or abdominal circumference between prenatally androgenized and normal males in this study, a more sensitive measurement of visceral fat with magnetic resonance imaging or computed tomography may reveal increased abdominal adiposity in PA males and provide a potential mechanism for insulin resistance.

The insulin secretory defect may result from impaired glucose sensing by the pancreatic ß-cell (52). In support of this, PA males manifest impaired glucose-stimulated insulin secretion, but administration of a sulfonylurea receptor agonist effectively induces insulin secretion. This suggests selective impairment in insulin secretion in response to glucose, rather than a generalized impairment of ß-cell insulin secretion (52), consistent with the nature of ß-cell dysfunction in type 2 diabetes mellitus in humans and monkeys (53, 54). Reprogramming of potassium-dependent ATP channels in the pancreatic ß-cell could lead to such alterations in pancreatic function by permanently impairing glucose-induced insulin secretion (55).

Although all male rhesus monkeys in this study exhibited fasting serum glucose levels in the normal range (56), an impaired ß-cell response to hyperglycemic episodes coupled with insulin resistance increase the likelihood of developing type 2 diabetes mellitus in later adulthood (57, 58). Similarly, ß-cell dysfunction in women with PCOS and their male relatives coupled with insulin resistance lead to an increased risk of type 2 diabetes mellitus early in adult life (1, 8, 15, 16, 57, 59, 60). Current evidence suggests that impaired ß-cell compensation for insulin resistance occurs early in the pathogenesis of type 2 diabetes in humans (61, 62), and ß-cell impairment may be present in the nondiabetic offspring of parents with type 2 diabetes (63, 64).

Because male and female monkeys exposed to the same altered intrauterine environment induced by exogenous testosterone develop similar metabolic abnormalities, it is possible that the deficits seen in PCOS families may also be caused by an altered intrauterine environment due to genetic factors, environmental exposures, or an interaction between the two. Because PA male monkeys demonstrate similar metabolic defects as PCOS brothers, PA males could be explored as a potential animal model for male PCOS. Moreover, PA male monkeys could provide an additional avenue for exploring the potential mechanisms by which prenatal testosterone exposure induces the permanent metabolic deficits that are highly prevalent in human populations.


   Acknowledgments
 
We gratefully acknowledge Jim Turk and Kerri Hable for technical assistance; Dan Wittwer, Fritz Wegner, and the Assay Services of WNPRC for assay assistance; Ron Gangnon for statistical support; Marc Drezner and Deborah Barnett for critical review of the manuscript; and the veterinary and animal care staff at WNPRC.


   Footnotes
 
This work was supported by NIH Grants T32-AG-00268-05, R01-AG-07831, PO1-AG-11915, P51-RR-000167, R01-RR-13635, and P50-HD-44405.

This study was presented in part at the 85th Annual Meeting of The Endocrine Society, Philadelphia, PA, 2003.

Abbreviations: AIRg, Acute insulin response to glucose; AIRTOL, acute insulin response to tolbutamide; AUC, area under the curve; BMI, body mass index; C, control; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate; DHT, dihydrotestosterone; DI, disposition index; FSIGT, frequently sampled iv glucose tolerance test; Gb, basal glucose; Ib, basal insulin; Kg, glucose disappearance rate; PA, prenatally androgenized; PCOS, polycystic ovary syndrome; SG, glucose effectiveness; SI, insulin sensitivity; TP, testosterone propionate.

Received May 14, 2004.

Accepted September 7, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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