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From The Clinical Research Centers |
Neuroendocrine Unit (S.G., C.C., C.H., T.S., S.P., A.K.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Steven Grinspoon, M.D., Neuroendocrine Unit, Bulfinch 457B, Massachusetts General Hospital, Boston, Massachusetts 02114.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Fifty HIV-infected men with acquired immunodeficiency syndrome wasting were compared with 20 age- and body mass index (BMI)-matched healthy control subjects. Insulin concentrations were significantly increased in HIV-infected patients compared to those in control patients (16.6 ± 1.8 vs. 10.4 ± 0.8 µU/mL; P < 0.05) and were increased in nucleoside reverse transcriptase (NRTI)-treated patients who did not receive a protease inhibitor (PI; 21.7 ± 4.3 vs. 10.4 ± 0.8 µU/mL; P < 0.05). Insulin concentrations and HOMA IR were inversely correlated with the serum free testosterone concentration (r = -0.36; P = 0.01 for insulin level; r = -0.30; P = 0.03 for HOMA), but not to body composition parameters, age, or BMI. In a multivariate regression analysis, free testosterone (P = 0.05), BMI (P < 0.01), and lean body mass (P = 0.04) were significant. Lower lean body mass and higher BMI predicted increased insulin resistance.
The HIV-infected patients demonstrated an increased trunk fat to total fat ratio (0.49 ± 0.02 vs. 0.45 ± 0.02; P < 0.05) and an increased trunk fat to extremity fat ratio (1.27 ± 0.09 vs. 0.95 ± 0.06, P = 0.01), but a reduced extremity fat to total fat ratio (0.44 ± 0.01 vs. 0.49 ± 0.01; P = 0.02) and reduced overall total body fat (13.8 ± 0.7 vs. 17.2 ± 0.9 kg; P < 0.01) compared to the control subjects. Increased truncal fat and reduced extremity fat were seen among NRTI-treated patients, but this pattern was most severe among patients receiving combined NRTI and PI therapy [trunk fat to extremity ratio, 1.47 ± 0.15 vs. 0.95 ± 0.06 (P < 0.01); extremity fat to total fat ratio, 0.40 ± 0.02 vs. 0.49 ± 0.01 (P < 0.05)].
Insulin responses to testosterone administration were investigated among 52 HIV-infected men with hypogonadism and wasting (weight <90% ideal body weight and/or weight loss >10%) randomized to either testosterone (300 mg, im, every 3 weeks) or placebo for 6 months. Testosterone administration reduced HOMA IR in the HIV-infected men (-0.6 ± 0.7 vs. +1.41 ± 0.8, testosterone vs. placebo, P = 0.05) in association with increased lean body mass (P = 0.02).
These data demonstrate significant hyperinsulinemia in HIV-infected patients, which can occur in the absence of PI use. In NRTI-treated patients not receiving PI, a precursor phenotype is apparent, with increased truncal fat, reduced extremity fat, and increased insulin concentrations. This phenotype is exaggerated in patients receiving PI therapy, with further increased truncal fat and reduced extremity fat, although hyperinsulinemia per se is not worse. Endogenous gonadal steroid levels are inversely related to hyperinsulinemia in HIV-infected men, but reduced lean body mass and increased weight are the primary independent predictors of hyperinsulinemia. Indexes of insulin sensitivity improve in response to physiological androgen administration among hypogonadal HIV-infected patients, and this change is again related primarily to increased lean body mass in response to testosterone administration.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Hypogonadism is relatively common among HIV-infected patients, for whom testosterone is commonly administered to increase lean body mass (6, 7, 8, 9). Although significant effects of testosterone on lean body mass have been reported (7, 8), the relationships between endogenous gonadal steroid concentrations, insulin sensitivity, and body composition are unknown among HIV-infected patients. Furthermore, it is unknown whether exogenous testosterone administration affects indexes of insulin sensitivity in this population. In non-HIV-infected, nondiabetic men, insulin concentrations correlate inversely with serum androgen concentrations (10). Insulin levels are increased in hypogonadal compared to eugonadal non-HIV-infected men (2), and the inverse association between serum insulin and testosterone remains after controlling for age, body mass index (BMI), and visceral fat in healthy men with normal serum androgen concentrations (11). Furthermore, limited studies in non-HIV-infected men have shown that testosterone administration may result in increased glucose disposal and increased insulin sensitivity in patients with excess body fat (12).
In this study we compare insulin concentrations in HIV-infected men with those in age- and BMI-matched controls and demonstrate significant fasting hyperinsulinemia. Our data demonstrate a significant inverse relationship between serum androgen concentrations and insulin in HIV-infected men, which is a function of reduced lean body mass in this population. Among hyperinsulinemic, hypogonadal men with HIV infection, physiological testosterone administration results in improvement in indexes of insulin sensitivity.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Cross-sectional comparison of HIV-infected men unselected for
gonadal status. Fifty HIV-infected men were compared with a
healthy control population of 20 men without acute or chronic illness,
who were matched for age, BMI, and minority representation (Table 1
). The HIV-infected subjects were
selected based on weight loss of more than 10% from the preillness
maximum or weight less to than 90% ideal body weight. On the average,
the HIV-infected subjects had a weight loss of 6.4 ± 1.4%
(P < 0.001) over the year preceding the study but were
of stable weight (mean weight change, -0.5 ± 0.7%;
P = 0.74) in the month before the study and were
matched to the control subjects for BMI. In contrast to the
longitudinal study (see below), HIV-infected subjects were not selected
based on gonadal function. Forty-percent of HIV-infected patients were
receiving PI therapy (duration, 9.0 ± 1.7 months), 76% were
receiving nucleoside reverse transcriptase inhibitor (NRTI) therapy
(11.3 ± 1.6 months), and 18% were receiving nonnucleoside
reverse transcriptase inhibitor (NNRTI) therapy (6.4 ± 1.7
months). Partial data from a subset of the HIV-infected patients have
been previously reported (13, 14). Subjects with diabetes mellitus or
receiving antidiabetogenic or other medications known to affect insulin
or glucose were excluded. Antiviral therapy was categorized into three
groups based on current antiviral treatment status [no treatment
(n = 12), NRTI alone (n = 18), and combined NRTI and PI
(n = 20)], and none of the patients had changed antiviral
medications within 2 months of the study. Patients receiving NNRTI
therapy were all receiving one or more concomitant antiviral
medications and were included in the treatment categories outlined
above. All subjects gave written consent as approved by the
subcommittee on human studies of Massachusetts General Hospital.
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Laboratory assessment and methodology
Gonadal function. Serum total and free testosterone were measured by RIA kits (Diagnostics Products, Los Angeles, CA) with intraassay coefficients of variation of 5–12% for total testosterone and 3.2–4.3% for free testosterone. Sex hormone-binding globulin (SHBG) was measured using published methods (16).
Glucose and insulin. Insulin (RIA, Linco Research, Inc., St. Louis, MO; RIA sensitivity, 2 µU/mL; intraassay coefficient of variation, 1.6–4.4%) and glucose were assessed after an overnight fast. The homeostasis model assessment (17) was used to calculate insulin resistance from fasting insulin and glucose concentrations. In this model, the formula for insulin resistance (IR) is: insulin resistance = [fasting insulin (µU/mL) x glucose (mmol/L)/22.5].
Anthropometric and functional indexes. Weight and height were measured on all subjects and expressed as BMI as well as percent ideal body weight based on Metropolitan Life Insurance Height and Weight Tables (18). Whole body lean and fat mass and the ratio of truncal fat and extremity fat to total body fat were determined by dual energy x-ray absorptiometry (DEXA; Hologic, Inc., Waltham, MA) (8). Regional areas of interest were determined using Hologic, Inc., software and were standardized among subjects (Users Guide, Hologic, Inc., Waltham, MA) (5).
Immune function. CD4 count (flow cytometry, Becton Dickinson Immunocytochemistry Systems, San Jose, CA) was determined for each patient.
Statistical analysis
The HIV-infected patients were first compared as a single group to the HIV-negative control group by the median rank test in the primary analysis. A subgroup analysis was performed comparing HIV-infected patients by antiviral treatment status to the control group using Dunnett’s test for the comparison of multiple groups to a control group. Simple correlation analyses were performed comparing insulin, anthropometric, and hormonal data. Standard least squares regression models were developed for insulin and homeostatic model for insulin resistance (HOMA IR) among the HIV-infected subjects in the cross-sectional comparison. Age, BMI, fat, and lean body mass were determined by DEXA; percent truncal fat, SHBG, and free testosterone were tested in the models as independent variables. The changes in HOMA IR and other clinical end points were compared between the testosterone-treated and placebo-treated HIV-infected patients with hypogonadism by the Wilcoxon rank test in the longitudinal study. Stepwise regression analyses were performed to determine the factors that affected the change in HOMA IR with treatment.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The clinical characteristics of the patients are shown in Table 1
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The HIV-infected men did not differ in age, BMI, or testosterone levels
from the control subjects. Minority status was also similar (14%
vs. 15%) between the HIV-infected and control subjects.
Insulin levels were significantly higher (16.6 ± 1.8
vs. 10.4 ± 0.8 µU/mL; P = 0.02), and
HOMA IR was increased in the HIV-infected patients (3.9 ± 0.5
vs. 2.4 ± 0.2; P = 0.05; Fig. 1).
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Comparison by treatment status between HIV-infected and healthy control subjects
Insulin levels were significantly increased in the NRTI-treated group (21.7 ± 4.3 vs. 10.4 ± 0.8 µU/mL; P < 0.05), but not in the combined NRTI- and PI-treated group, compared to those in the control subjects. Similarly, HOMA IR was increased in the NRTI-treated group compared to that in the control subjects (5.4 ± 0.1.1 vs. 2.4 ± 0.2; P < 0.05). Neither insulin (r = 0.02; P = 0.95) nor HOMA IR (r = 0.04; P = 0.86) correlated with duration of PI use.
Compared to control subjects, only the combined NRTI- and PI-treated
subjects demonstrated an increased trunk fat to extremity fat ratio and
a reduced extremity to total fat mass ratio (Fig. 2). However, a significantly increased trunk
fat to extremity fat ratio (P < 0.05) and a reduced
extremity to total fat ratio (P < 0.05) were seen
among the NRTI-treated, non-PI-treated, patients compared to those in
nontreated HIV-infected subjects (Fig. 2). Compared to control
subjects, the combined NRTI- and PI-treated patients demonstrated
increased triglyceride levels.
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Univariate and multivariate correlations are shown in Table 2. Insulin concentrations and HOMA IR
were inversely correlated to the serum free testosterone concentration
(r = -0.36; P = 0.01 for insulin concentration;
r = -0.30; P = 0.03 for HOMA), but not to other
parameters in univariate analyses, including body composition, age,
BMI, or SHBG levels. In a multivariate regression analysis, free
testosterone (P = 0.05), BMI (P =
0.01), and lean body mass (P = 0.04) were significant
in the model for insulin (r2 = 0.26), controlling
for age and trunk fat. In contrast, only BMI (P = 0.01)
and lean body mass (P = 0.02) were significant in the
model for HOMA (r2 = 0.31).
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At baseline, insulin (15.3 ± 1.9 µU/mL; normal range,
5.0–15.0 µU/mL) and triglyceride (162 ± 13 mg/dL; normal
range, 40–150 mg/dL) levels were increased, whereas HDL levels were
reduced (26 ± 1 mg/dL; normal range, >34 mg/dL), and glucose
levels were normal (87 ± 2 mg/dL; normal range, 70–110 mg/dL)
among the hypogonadal subjects. Testosterone administration reduced
HOMA IR in the hypogonadal HIV-infected men (-0.6 ± 0.7
vs. +1.41 ± 0.8, testosterone vs. placebo;
P = 0.05; Table 3 and
Fig. 3); however, this change was not related
to changes in whole body or regional fat, but, rather, to increased
lean body mass (P = 0.02) in a stepwise regression
model. PI use did not differ between the groups at baseline or
throughout the protocol (8). No effects of testosterone on lipid
levels, glucose, or fat mass were seen (Table 3).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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These data demonstrate fasting hyperinsulinemia and reduced insulin sensitivity among HIV-infected patients with wasting. As a group, the HIV-infected men demonstrated increased truncal fat and reduced extremity fat. However, because our patients were not selected on the basis of clinical lipodystrophy but for weight loss, the findings of increased truncal fat mass and hyperinsulinemia are all the more significant. The lipodystrophy syndrome is a recently described syndrome increasingly common among HIV-infected patients, characterized by fat redistribution that is truncal in nature and often associated with insulin resistance (3, 4). In recent studies, as many as 83% of HIV-infected patients receiving PI therapy have been categorized with the lipodystrophy syndrome, characterized by truncal fat accumulation and loss of extremity fat (1). The body composition findings among patients with clinical lipodystrophy are therefore qualitatively similar but quantitatively more severe than the changes observed by DEXA in this study. The abnormalities in regional body composition that we report in this study may constitute a precursor phenotype in HIV-infected men with weight loss, which can be demonstrated among NRTI-treated men in the absence of PI. With the addition of PI therapy, further increased truncal adiposity, reduced extremity fat mass, and increased triglyceride levels are seen. It is unknown whether this constellation of findings may impart increased long term cardiovascular risk to affected patients.
The mechanism of the lipodystrophy syndrome is not known and has been suggested to relate to a direct effect of PI therapy on fat metabolism through homology and inhibition of the lipoprotein-related peptide receptor or through an effect to increase apoptosis of peripheral fat through the retinoic acid receptor (19). However, the lipodystrophy syndrome may be independent of PI therapy and related in part to metabolic abnormalities associated with HIV disease. Among NRTI-treated patients not receiving PI therapy, significant loss of extremity fat and an increased trunk fat to extremity fat ratio were found. These data suggest that peripheral fat loss and increased truncal fat may begin with the introduction of NRTI therapy independently of protease inhibitor therapy, which, when initiated, stimulates further truncal fat accumulation and peripheral fat loss. Whether this affect on body composition is due to a specific effect on fat metabolism or a generalized improvement in immune function or is associated with generalized weight recovery is unknown. In this study, BMI was not different among the groups, suggesting specific effects on metabolism independent of weight. Further prospective studies are necessary to determine the specific role of antiviral therapies on body composition and fat metabolism.
An important question among HIV-infected patients is whether the observed hyperinsulinemia relates to the use of PI therapy. In patients receiving PI therapy, Walli et al. have reported a high degree of insulin resistance, such that over 60% of subjects have abnormal oral glucose tolerance testing (3). However, little is generally known about patients without clinical lipodystrophy but with early loss of extremity fat and increased truncal fat in the setting of NRTI therapy, which may be a preclinical form of lipodystrophy. In this study, we demonstrate significant fasting hyperinsulinemia even among non-PI-treated patients with significant loss of extremity and increased truncal fat. Similarly, we have recently shown significant fasting hyperinsulinemia in non-PI-treated, HIV-infected women with a similar degree of weight loss (5). Our data strongly suggest that hyperinsulinemia in HIV-infected men and women is not simply a function of PI use, but may be related in part to baseline metabolic abnormalities and seen in association with other antiviral therapies.
Endogenous gonadal steroid concentrations were inversely associated with insulin concentrations in our study patients. In non-HIV-infected men, insulin levels are strongly related to fat mass, particularly to visceral fat mass (11, 20). However, insulin levels were not related to fat mass or SHBG levels in our population. Therefore, these data do not support the hypothesis that increased SHBG levels may relate to increased insulin sensitivity in patients with AIDS (21). In contrast, our data demonstrate increased insulin resistance that is not a function of increased SHBG. Instead, the strongest correlations that we observed were to endogenous gonadal steroid levels. For example, there was an inverse correlation between fasting insulin levels and free testosterone (r = -0.36; P = 0.01). Our data demonstrating an inverse relationship between serum free testosterone and insulin concentrations are in agreement with data from non-HIV-infected men. In the Telecom study of healthy adult men, lower plasma testosterone levels were associated with increased fasting and 2-h glucose and insulin levels (2).
We found that reduced lean body mass and increased BMI predicted increased insulin concentrations more than whole body or regional fat. Similarly, Seidell et al. demonstrated that free testosterone levels were inversely associated with insulin levels in healthy men, controlling for BMI, age, and visceral fat (11). Because we did not directly assess visceral fat, but only the distribution of fat by DEXA, the relationship between visceral fat and insulin concentrations could not be assessed in this study. The HIV-infected and normal control patients in this study were matched for BMI; however, the HIV-infected patients were selected for significant weight loss (6% in the year before the study). Although weight was stable in the month before the study, weight loss per se could affect insulin levels and other metabolic parameters.
Insulin resistance, as assessed by HOMA, decreased in response to testosterone administration in hypogonadal men with AIDS wasting independent of PI use. At baseline, insulin levels were increased, but glucose levels normal, indicating insulin resistance. Insulin levels decreased from 14.3 ± 2.7 to 11.3 ± 1.3 µU/mL in the testosterone-treated subjects and increased from 16.2 ± 2.9 to 20.5 ± 4.4 µU/mL in the placebo-treated subjects. In contrast, no significant effects of testosterone on glucose or lipid levels were seen in this study. The decrease in insulin resistance was associated most significantly with increased lean body mass. Reduced lean body mass was also a significant determinant of increased insulin in the cross-sectional comparison of HIV-infected patients and control subjects. Therefore, the reduction of hyperinsulinemia in association with increased lean body mass in response to testosterone is consistent with the cross-sectional data and suggests that reduced lean body mass may contribute to hyperinsulinemia in this population.
The mechanism by which reduced lean body mass is associated with increased insulin levels is not clear. Reduced lean body mass may be a marker for abnormal fat redistribution or other related body composition factors. Our data suggest that the relationship between endogenous gonadal steroid levels and insulin is not direct in HIV-infected men, but may instead be a function of altered body composition. However, because the HIV-infected subjects in the longitudinal study of testosterone administration had significant loss of muscle mass at baseline and were underweight (8), direct comparisons with a non-HIV-infected hypogonadal population characterized by increased body weight and increased fat mass cannot be made. Nonetheless, hyperinsulinemia and relative insulin resistance with normal blood glucose levels were observed at baseline in our population of HIV-infected hypogonadal men. Therefore, the beneficial effect of physiological testosterone administration on insulin resistance in association with increased lean body mass is clinically significant. Further studies, using more sensitive techniques to determine insulin sensitivity, are needed to assess the effect of testosterone in HIV-infected men with hypogonadism.
Although recent data demonstrate an effect of testosterone administration to reduce truncal fat, as measured by DEXA in non-HIV-infected healthy men (22), and to increase the glucose disposal rate on euglycemic, hyperinsulinemic clamp testing in obese, middle age non-HIV-infected men (12), data from this study cannot be extrapolated to the use of testosterone in eugonadal HIV-infected men with lipodystrophy, in whom different effects on insulin and fat may be observed. In this study, insulin sensitivity was assessed by a static parameter. Although the fasting insulin concentration and HOMA are reasonable surrogates for insulin sensitivity, which have been shown to correlate well with frequently sampled glucose tolerance testing and the euglycemic, hyperinsulinemic clamp (23), the relatively high variability of HOMA, estimated between 30–40% in prior studies (23), suggests that more sensitive and precise measures of insulin resistance may better assess the effects of testosterone administration on insulin sensitivity in this population. Further studies of testosterone effects on visceral adiposity and insulin sensitivity using dynamic indices of insulin resistance in patients with HIV lipodystrophy are needed.
At baseline, triglyceride levels were increased and HDL levels reduced in the hypogonadal subjects receiving testosterone. Increased triglyceride and reduced HDL levels may relate in part to increased very low density lipoprotein production and reduced clearance in HIV disease (24) as well as to hypogonadism itself, which is associated with increased triglyceride levels in non-HIV-infected men (25). No significant effect of testosterone on lipid parameters was seen in the study subjects. In contrast, physiological testosterone replacement is associated with complex effects on lipid parameters in non-HIV-infected patients, with increased cholesterol and low density lipoprotein observed in one study of testosterone administration in men with primary hypogonadism (26). The effects of physiological testosterone in HIV-infected hypogonadal men cannot be extrapolated to non-HIV-infected men because of the effects of HIV disease on lipid metabolism. In addition, antiviral therapy and other factors may affect the lipid response to testosterone in the lipodystrophy syndrome.
These data demonstrate significant fasting hyperinsulinemia in HIV-infected men, independent of PI use. Our data suggest that hyperinsulinemia occurs even among patients with weight loss, and, as such, hyperinsulinemia and subclinical fat redistribution may be a precursor phenotype for the development of overt lipodystrophy with weight gain in the setting of immune recovery and PI therapy. These data do not rule out a direct effect of PI therapy on fat metabolism and elucidate metabolic abnormalities in HIV-infected men associated with NRTI use in the absence of PI therapy. Reduced androgen levels and lean body mass contribute at least in part to hyperinsulinemia in a subset of HIV-infected patients, in whom testosterone administration improves insulin sensitivity. Further investigation, using more detailed and sensitive measures of insulin resistance and visceral adiposity, are required to assess long term response to testosterone in HIV-infected patients. In addition, investigation of the effects of testosterone and anabolic steroids in eugonadal HIV-infected patients is critical, particularly as the use of testosterone and such agents is considered to reduce visceral adiposity in the HIV lipodystrophy syndrome.
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Acknowledgments |
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Footnotes |
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Received July 29, 1999.
Revised September 10, 1999.
Accepted September 15, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, P < 0.05
(compared to no treatment); 