Among participants without previously diagnosed diabetes, GTT in the FRAM cohort found higher 2-h glucose levels in HIV-infected participants compared with control participants. The prevalence of IGT was slightly higher in HIV-infected participants, although the difference did not reach statistical significance. The prevalence of IGT in those without IFG was also slightly higher in HIV-infected participants. Undiagnosed IGT may therefore be more common in the HIV-infected population.
HIV-infected participants had lower BMI than control participants. Nevertheless, regional body fat significantly contributed to group differences in 2-h glucose and IGT. Both increased upper trunk SAT and decreased leg SAT were associated with higher 2-h glucose and IGT. Because IGT is associated with progression to diabetes, future risk of diabetes may be elevated in HIV-infected persons who lose leg SAT, which is often profound (11
) and unlikely to recover with time (15
). Loss of leg SAT is readily recognizable by most clinicians, and individuals with this finding may benefit from GTT even if fasting glucose is normal.
We found a relatively small 7–8 mg/dL increase in 2-h glucose in HIV-infected persons. To place this in perspective, the Cardiovascular Health Study found a 2% increased risk of incident cardiovascular disease event for every 10 mg/dL increase in 2-h glucose, plus an additional 29% increase in risk for those with 2-h values >154 mg/dL, in demographic-adjusted analysis (16
). Therefore, increased 2-h oral glucose tolerance test values may contribute to the increased cardiovascular disease risk in HIV-infected persons.
The association of regional adiposity with insulin resistance and diabetes has been studied in the general population. VAT is associated with insulin resistance and widely regarded as the regional depot most associated with metabolic disturbances. However, other studies have found important associations between SAT depots and insulin resistance (17
). For example, in 39 middle-aged men, the sum of truncal skinfold thicknesses was significantly and negatively associated with insulin sensitivity, even after adjusting for total AT (17
). In addition, both abdominal and truncal SAT had stronger correlations with insulin sensitivity than did VAT (17
). Likewise, in obese women, truncal SAT was independently associated with insulin resistance after adjustment for total AT and VAT (18
). In 783 young men, abdominal SAT, but not VAT, independently predicted higher insulin resistance (19
). These studies did not specifically measure upper trunk SAT, so it is of interest that the inclusion of this depot in our multivariable models was adequate to explain the association of increased truncal AT with abnormal glucose metabolism. VAT showed little independent association with 2-h glucose or IGT in our models after controlling for upper trunk and leg SAT.
Gluteofemoral (leg) SAT has been directly associated with increased insulin sensitivity in the general population, in contrast with SAT in the abdomen and trunk. In the Hoorn Study, increased leg fat was associated with lower HOMA insulin resistance in both men and women (21
). In the Health ABC study, increased leg fat was independently associated with more favorable fasting and postload glucose levels in men, with weaker results in women (20
Subcutaneous fat is the major source of the adipokines, leptin and adiponectin, which improve insulin sensitivity. In HIV-infected patients with significant lipoatrophy, the normal relationship between SAT depots and adiponectin levels is lost or even reversed (12
). In other words, in HIV lipoatrophy, depleted AT is associated with lower rather than higher levels of adiponectin, contrary to the general population. Low adiponectin and leptin levels may contribute to insulin resistance in HIV-associated lipoatrophy.
Finally, current tenofovir use was associated with lower 2-h glucose, consistent with a report that patients who switched from stavudine regimens to tenofovir had an average 4 mg/dL decrease in glucose over 48 weeks (22
). Both stavudine and zidovudine were associated with higher postprandial glucose in our study, but their associations did not reach statistical significance. We also found that tenofovir’s protective effect was not mediated through differences in total or regional adiposity. The increasing use of tenofovir, rather than the earlier thymidine-analog nucleoside reverse transcriptase inhibitors, especially in those with lipoatrophy, may therefore be an ameliorating factor to reduce the risk of diabetes in HIV-infected persons.
PI use showed little association with glucose levels, in contrast with previous studies (23
). To date, only indinavir use has been associated with elevated fasting glucose in healthy volunteers (8
). By the time of the FRAM2 examination, few participants were taking indinavir. Furthermore, although insulin resistance contributes to increased fasting glucose, defects in insulin secretion are more important. Current-generation PIs may not affect insulin secretion (24
The primary limitations of this study are its cross-sectional design and the use of calibrated glucose values for the control subjects. However, analysis of factors associated with 2-h glucose is not affected by the calibration, because the analyses were done separately in HIV-infected and control participants. GTT was not performed at the first FRAM examination, so changes in glucose tolerance over time could not be studied. Also, we were unable to measure liver fat, which has been strongly associated with increased risk of IFG, IGT, and insulin resistance, independently of visceral fat (25
). Strengths of this study include the large population-based HIV cohort and the use of a nationally representative control group. Finally, the use of MRI strengthens the analysis of regional adiposity and its relationship to GTT parameters.
In conclusion, our study suggests that HIV infection is associated with higher 2-h glucose on GTT and a somewhat higher prevalence of IGT. This increase may be driven by differences in body fat. The natural history of this prediabetic state in HIV infection and its association with cardiovascular disease are unknown and need further study. Our data support a role for greater upper trunk SAT and lower leg SAT in disturbed glucose metabolism in both HIV-infected and control subjects. Future studies should address physiologic mechanisms by which upper trunk SAT is metabolically deleterious and leg SAT is protective.