In this large ethnically-diverse cohort of women with or at-risk for HIV infection, past opiate use was associated with increased diabetes prevalence independent of HCV infection, HIV status, or antiretroviral use. In addition, current opiate use was independently associated with an increased risk of incident diabetes. Among current opiate users, women infected with HCV had a higher diabetes incidence than did women who were uninfected. While classic diabetes risk factors, including older age, obesity and a family history of diabetes were also predictive of diabetes, the association of recent ART use with diabetes was not statistically significant.
To our knowledge, this is the first study to use prospectively collected data to investigate the possible opiate-diabetes relationship. Prior cross-sectional studies have reported associations between opiate use and disordered glucose metabolism, however they did not control for HCV status, which may have confounded the observed relationship. In the Menopause Study, a cohort of mid-life women with or at-risk for HIV infection, methadone use was found to be associated with prevalent diabetes, with an increased odds of diabetes for each quartile of current methadone dose.21
This study also found that current opiate use (heroin or methadone) was associated with lower insulin secretion, estimated using the 30-minute incremental ratio of insulin to glucose. A similar study in CHAMPS, a comparable cohort of men with or at-risk for HIV infection, also found an independent association between methadone use and prevalent diabetes.22
Furthermore in this cohort, a history of heroin use was associated with greater insulin resistance. Several small studies of HIV-uninfected patients have also demonstrated an association between opiate use and abnormal glucose metabolism. One study suggested that opiate use may induce insulin resistance, as higher insulin levels while fasting and after an oral glucose load were observed in heroin users compared to healthy controls.9
Other studies have reported a lower acute insulin response after an intravenous glucose load in heroin users compared to control subjects, suggesting impaired beta cell function.10,11
Abnormal glucose tolerance has also been observed in experimental studies of methadone-addicted rats.7
While these data provide further evidence that opiate use may affect glucose metabolism, the fact that certain studies point to beta cell dysfunction, and other studies to effects on insulin sensitivity, leaves the mechanisms uncertain. In animal models, morphine administration was found to induce glucagon release, suggesting that opiates may exert a direct effect on the pancreas, resulting in hepatic glucose output.8
Another animal study found that opiate-induced glucose intolerance was accompanied by both a reduction in the activity of specific glycolytic enzymes, and an elevation in the activity of gluconeogenic enzymes in the liver of exposed animals.7
Further experimental data suggest that opiates can inhibit insulin signaling through direct cross talk between downstream signaling pathways of the μ-opioid receptor and the insulin receptor.23
Prior studies have found that HCV infection is associated with disorders of glucose metabolism, particularly among individuals at increased risk of diabetes due to greater age and/or BMI.24,25
We found that HCV infection, as well as greater HCV RNA levels, appeared to be positively associated with incident diabetes, although the associations were not statistically significant in all models. One retrospective cohort analysis of 1149 HIV-infected persons on HAART over a median follow-up of 8.9 months found a two-fold increase in hyperglycemia incidence among HCV-infected persons (4.9 cases/100 person-years) compared with uninfected persons (2.3 cases/100 person-years).3
Unlike the present study, that study did not adjust for family history of diabetes, a key diabetes risk factor, and did not obtain glucose levels systematically for all cohort members, which may have resulted in selection bias. Biological evidence to support an association between HCV and diabetes include several studies demonstrating that HCV proteins interfere with insulin signaling.26-28
In addition HCV RNA has been identified in pancreatic tissue of HIV/HCV co-infected patients, suggesting that HCV may have a direct influence on islet cell function.29
We did not find a strong association between ART status and incident diabetes when compared to HIV-uninfected women, in contrast to another study in men, which did not control for several key factors associated with diabetes including family history of diabetes and HCV status.1
Our findings may also be partially attributable to changing patterns of antiretroviral use, as newer PIs have less of an effect on insulin sensitivity than indinavir,30-32
which was commonly used early in the HAART era. Among HIV-infected individuals, cumulative exposure to nucleoside reverse transcriptase inhibitors (NRTIs) has been associated with risk of diabetes incidence and insulin resistance,2,33
which may be attributable to NRTI-induced mitochrondrial dysfunction.34
The strengths of our study include the prospective design, the availability of fasting glucose levels to define diabetes, and the use of HCV RNA levels as an indicator of persistent HCV infection. Inclusion of data on family history of diabetes also allowed us to adjust for this important risk factor. Furthermore, our analysis was strengthened by inclusion of an HIV-uninfected comparison group with a similar demographic and behavioral profile.
Our study also has certain limitations. First, as in other analyses of diabetes in HIV cohorts,1
we defined diabetes based on a single fasting glucose measurement, rather than after confirmation on a subsequent day as recommended by the American Diabetes Association.35
Second, we were not able to distinguish whether diabetes medications were used to treat diabetes or for other reasons such as to treat insulin resistance or changes in fat distribution associated with HIV infection. In addition, we only measured plasma HCV RNA in HCV seropositive women. Recent data suggest that some HCV seronegative HIV-infected individuals may have detectable HCV RNA, particularly in the setting of a low CD4+ count.36
Therefore, some HCV-infected women may have been misclassified. Finally, the findings in our cohort of predominantly African American and Hispanic women may not apply to HIV-infected populations with different sociodemographic characteristics. However given that drug use, HCV infection and diabetes all disproportionately affect these racial and ethnic groups,37,38
understanding the association of these disorders in this population is of great importance.
In summary, we observed that opiate use was associated with increased diabetes prevalence and incidence among HIV-infected and at-risk-uninfected women, independent of HCV infection or antiretroviral use. HCV infection also appeared to increase the risk of incident diabetes. Based on our findings, routine monitoring of fasting glucose levels in women with or at-risk for HIV infection who use opiates or have persistent HCV infection may be warranted.