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Association Between Systemic Inflammation and Incident Diabetes Pathophysiology/Complications ORIGINAL ARTICLE Association Between Systemic Inflammation and Incident Diabetes in HIV-Infected Patients After Initiation of Antiretroviral Therapy 1 3 TODD T. BROWN, MD, PHD CECILIA SHIKUMA, MD nucleoside reverse transcriptase inhibi- 2 4 KATHERINE TASSIOPOULOS, DSC, MPH GRACE A. MCCOMSEY, MD tors, zidovudine and stavudine, also have 2 RONALD J. BOSCH, PHD direct and indirect effects on glucose me- tabolism (4,5). Chronic infection with HIV may also contribute to glucose ab- OBJECTIVE — To determine whether systemic inflammation after initiation of HIV- normalities among HIV-infected patients. antiretroviral therapy (ART) is associated with the development of diabetes. In the Multicenter AIDS Cohort Study, in- sulin resistance markers were higher in all RESEARCH DESIGN AND METHODS — We conducted a nested case-control study, groups of HIV-infected men compared comparing 55 previously ART-naive individuals who developed diabetes 48 weeks after ART with HIV-uninfected control subjects, initiation (case subjects) with 55 individuals who did not develop diabetes during a comparable even among those who were not receiving follow-up (control subjects), matched on baseline BMI and race/ethnicity. Stored plasma sam- ples at treatment initiation (week 0) and 1 year later (week 48) were assayed for levels of ART (6), suggesting an effect of HIV in- high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and the soluble receptors of fection itself. tumor necrosis factor-␣ (sTNFR1 and sTNFR2). Systemic inflammation has been asso- ciated with incident diabetes in multiple RESULTS — Case subjects were older than control subjects (median age 41 vs. 37 years, P ϭ cohorts in the general population (7–9). 0.001), but the groups were otherwise comparable. Median levels for all markers, except hs-CRP, Proinflammatory cytokines, such as tu- decreased from week 0 to week 48. Subjects with higher levels of hs-CRP, sTNFR1, and sTNFR2 mor necrosis factor (TNF)-␣, may induce at 48 weeks had an increased odds of subsequent diabetes, after adjustment for baseline marker insulin resistance by binding to insulin- Ͻ Ͼ 3 level, age, BMI at week 48, CD4 count at week 48 ( vs. 200 cells/mm ), and indinavir use (all responsive elements in skeletal muscle P Յ 0.05). After further adjustment for week 48 glucose, effects were attenuated and only trend (10). Among HIV-infected patients, sTNFR1 remained significant (odds ratio, highest quartile vs. lowest 23.2 [95% CI 1.28–423], P ϭ 0.03). markers of systemic inflammation de- crease quickly with ART initiation (11) CONCLUSIONS — Inflammatory markers 48 weeks after ART initiation were associated but do not normalize (12). It is speculated with increased risk of diabetes. These findings suggest that systemic inflammation may contrib- that this residual inflammation with effec- ute to diabetes pathogenesis among HIV-infected patients. tive ART may contribute to the pathogen- esis of comorbidities in HIV-infected Diabetes Care 33:2244–2249, 2010 patients, including diabetes (13). We un- dertook a case-control study, nested ith the advent of effective antiret- occur commonly in HIV-infected pa- within an observational study of the AIDS roviral therapy (ART), morbidity tients, and some cohorts have shown a Clinical Trial Group (ACTG) to determine W and mortality have decreased higher than expected risk of insulin resis- whether markers of systemic inflamma- dramatically among HIV-infected pa- tance and diabetes compared with that for tion measured 48 weeks after ART ini- tients and the proportion of older HIV- HIV-negative control populations (1,2). tiation were associated with the develop- infected patients is rising. As a result, The etiology is multifactorial. Certain ment of diabetes. aging-related comorbidities, such as dia- protease inhibitors, such as indinavir betes, have become increasingly impor- (IDV), lopinavir, and ritonavir, have been RESEARCH DESIGN AND tant in the management of HIV-infected shown to reversibly induce insulin resis- METHODS — The ACTG Longitudi- patients. tance, probably by inhibition of glucose nal Linked Randomized Trials (ALLRT) Abnormalities in glucose metabolism translocation through GLUT4 (3). The cohort was designed to enroll HIV- infected individuals previously random- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● ized into approved parent ACTG clinical From the 1Division of Endocrinology and Metabolism, Johns Hopkins University, Baltimore, Maryland; the trials (parent studies) for the purpose of 2Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts; the evaluating clinical, virological, immuno- 3 4 Division of Infectious Diseases, University of Hawaii, Honolulu, Hawaii; and the Division of Pediatric logical, metabolic, and pharmacological Infectious Diseases and Rheumatology, Case School of Medicine, Cleveland, Ohio. Corresponding author: Todd T. Brown, [email protected]. outcomes associated with long-term Received 6 April 2010 and accepted 17 July 2010. Published ahead of print at http://care.diabetesjournals. treatment with potent ARTs. Individuals org on 27 July 2010. DOI: 10.2337/dc10-0633. could be treatment-naive or treatment- © 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly experienced at entry into their parent cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. study. Enrollment into ALLRT began in org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby January 2000. As of October 2008, 3,405 marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. previously treatment-naive individuals 2244 DIABETES CARE, VOLUME 33, NUMBER 10, OCTOBER 2010 care.diabetesjournals.org Brown and Associates and 1,225 treatment-experienced indi- range from 4.4 to 7.6% coefficient of vari- Conditional logistic regression was viduals were enrolled into ALLRT. All ation (average 5.6% coefficient of varia- used to model the association between subjects provided written informed con- tion). The sensitivity of this assay system week 48 levels of each inflammatory sent, and each ACTG study site received for these cytokines ranged from 0.5 to 16 marker and diabetes incidence, taking approval from the designated institu- pg/ml. C-reactive protein was measured into account matching and adjusting for tional review board before protocol initi- using a highly sensitive ELISA (ALPCO the other potential confounders. The low- ation. Details of the ALLRT protocol have Diagnostics, Windham, NH). The linear est marker quartile was the reference cat- been described previously (14). range of the assay standards is 0.0019– egory in each model. Each model The eligible population for this pro- 0.15 mg/l, and samples with values included categories of week 48 marker spective, nested case-control study in- greater than the highest standard were di- quartile, natural log-transformed baseline cluded all HIV-infected individuals from luted and reanalyzed. marker level and age. Model building pro- treatment-naive parent studies co- ceeded by adding, one at a time, univari- enrolled in ALLRT, with the exception of Measures ate predictors of diabetes (P Յ 0.10). P Յ parent studies for which ART data were Outcome. An incident case of diabetes 0.05 was considered statistically signifi- still blinded. Eligible individuals were re- was defined as having either two fasting cant. Variables that changed odds ratios quired to have had fasting or nonfasting blood glucose levels Ն126 mg/dl (or two by Ն15% were kept in the model as po- blood glucose measurements before and consecutive nonfasting blood glucose lev- tential confounders. To assess trend in di- after ART initiation and during the fol- els Ն200 mg/dl) or a diagnosis of diabetes abetes incidence over marker quartiles, low-up period, as well as plasma samples recorded in the medical record. The first quartiles for each marker were included taken at the time of treatment initiation high glucose level and the diagnosis date in the model as ordinal variables. Because and at week 48, for measurement of in- had to occur at least 1 year after ART of concern that hyperglycemia in the non- flammatory markers. We used data sub- initiation. diabetic range may lead to inflammation, mitted to our data management center as Inflammatory markers. Week 48 levels we reevaluated each model after adjust- of October 2008. of high-sensitivity (hs-CRP), interleukin ment for glucose values at 48 weeks. In All potential case or control subjects (IL)-6, and the soluble receptors of tumor these models, a variable indicating were required to have fasting or non- necrosis factor-␣ (sTNFR1 and sTNFR2) whether the glucose determination was fasting blood glucose levels Ͻ100 mg/dl were each grouped into quartiles. Base- made in the fasting state (yes or no) was at the time of treatment initiation (base- line levels of each marker were natural also included. line) or within 16 weeks after initiation log-transformed. and could not have a history of hypo- In addition to the matching factors RESULTS — Of the 3,405 individuals glycemic medication use or diabetes. All BMI at baseline and race/ethnicity (white from the treatment-naive studies enrolled individuals who developed diabetes Ն1 non-Hispanic, black non-Hispanic, and as of October 2008, 1,217 were from par- years after
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