Insulin resistance is a contributor to the metabolic syndrome, a cluster of risk factors (in childhood including abdominal obesity, hypertriglyceridemia, low HDL cholesterol, hypertension, and elevated fasting plasma glucose)  that predisposes to CVD and type 2 diabetes. This was first described in HIV-infected adults 35 years ago . The exact etiology of insulin resistance in the HIV setting remains unknown, but is likely multifactorial, with contributions from traditional risk factors (e.g. obesity, family history, and racial/ethnic background), comorbid conditions (e.g. hepatitis C virus infection), Antiretroviral-related factors (e.g. direct effects of protease inhibitors, cumulative exposure to nucleoside reverse transcriptase inhibitors, hepatic steatosis, and fat redistribution), and HIV itself (e.g. chronic inflammation) . Mechanistically, insulin resistance may result from an abnormal hormonal secretory profile by adipose tissue; noncompetitive, reversible direct inhibition of the insulin-responsive facilitative glucose transporter isoform 4 (GLUT4) in muscle and fat; and/or mitochondrial abnormalities including reduction in mitochondrial DNA (mtDNA) copies/cell and decreased oxygen consumption [18–22].
We demonstrate in this study that the prevalence of insulin resistance in the PHIV+ children in PHACS/AMP was 27.3 and 34.1% in the PHEU group. After adjustments for Tanner stage, age, sex, and race/ethnicity, however, there was no significant difference in the prevalence of insulin resistance between the two groups. In this report, insulin resistance in the PHIV+ cohort was almost twice as prevalent as in our prior study ; however, only five of 62 individuals who developed insulin resistance over time had an abnormality of glucose tolerance (versus 10 of 45 with insulin resistance in our previous study) and none met criteria for diabetes in either study. This contrasts with two cases of diabetes at baseline, with no incident cases, and no cases of IFG at baseline and two incident cases in the National Institute of Child Health and Human Development International Site Development Initiative (NISDI) Pediatric Latin American Countries Epidemiologic Study (PLACES) cohort . This increase in prevalence of insulin resistance in the current study (compared to our prior report) is likely related to the older age and greater degree of pubertal maturation in the current PHIV cohort. Use of a central laboratory for assessment of insulin and glucose compared to local laboratories, as was done in the previous analysis, may also account for some of the difference in prevalence of insulin resistance among PHIV in both studies. The prevalence of insulin resistance in HIV+ youth in other recent smaller studies ranged from 5.3 to 6.8% in Latin America [8,23], 10.0% in South Africa , 11.2–40.7% in Spain [4,7,24,25], and 42.9% in Thailand . A possible explanation for these disparate results includes the fact that different definitions of insulin resistance by HOMA are used in different series, reflecting a failure to adjust for the normally lower insulin sensitivity that occurs during puberty compared with prepuberty. Historically, the reported prevalence of insulin resistance is 25–33% in HIV-infected adults . Of note, our current prevalence in HIV+ youth approximates the 34.9% prevalence of insulin resistance by HOMA-IR recently reported in 219 HIV-infected Peruvian adults with HIV on highly active ART .
In a previous study of this cohort, PHEU children had higher BMI z scores than did PHIV+, and were more likely to be obese . Our finding of an approximately 30% prevalence of insulin resistance in both groups in the current analysis is substantially higher than the prevalence reported in over 2000 Korean nonoverweight, nonobese healthy adolescents (4.9%) , but mirrors the high prevalence of insulin resistance found in otherwise healthy obese youth. In a study of 1356 obese youth (2–19 years), 53.8% of 9–11-year-olds, and 79.3% of those more than 12 years old manifested insulin resistance by HOMA-IR, although the cutoff used of 2.5 did not take into account the naturally decreased insulin sensitivity of puberty . In a study of 100 obese Spanish youth (11.6 ± 2.7 years), the prevalence of insulin resistance was 29% by HOMA-IR . Of note, other methods of assessment of insulin resistance may yield different prevalence of insulin resistance. For example, in the aforementioned Spanish study of non-HIV-infected obese youth, when defining insulin resistance by serum insulin responses to an oral glucose load, the prevalence of insulin resistance increased to 50% , which may reflect greater sensitivity of detection of insulin resistance derived from 2-h OGTT glucose and insulin data than by fasting values alone . The gold standard for quantifying insulin resistance in adolescents is the euglycemic hyperinsulinemic clamp. The frequently sampled intravenous glucose tolerance test (FSIVGTT) and steady-state plasma glucose (SSPG) methods are also valid measurements. However, for large cohort studies, these methods are labor-intensive, require intravenous infusions and frequent blood sampling, are burdensome for participants, are expensive, and require a research setting for optimal performance .
Longitudinal data regarding the natural history of insulin resistance in HIV+ children are relatively sparse . In a Latin American cohort, 3.8% developed insulin resistance during follow-up (in addition to 5.5% of children who had insulin resistance at baseline) . In multivariable analyses, only higher BMI z score and waist circumference were significantly associated with development of new insulin resistance in our study, although females had a marginally significantly increased risk of insulin resistance compared with males. Conversely, only male sex and lower BMI z score were associated with resolution of insulin resistance, although in the model including waist circumference, use of lopinavir/ritonavir at baseline was significantly associated with an over two-fold rate of resolution compared with no use at baseline. A lower waist circumference was also marginally associated with resolution of insulin resistance. The associations of female gender and increased BMI/waist circumference are not unexpected as these are well known to predict risk of insulin resistance in healthy populations . Thus, it stands to reason then that resolution of insulin resistance would be greater in males and with decreasing BMI/waist circumference even in an HIV+ population.
Other studies have suggested a relationship between the use of protease inhibitors and insulin resistance. The association of improvement in insulin sensitivity that we found with usage of lopinavir/ritonavir is somewhat unexpected and of unclear etiology. Lack of adherence to lopinavir/ritonavir is an unlikely explanation given that viral loads were higher during follow-up among those whose insulin resistance did not resolve. In normal men, short-term use of this combination leads to a deterioration in glucose tolerance at the 2-h time point of an OGTT, without a significant change in insulin-mediated glucose disposal rate as determined by a euglycemic hyperinsulinemic clamp . In a cross-sectional study in consecutive HIV-infected adults treated with regimens containing efavirenz, lopinavir/ritonavir, or atazanavir, HOMA-IR was greatest in those individuals treated with lopinavir/ritonavir . Furthermore, in adult men with HIV, the incidence of insulin resistance and metabolic syndrome was increased by use of lopinavir/ritonavir .
Factors known to be associated with increasing insulin resistance in healthy children also include puberty and race/ethnicity . Puberty was not a factor in our comparison between PHIV and PHEU youth as we adjusted for Tanner stage in statistical analysis. As to race/ethnicity, there were no significant differences between groups recognizing that insulin resistance is ordinarily most common in African Americans and Hispanics, which constituted the bulk of our cohort (∼90% in both groups) perhaps making it difficult to detect differences between other races/ethnicities.
There are strengths and limitations to the study. This is a well characterized longitudinal cohort in which glucose and insulin levels were assayed in a central laboratory to standardize measurements. We may have had limited power to detect differences in the incidence or resolution of insulin resistance by factors that are not common and we needed to impute Tanner staging in some participants who had not reached Tanner stage 5. Additionally, allocation to treatment with antiretrovirals was not randomized so that these drugs may have been used differently in groups that also had different insulin resistance risks.
Although only a small percentage of those youth in our study with insulin resistance, even when persistent, had associated disturbances in glucose metabolism, the possibility of future abnormalities, including type 2 diabetes, as well as development of other components of the metabolic syndrome, that is, high blood pressure and unfavorable lipid profiles, remains a concern as HIV-infected youth face an increasing risk of obesity in adulthood and a lifetime exposure to both HIV disease and its treatment.
We thank the children and families for their participation in PHACS, and the individuals and institutions involved in the conduct of PHACS.
The following institutions, clinical site investigators, and staff participated in conducting PHACS AMP and AMP Up in 2015, in alphabetical order: Ann & Robert H. Lurie Children's Hospital of Chicago: Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter; Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, Lynnette Harris; Bronx Lebanon Hospital Center: Murli Purswani, Mahboobullah Baig, Anna Cintron; Children's Diagnostic & Treatment Center: Ana Puga, Sandra Navarro, Patricia A. Garvie, James Blood; Children's Hospital, Boston: Sandra K. Burchett, Nancy Karthas, Betsy Kammerer; Jacobi Medical Center: Andrew Wiznia, Marlene Burey, Molly Nozyce; Rutgers – New Jersey Medical School: Arry Dieudonne, Linda Bettica; St. Christopher's Hospital for Children: Janet S. Chen, Maria Garcia Bulkley, Latreaca Ivey, Mitzie Grant; St. Jude Children's Research Hospital: Katherine Knapp, Kim Allison, Megan Wilkins; San Juan Hospital/Department of Pediatrics: Midnela Acevedo-Flores, Heida Rios, Vivian Olivera; Tulane University School of Medicine: Margarita Silio, Medea Gabriel, Patricia Sirois; University of California, San Diego: Stephen A. Spector, Kim Norris, Sharon Nichols; University of Colorado Denver Health Sciences Center: Elizabeth McFarland, Juliana Darrow, Emily Barr, Paul Harding; University of Miami: Gwendolyn Scott, Grace Alvarez, Anai Cuadra.
This work was performed as part of the Pediatric HIV/AIDS Cohort Study (PHACS) which is supported by the NICHD with co-funding from NIAID, NIDA, NIMH, NIDCD, NHLBI, NINDS, and NIAAA, through cooperative agreements with the Harvard University School of Public Health (U01 HD052102-04) and the Tulane University School of Medicine (U01 HD052104-01). J.J. is also supported by NICHD K23HD070760 and M.G. is also supported by NIH/DHHS grant number P20 GM113134.
Authors’ contributions: T.L.M. and M.S. contributed to data collection; K.P. analyzed the data; M.E.G., D.L.J., J.W., T.L.M., R.H., M.G., T.S., M.S., J.J., J.K.T., R.B.V.D., and L.A.D. interpreted the data; and M.E.G. and K.P. drafted the manuscript. K.P. takes responsibility for the integrity of the data analysis. All authors revised the manuscript and approved the final version of manuscript.
The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard T.H. Chan School of Public Health (HD052102) (Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104) (Principal Investigator: Russell Van Dyke; Co-Principal Investigators: Kenneth Rich, Ellen Chadwick; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (Principal Investigator: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc. (Principal Investigator: Julie Davidson).
Note: The conclusions and opinions expressed in this article are those of the authors and do not necessarily reflect those of the National Institutes of Health or US Department of Health and Human Services.
Conflicts of interest
M.E.G. is a consultant to Daiichi-Sankyo and receives royalties from McGraw-Hill and UpToDate. L.A.D. has or had research contracts from Medtronic, Merck, Lexicon, Novo Nordisk, and Sanofi; serves on a data safety monitoring board for Janssen; has served on an advisory board for Merck; and receives royalties from Wolters Kluwer. K.P., D.L.J., J.W., T.LM., R.H., M.G., T.S., M.S., J.J., J.K.T., and R.B.V.D. have nothing to disclose.
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Keywords:Copyright © 2018 Wolters Kluwer Health, Inc.
BMI; homeostatic model assessment of insulin resistance; insulin resistance; oral glucose tolerance test; waist circumference