Abstract
BackgroundBlood sugar metabolism abnormalities have been identified in HIV-infected individuals and associated with HIV-associated neurocognitive disorders (HAND). These abnormalities may occur as a result of chronic HIV infection, long-term use of combined antiretroviral treatment (CART), aging, genetic predisposition, or a combination of these factors, and may increase morbidity and mortality in this population.ObjectiveTo determine if changes in soluble and cell-associated insulin receptor (IR) levels, IR substrate-1 (IRS-1) levels, and IRS-1 tyrosine phosphorylation are associated with the presence and severity of HAND in a cohort of HIV-seropositive women.Methods and ResultsThis is a retrospective cross-sectional study using patient database information and stored samples from 34 HIV-seropositive women and 10 controls without history of diabetes from the Hispanic-Latino Longitudinal Cohort of Women. Soluble IR subunits [sIR, ectodomain (α) and full-length or intact (αβ)] were assayed in plasma and CSF samples by ELISA. Membrane IR levels, IRS-1 levels, and IRS-1 tyrosine phosphorylation were analyzed in CSF white cell pellets (WCP) using flow cytometry.HIV-seropositive women had significantly increased levels of intact or full-length sIR in plasma (p<0.001) and CSF (p<0.005) relative to controls. Stratified by HAND, increased levels of full-length sIR in plasma were associated with the presence (p<0.001) and severity (p<0.005) of HAND. A significant decrease in IRS-1 tyrosine-phosphorylation in the WCP was also associated with the presence (p<0.02) and severity (p<0.02) of HAND.ConclusionsThis study provides evidence that IR secretion is increased in HIV-seropositive women, and increased IR secretion is associated with cognitive impairment in these women. Thus, IR dysfunction may have a role in the progression of HAND and could represent a biomarker for the presence and severity of HAND.
Highlights
The prevalence of HIV-associated neurocognitive disorders (HAND) has increased due to the widespread use of combined antiretroviral treatment (CART) and resulting longer survival of HIV-infected patients [1,2,3]
This study provides evidence that insulin receptor (IR) secretion is increased in HIV-seropositive women, and increased IR secretion is associated with cognitive impairment in these women
IR dysfunction may have a role in the progression of HAND and could represent a biomarker for the presence and severity of HAND
Summary
The prevalence of HIV-associated neurocognitive disorders (HAND) has increased due to the widespread use of combined antiretroviral treatment (CART) and resulting longer survival of HIV-infected patients [1,2,3]. In the United States, HAND’s prevalence among HIV-infected individuals on CART is as high as 50%, and HAND continues to be a significant cause of morbidity in chronically infected patients [4,5]. Insulin resistance and diabetes have been associated with risk of cognitive impairment and dementia in the general population [19,25,26,27,28,29] and in patients with HIV [12,13]. Blood sugar metabolism abnormalities have been identified in HIV-infected individuals and associated with HIV-associated neurocognitive disorders (HAND) These abnormalities may occur as a result of chronic HIV infection, longterm use of combined antiretroviral treatment (CART), aging, genetic predisposition, or a combination of these factors, and may increase morbidity and mortality in this population
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