Soluble and Cell-associated Insulin Receptor Dysfunction Correlates with Severity of HAND in HIV-infected Women

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 May 26

PMID 22629383

Citations 13

Authors

Yamil Gerena

Richard L Skolasky

Joyce M Velez

Dianedis Toro-Nieves

Raul Mayo

Avindra Nath

Valerie Wojna

Affiliations

Soon will be listed here.

Abstract

Background: 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, 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.

Objective: To 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 Results: This 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.

Conclusions: This 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.

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Soluble Insulin Receptor Levels in Plasma, Exosomes, and Urine and Its Association With HIV-Associated Neurocognitive Disorders.

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References

Kaul M . HIV-1 associated dementia: update on pathological mechanisms and therapeutic approaches. Curr Opin Neurol. 2009; 22(3):315-20. PMC: 2779773. DOI: 10.1097/WCO.0b013e328329cf3c. View

Valcour V, Shikuma C, Shiramizu B, Williams A, Watters M, Poff P . Diabetes, insulin resistance, and dementia among HIV-1-infected patients. J Acquir Immune Defic Syndr. 2004; 38(1):31-6. PMC: 1415271. DOI: 10.1097/00126334-200501010-00006. View

Wojna V, Skolasky R, McArthur J, Maldonado E, Hechavarria R, Mayo R . Spanish validation of the HIV dementia scale in women. AIDS Patient Care STDS. 2007; 21(12):930-41. DOI: 10.1089/apc.2006.0180. View

Antinori A, Arendt G, Becker J, Brew B, Byrd D, Cherner M . Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007; 69(18):1789-99. PMC: 4472366. DOI: 10.1212/01.WNL.0000287431.88658.8b. View

Sacktor N, McDermott M, Marder K, Schifitto G, Selnes O, McArthur J . HIV-associated cognitive impairment before and after the advent of combination therapy. J Neurovirol. 2002; 8(2):136-42. DOI: 10.1080/13550280290049615. View

Cohen R, Gongvatana A . The persistence of HIV-associated neurocognitive dysfunction and the effects of comorbidities. Neurology. 2010; 75(23):2052-3. DOI: 10.1212/WNL.0b013e318200d833. View

Levine S . Molecular mechanisms of soluble cytokine receptor generation. J Biol Chem. 2008; 283(21):14177-81. PMC: 2386928. DOI: 10.1074/jbc.R700052200. View

Ragin A, Storey P, Cohen B, Edelman R, Epstein L . Disease burden in HIV-associated cognitive impairment: a study of whole-brain imaging measures. Neurology. 2004; 63(12):2293-7. PMC: 3462070. DOI: 10.1212/01.wnl.0000147477.44791.bd. View

Demsky Y, Gass C, Golden C . Interpretation of VIQ-PIQ and intersubtest differences on the Spanish version of the WAIS. Assessment. 1998; 5(1):25-30. DOI: 10.1177/107319119800500105. View

10.

Maschke M, Kastrup O, Esser S, Ross B, Hengge U, Hufnagel A . Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART). J Neurol Neurosurg Psychiatry. 2000; 69(3):376-80. PMC: 1737101. DOI: 10.1136/jnnp.69.3.376. View

11.

Shapshak P, Kangueane P, Fujimura R, Commins D, Chiappelli F, Singer E . Editorial neuroAIDS review. AIDS. 2010; 25(2):123-41. PMC: 4464840. DOI: 10.1097/QAD.0b013e328340fd42. View

12.

Bateman J, McNeill H . Insulin/IGF signalling in neurogenesis. Cell Mol Life Sci. 2006; 63(15):1701-5. PMC: 11136372. DOI: 10.1007/s00018-006-6036-4. View

13.

Howard A, Floris-Moore M, Arnsten J, Santoro N, Fleischer N, Lo Y . Disorders of glucose metabolism among HIV-infected women. Clin Infect Dis. 2005; 40(10):1492-9. PMC: 2104646. DOI: 10.1086/429824. View

14.

McArthur J, Brew B . HIV-associated neurocognitive disorders: is there a hidden epidemic?. AIDS. 2010; 24(9):1367-70. DOI: 10.1097/QAD.0b013e3283391d56. View

15.

Chiu S, Cline H . Insulin receptor signaling in the development of neuronal structure and function. Neural Dev. 2010; 5:7. PMC: 2843688. DOI: 10.1186/1749-8104-5-7. View

16.

Tebas P . Insulin resistance and diabetes mellitus associated with antiretroviral use in HIV-infected patients: pathogenesis, prevention, and treatment options. J Acquir Immune Defic Syndr. 2008; 49 Suppl 2:S86-92. DOI: 10.1097/QAI.0b013e31818651e6. View

17.

Hotamisligil G . Inflammation and metabolic disorders. Nature. 2006; 444(7121):860-7. DOI: 10.1038/nature05485. View

18.

Ronnemaa E, Zethelius B, Sundelof J, Sundstrom J, Degerman-Gunnarsson M, Berne C . Impaired insulin secretion increases the risk of Alzheimer disease. Neurology. 2008; 71(14):1065-71. DOI: 10.1212/01.wnl.0000310646.32212.3a. View

19.

Sesti G . Pathophysiology of insulin resistance. Best Pract Res Clin Endocrinol Metab. 2006; 20(4):665-79. DOI: 10.1016/j.beem.2006.09.007. View

20.

Valcour V, Sacktor N, Paul R, Watters M, Selnes O, Shiramizu B . Insulin resistance is associated with cognition among HIV-1-infected patients: the Hawaii Aging With HIV cohort. J Acquir Immune Defic Syndr. 2006; 43(4):405-10. DOI: 10.1097/01.qai.0000243119.67529.f5. View