HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Koster, J. C. Articles by Hruz, P. W. Search for Related Content PubMed PubMed Citation Articles by Koster, J. C. Articles by Hruz, P. W. Social Bookmarking                What's this?

HIV Protease Inhibitors Acutely Impair Glucose-Stimulated Insulin Release

¹ Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri
² Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri

HIV protease inhibitors (PIs) acutely and reversibly inhibit the insulin-responsive glucose transporter Glut 4, leading to peripheral insulin resistance and impaired glucose tolerance. Minimal modeling analysis of glucose tolerance tests on PI-treated patients has revealed an impaired insulin secretory response, suggesting additional pancreatic ß-cell dysfunction. To determine whether ß-cell function is acutely affected by PIs, we assayed glucose-stimulated insulin secretion in rodent islets and the insulinoma cell line MIN6. Insulin release from MIN6 cells and rodent islets was significantly inhibited by the PI indinavir with IC₅₀ values of 1.1 and 2.1 µmol/l, respectively. The uptake of 2-deoxyglucose in MIN6 cells was similarly inhibited (IC₅₀ of 2.0 µmol/l), whereas glucokinase activity was unaffected at drug levels as high as 1 mmol/l. Glucose utilization was also impaired at comparable drug levels. Insulin secretogogues acting downstream of glucose transport mostly reversed the indinavir-mediated inhibition of insulin release in MIN6 cells. Intravenous infusion of indinavir during hyperglycemic clamps on rats significantly suppressed the first-phase insulin response. These data suggest that therapeutic levels of PIs are sufficient to impair glucose sensing by ß-cells. Thus, together with peripheral insulin resistance, ß-cell dysfunction likely contributes to altered glucose homeostasis associated with highly active antiretroviral therapy.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				E. L. Bradshaw, X.-A. Li, T. Guerin, W. V. Everson, M. E. Wilson, A. J. Bruce-Keller, R. N. Greenberg, L. Guo, S. A. Ross, and E. J. Smart Nucleoside reverse transcriptase inhibitors prevent HIV protease inhibitor-induced atherosclerosis by ubiquitination and degradation of protein kinase C Am J Physiol Cell Physiol, December 1, 2006; 291(6): C1271 - C1278. [Abstract] [Full Text] [PDF]

				Y. Neye, M. Dufer, G. Drews, and P. Krippeit-Drews HIV Protease Inhibitors: Suppression of Insulin Secretion by Inhibition of Voltage-Dependent K+ Currents and Anion Currents J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 106 - 112. [Abstract] [Full Text] [PDF]

				A. K. Gupta, G. J. Cerniglia, R. Mick, W. G. McKenna, and R. J. Muschel HIV Protease Inhibitors Block Akt Signaling and Radiosensitize Tumor Cells Both In vitro and In vivo Cancer Res., September 15, 2005; 65(18): 8256 - 8265. [Abstract] [Full Text] [PDF]

				H. Zhou, W. M. Pandak Jr., V. Lyall, R. Natarajan, and P. B. Hylemon HIV Protease Inhibitors Activate the Unfolded Protein Response in Macrophages: Implication for Atherosclerosis and Cardiovascular Disease Mol. Pharmacol., September 1, 2005; 68(3): 690 - 700. [Abstract] [Full Text] [PDF]

				L. Q. Hong-Brown, A. M. Pruznak, R. A. Frost, T. C. Vary, and C. H. Lang Indinavir alters regulators of protein anabolism and catabolism in skeletal muscle Am J Physiol Endocrinol Metab, September 1, 2005; 289(3): E382 - E390. [Abstract] [Full Text] [PDF]

				P. El Beitune, G. Duarte, M. C. Foss, R. M. Montenegro Jr, S. M. Quintana, E. A. Figueiro-Filho, and A. A. Nogueira Effect of Maternal Use of Antiretroviral Agents on Serum Insulin Levels of the Newborn Infant Diabetes Care, April 1, 2005; 28(4): 856 - 859. [Abstract] [Full Text] [PDF]

				A. Bitnun, E. Sochett, P. T. Dick, T. To, C. Jefferies, P. Babyn, J. Forbes, S. Read, and S. M. King Insulin Sensitivity and {beta}-Cell Function in Protease Inhibitor-Treated and -Naive Human Immunodeficiency Virus-Infected Children J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 168 - 174. [Abstract] [Full Text] [PDF]

				J. Hertel, H. Struthers, C. B. Horj, and P. W. Hruz A Structural Basis for the Acute Effects of HIV Protease Inhibitors on GLUT4 Intrinsic Activity J. Biol. Chem., December 31, 2004; 279(53): 55147 - 55152. [Abstract] [Full Text] [PDF]

				M Schutt, J Zhou, M Meier, and H H Klein Long-term effects of HIV-1 protease inhibitors on insulin secretion and insulin signaling in INS-1 beta cells J. Endocrinol., December 1, 2004; 183(3): 445 - 454. [Abstract] [Full Text] [PDF]