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AIDS:
Editorial Comment

HIV protease inhibitors and glucose metabolism

Grunfeld, Carl

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From the University of California, San Francisco, Veterans Affairs Medical Center, Metabolism Section 111F, San Francisco, California, USA.

Requests for reprints to: C. Grunfeld, University of California, San Francisco, Veterans Affairs Medical Center, Metabolism Section 111F, 4150 Clement Street, San Francisco, CA 94121, USA.

Received: 14 January 2002; accepted: 14 January 2002.

See also pp. 859

Beginning with early reports of hyperglycemia associated with HIV protease inhibitor (PI) drugs through recent studies of insulin resistance, it has become evident that these highly effective drugs have side-effects that must be understood and taken into account clinically [1]. It is also apparent that the effects of PI on glucose and lipid metabolism need to be examined independently of syndromes of fat redistribution or lipodystrophy, which occur in patients who have never been treated with PI [2,3].

Our understanding of these effects of therapy is increasing. Earlier, Murata et al. reported that PI blocked the transport of glucose via the transporter Glut4 [4]. Activation of Glut4 by insulin is essential to storage of glucose in muscle and fat after a meal. They showed that in the presence of a PI, insulin action was normal, with activation of the complex kinase cascade induced by insulin and translocation of Glut4 from internal vesicles to the plasma membrane; however the transport of glucose was inhibited. Indeed, using transfection of Xenopus eggs, an insulin-in dependent model, PI were shown to block Glut4, but not Glut1. The effects of PI were rapid – occurring within minutes.

However, several questions remained that are answered in this issue of AIDS [5] and elsewhere. There were concerns that the concentrations of PI required for these effects were too high to be meaningful in vivo and questions arose about specificity. In this report, Murata, Hruz and Muekler show that PI at therapeutic concentrations (3–11 μM) block glucose transport in rat adipocytes, the classic cell for studying insulin action [5]. The effects are more sensitive than shown with Xenopus or 3T3-L1 cultured fat cells. Given the non-competitive nature of the Glut4 inhibition, a proper membrane environment can be key. The effects are very specific for Glut4, with no activity against Glut1, the basal transporter. There was minimal inhibition of Glut2, with an apparent KI 10-fold higher than for Glut4. That finding does raise the possibility of some in vivo blockade of Glut2, found in intestine, liver and pancreatic β-cells, which are located in the portal circulation, where levels may be higher during absorption of PI.

The work of Murata et al. suggests that the first metabolic effect of PI is on glucose disposal, with little other effect on insulin action [4,5]. This proposal is consistent with recent data from our group, where one PI, indinavir, when given for 4 weeks to HIV-seronegative individuals, was shown to block insulin-mediated glucose disposal, but have no effects on lipids [6]. It is likely that some of the effects of PI on lipid metabolism are drug-specific [7,8] and others secondary restoration to health or changes in body composition [1].

Another implication is that the effects of PI on glucose metabolism are rapid, which has now been shown in vivo. Hruz et al. have shown that PI block the uptake of glucose into muscles in animals with a rapid onset and offset [9]. We have shown that PI block insulin-stimulated glucose disposal within 30 min of administration to HIV-seronegative humans [10]. Given the concentration dependence presented in this issue [5], these studies suggest that the maximal effect will be seen when the drug is at near peak levels, which may explain the more impressive effects of PI during glucose tolerance testing [11], where maximal activation of Glut4 coincides with maximal PI levels after a morning dose. However, the effects of a PI may be missed if the morning dose is omitted and trough levels are in the circulation, a common event clinically, particularly with PI that are recommended to be taken with food.

These data emphasize the importance of studying the metabolic effects of each PI and other anti-retroviral drugs in the fasting state and during glucose disposal, with measurements of PI levels. The effects of each drug needs to be evaluated independently of the changes in fat distribution being reported in HIV infection. Indeed, many should be studied independently of HIV infection itself, as in the papers discussed above.

While further studies are needed, enough is known that we may begin to characterize the metabolic effects of each antiretroviral drug. These effects and family histories of diabetes and/or hyperlipidemia now need to be considered when planning strategies for sequential regimens for inhibiting HIV. Hopefully, in the near future there will be adequate virologic, immunolgic and metabolic data to plan rational regimens for specific patients. Finally, with these studies and others, new generations of drugs may be designed that do not have metabolic side-effects.

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References

1. Safrin S, Grunfeld C. Fat distribution and metabolic changes in patients with HIV infection [editorial]. AIDS 1999, 13: 2493–2505.

2. Lo JC, Mulligan K, Tai VW, Algren H, Schambelan M. ` Buffalo hump’ in men with HIV-1 infection. Lancet 1998, 351: 867–870.

3. Saint-Marc T, Partisani M, Poizot-Martin I. et al. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS 1999, 13: 1659–1667.

4. Murata H, Hruz PW, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem 2000, 275: 20251–20254.

5. Murata H, Hruz PW, Mueckler M. Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. AIDS 2002, 16: 859–863.

6. Noor MA, Lo JC, Mulligan K. et al. Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS 2001, 15: F11–F18.

7. Periard D, Telenti A, Sudre P. et al. Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study. Circulation 1999, 100: 700–705.

8. Purnell JQ, Zambon A, Knopp RH. et al. Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects. AIDS 2000, 14: 51–57.

9. Hruz PW, Murata H, Qiu H, Mueckler M. Indinavir induces acute and reversible insulin resistance in rats Diabetes (in press).

10. Noor MA, Seneviratne T, Aweeka FT. et al. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: A randomized, placebo-controlled study. AIDS 2002, 16: F1–F8.

11. Behrens G, Dejam A, Schmidt H. et al. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. AIDS 1999, 13: F63–F70.

Cited By:

This article has been cited 2 time(s).

Clinical Chemistry and Laboratory Medicine
Body composition and nutritional parameters in HIV and AIDS patients
Salomon, J; de Truchis, P; Melchior, JC
Clinical Chemistry and Laboratory Medicine, 40(): 1329-1333.

Croatian Medical Journal
Effect of rosiglitazone and metformin on insulin resistance in patients infected with human immunodeficiency virus receiving highly active antiretroviral therapy containing protease inhibitor: Randomized prospective controlled clinical trial
Silic, A; Janez, A; Tomazic, J; Karner, P; Vidmar, L; Sharma, P; Maticic, M
Croatian Medical Journal, 48(6): 791-799.
10.3325/cmj.2007.6.791
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Keywords:

HIV; protease inhibitors; indinavir; Glut4; insulin; glucose transport

© 2002 Lippincott Williams & Wilkins, Inc.

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