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Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: A randomized, placebo-controlled study

Noor, Mustafa A.a,b; Seneviratne, Taraa,b; Aweeka, Francesca T.c; Lo, Joan C.a,d; Schwarz, Jean-Marca,d,e; Mulligan, Kathleena,d; Schambelan, Morrisa,d; Grunfeld, Carla,b

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From the From the Department of aMedicine, University of California, the bMetabolism and Endocrine Sections, San Francisco Department of Veterans Affairs Medical Center, the Department of cPharmacology University of California, the dDivision of Endocrinology, San Francisco General Hospital, San Francisco and the eDepartment of Nutritional Sciences, University of California, Berkeley, Berkeley, California, USA.

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

Note: Presented in part at the Third International Workshop on Lipodystrophy and Adverse Drug Reactions in HIV. Athens, October 2001.

Received: 26 November 2001;

revised: 17 December 2001; accepted: 19 December 2001.

Sponsorship: Supported by a Pilot Study grant from the Center for AIDS Clinical Research at UCSF (CARC- 2000 to C.G.) and by grants from the Universitywide AIDS Research Program (ID01-SF-14 to C.G. and 99-SF-44 to M.N.) and the National Institutes of Health (NIH) DK52615 to K.M and DK45833 to M.S. The studies were conducted in the General Clinical Research Center at San Francisco General Hospital supported by a grant (RR-00083) from the National Center for Research Resources (NCRR), NIH. J.L. is a Clinical Associate Physician supported by the NCRR. C.G. is supported by the University of California AIDS Clinical Research Center and the Research Service of the Department of Veterans Affairs.

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Background: Therapy with HIV protease inhibitors (PI) causes insulin resistance even in the absence of HIV infection, hyperlipidemia or changes in body composition. The mechanism of the effects on insulin action is unknown. In vitro studies suggest that PI selectively and rapidly inhibit the activity of the insulin-responsive glucose transporter GLUT-4. We hypothesized that a single dose of the PI indinavir resulting in therapeutic plasma concentrations would acutely decrease insulin-stimulated glucose disposal in healthy human volunteers.

Methods: Randomized, double-blind, cross-over study comparing the effect of 1200 mg of orally administered indinavir and placebo on insulin-stimulated glucose disposal during a 180-min euglycemic, hyperinsulinemic clamp. Six healthy HIV-seronegative adult male volunteers were studied twice with 7 to 10 days between studies.

Results: There were no significant differences in baseline fasting body weight, or plasma glucose, insulin, lipid and lipoprotein levels between placebo- and indinavir-treated subjects. During steady-state (t60−−180 min) insulin reached comparable levels (394 ± 13 versus 390 ± 11 pmol/l) and glucose was clamped at approximately 4.4 mmol/l under both conditions. The average maximum concentration of indinavir was 9.4 ± 2.2 μM and the 2-h area under the curve was 13.5 ± 3.1 μM⋅h. Insulin-stimulated glucose disposal per unit of insulin (M/I) decreased in all subjects from 14.1 ± 1.2 to 9.2 ± 0.8 mg/kg⋅min per μ UI/ml (95% confidence interval for change, 3.7–6.1;P < 0.001) on indinavir (average decrease, 34.1 ± 9.2%). The non-oxidative component of total glucose disposal (storage) decreased from 3.9 ± 1.8 to 1.9 ± 0.9 mg/kg⋅min (P < 0.01). Free fatty acid levels were not significantly different at baseline and were suppressed equally with insulin administration during both studies.

Conclusions: A single dose of indinavir acutely decreases total and non-oxidative insulin-stimulated glucose disposal during a euglycemic, hyperinsulinemic clamp. Our data are compatible with the hypothesis that an acute effect of indinavir on glucose disposal in humans is mediated by a direct blockade of GLUT-4 transporters.

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Treatment of HIV-infected patients with protease inhibitors (PI) has been associated with insulin resistance [1–3], hyperglycemia and development of diabetes mellitus [4]. Longitudinal studies in HIV-positive patients indicate that initiation of regimens including indinavir [5] or a vartiety of PI drugs [6] are associated with the onset of insulin resistance prior to any changes in body composition. Recently, using measurements of fasting insulin levels, oral glucose tolerance testing and a euglycemic hyperinsulinemic clamp, we found that indinavir induces significant insulin resistance in healthy HIV-seronegative volunteers [7]. Because insulin resistance occurred before any significant changes in lipids and lipoprotein levels or body composition and in the absence of HIV infection, the earliest metabolic effect of PI may be their effect on carbohydrate metabolism.

The mechanism by which indinavir or other PI cause insulin resistance is unknown. In vitro studies using pre-adipocyte cells suggest that PI, including indinavir, directly interfere with the transport function of the insulin-regulated glucose transporter, GLUT-4 [8]. This effect is observed at near-peak concentrations (10 μM or 6140 ng/ml) of PI and is selectively specific for GLUT-4. More importantly, inhibition of glucose transport occurs within minutes, without any effects on intracellular signaling, which implies a direct effect of indinavir on the GLUT-4 transporters per se. Indinavir also decreases insulin- and contraction-stimulated glucose transport in isolated rat skeletal muscle in vitro [9], consistent with a selective and acute blockade of the GLUT-4 transporter.

GLUT-4 transporters are known to mediate glucose disposal and storage into insulin-responsive tissue in hyperinsulinemic states such as occurs post-prandially or during a euglycemic, hyperinsulinemic clamp procedure. Using this technique, we previously demonstrated a decrease in insulin-stimulated glucose disposal rate after 4 weeks of therapy with indinavir in healthy volunteers [7]. In this study, we now test the hypothesis that a single dose of indinavir sufficient to achieve therapeutic plasma concentrations in healthy volunteers would acutely decrease total and non-oxidative insulin-stimulated glucose during a euglycemic, hyperinsulinemic clamp.

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Six healthy men were recruited from staff at the University of California, San Francisco (UCSF) and from the community. The subjects had no history of medical illnesses (including nephrolithiasis), showed no abnormalities on screening physical examination or routine hematology and chemistry tests, had stable weight over the preceding 6 months and a negative HIV-1 antibody test prior to the study. The study protocol was approved by the Committee on Human Research of UCSF and informed consent was obtained from each subject.

Exclusion criteria included body mass index > 27 kg/m2, serum total cholesterol > 6.2 mmol/l, triglycerides > 3.8 mmol/l, fasting glucose > 7.0 mmol/l, serum aspartate or alanine aminotransferases > 50 U/l and creatinine > 124 μM.

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Study design

This was a randomized, double-blind, placebo- controlled, cross-over study. The subjects were instructed to abstain from vigorous exercise and to eat a diet containing at least 150 g of carbohydrates for 3 days prior to each study. During these 3-day periods, the subjects kept a diet journal, which was reviewed to assess dietary adherence. The subjects were admitted to the General Clinical Research Center (GCRC) at San Francisco General Hospital (SFGH) the evening prior to the study and began a 24-h urine collection. After an overnight (> 10 h) fast, blood was drawn for baseline studies at 0800 hours. The subjects randomly received either indinavir (Crixivan; Merck & Co., Rahway, New Jersey, USA) 1200 mg or placebo (kindly provided by Merck & Co.) at 0900 hours (t = 0), and underwent a euglycemic, hyperinsulinemic clamp procedure performed from 0900–1200 hours (t0−−180) by an investigator blinded to the study medication. The subjects completed a 24-h urine collection prior to discharge and returned to GCRC within 7–10 days at which time they were crossed over to the alternative treatment and the studies were repeated.

We chose a 1200 mg dose because indinavir plasma concentrations are highly variable, the time to peak concentration is less than 1 h and the half-life is only 1.8 h [10]. Because of these factors, we anticipated that in some subjects the administration of an 800 mg dose, as is typically used in three-times daily regimens, might not achieve and maintain plasma concentrations observed under steady-state conditions. Therefore, we surmised that a 1200 mg dose would assure plasma concentrations within the therapeutic range for the duration of the 3-h euglycemic hyperinsulinemic clamp procedure. It should be noted that 1200 mg is an indinavir dose that has been evaluated clinically in twice-daily regimens [11].

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Euglycemic hyperinsulinemic clamp

The clamp was performed as described by DeFronzo et al [12]. Teflon cannulae were placed into an antecubital vein for infusion and into a vein in the dorsum of the contralateral hand, which was kept in a heated box at 50–55°C, for arterialized venous blood sampling. Subjects fasted overnight prior to the procedure. At t = 0 min, insulin (Humulin R; Eli Lilly, Indianapolis, Indiana, USA) was administered as a primed continuous intravenous infusion for 10 min, followed by a constant infusion at the rate of 40 mU/m2⋅min until t = 180 min. Whole blood glucose concentration was measured every 5 min after the start of the insulin infusion. A variable infusion of 20% dextrose was used to maintain the plasma glucose concentration at 4.5 mmol/l with a coefficient of variation < 5% based on the negative feedback principle. Blood samples were also collected for post hoc determination of plasma glucose and serum insulin concentrations.

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Resting energy expenditure

O2 consumption and CO2 production were measured by indirect calorimetry (DeltaTrac metabolic monitor, Yorba Linda, California, USA). Non-protein respiratory quotient and substrate oxidation rates were calculated after correction for protein oxidation as estimated by urea nitrogen excretion measured in the 24-h urine collection [13]. The rate of non-oxidative glucose metabolism was calculated by subtracting the rate of carbohydrate oxidation from the rate of dextrose infusion during the clamp. At the insulin levels achieved during this procedure, hepatic glucose production is expected to be suppressed completely in healthy subjects.

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Fasting lipids and free fatty acids were measured by enzymatic colorimetric methods (Sigma Diagnostics, St. Louis, Missouri, USA and Wako Chemicals, Richmond, Virginia, USA, respectively). Whole blood and plasma glucose and lactate were measured using a glucose analyzer (YSI 2300 STAT-Plus Glucose & Lactate Analyzer, YSI Inc., Yellow Springs, Ohio, USA). Serum insulin levels were determined by Coat-A-Count radioimmunoassay (Diagnostic Products Corp, Los Angeles, California, USA) with intra-assay coefficient of variation of 7.3%, lower detection limit of 9.3 pmol/l and 20% cross reactivity with proinsulin.

Indinavir levels were measured by liquid chromatography, tandem mass spectrometry within the Drug Research Unit, SFGH. The method has a lower detection limit of 5 nM, inter- and intra-assay coefficient of variations ranging from 1.6 to 2.6 and 2.4 to 5.3 % respectively [14]. The area under the concentration time curve (AUC) during steady state (t60−−180 min) post-indinavir dosing was estimated using the linear–linear trapezoidal rule.

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Statistical analyses

Data were analyzed using Sigma Stat v. 2.03 (SPSS, Inc. San Rafael, California, UDS). Paired t tests were used for normally distributed data. One-way analysis of variance (ANOVA) was used to test for the difference between treatments in repeated measurements of glucose during the clamp procedure. Non-parametric data were analyzed using Mann–Whitney or Wilcoxon Rank Sum test. Data are presented as mean ± SEM. P-values are two-tailed.

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The subjects ranged in age from 31 to 52 years (mean, 37.7 ± 7.5 years); four were Caucasian, one was Asian and one was African–American. Baseline body weight, fasting serum insulin, plasma glucose, lipids and lipoprotein levels did not differ prior to each study (Table 1). The plasma level of indinavir reached a concentration of 9.4 ± 2.2 μM at t60 and remained > 4.5 μM for the duration of the study (Fig. 1). The 2-h AUC (AUC60−−180 ) was 13.5 ± 3.1 μM⋅h. During the euglycemic, hyperinsulinemic clamp, steady state (t60−−180 min) insulin levels of approximately 400 pmol/l (394 ± 13 versus 390 ± 11 pmol/l) and glucose levels of approximately 4.4 mmol/l (4.3 ± 0.2 versus 4.4 ± 0.2 mmol/l) were achieved and maintained until the end of the study (Fig. 2a).

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Table 1
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The rate of dextrose infusion required to maintain euglycemia during steady state was significantly lower in the study on indinavir compared to placebo (P < 0.05 by one-way ANOVA on repeated measures;Fig. 2b). Insulin-stimulated glucose disposal rate per unit of insulin (M/I) declined in all six subjects by an average of 34.1 ± 9.2% in the study on indinavir compared to placebo. Mean M/I decreased from 14.1 ± 1.2 to 9.2 ± 0.8 mg/kg⋅min per μ U/ml (95% confidence interval of the difference, 3.1–6.7;P < 0.001;Fig. 3a). The non-oxidative component of total glucose disposal decreased from 3.9 ± 1.8 to 1.9 ± 0.9 mg/kg⋅min (P < 0.01;Fig. 3b). Fasting free fatty acid levels were suppressed comparably with insulin administration in both studies (Fig. 4).

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Fig. 4
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Our results show that a single oral dose of the HIV PI indinavir induced insulin resistance in healthy HIV-negative volunteers. The onset of insulin resistance was rapid and occurred at plasma concentrations of indinavir approximating steady-state levels observed in HIV-infected patients maintained on standard clinical doses of this agent [15]. The magnitude of the decline in insulin-stimulated glucose disposal was approximately 34% and consistent in all subjects. Moreover, most of this reduction in glucose utilization was accounted for by a significant reduction in the rate of non-oxidative glucose disposal suggesting decreased glucose storage. The present finding, therefore, is compatible with the hypothesis that the first event leading to the development of impaired glucose tolerance and type II diabetes in patients treated with the PI indinavir is insulin resistance in skeletal muscle and adipocytes.

Muscle cells and adipocytes are the primary sites for insulin-stimulated glucose disposal [16]. In response to insulin signaling, specialized glucose transporter vesicles are translocated from intracellular sites to the plasma membrane, thereby facilitating transport of glucose into the cells [17,18]. GLUT-4 is the main insulin-responsive glucose transporter in both muscle and adipose tissue. Intracellular transport of glucose by GLUT-4 is a rate-limiting step in insulin-stimulated glucose disposal and the abundance of GLUT-4 in different muscle types correlates roughly with the ability of those muscles to take up glucose [19].

In vitro studies of the effect of PI on glucose uptake in 3T3-L1 adipocytes and skeletal muscle have shown that various PI including indinavir, amprenavir, ritonavir [8] and nelfinavir [9] when added at close to peak therapeutic concentration of 10 μM or greater, cause inhibition of insulin-stimulated glucose uptake. For example, at this concentration, indinavir caused a 26% inhibition of glucose uptake within minutes of addition to the culture medium [8]. Moreover, indinavir at 5 μM decreased both insulin- and contraction-stimulated glucose transport by average of 40% in isolated rat skeletal muscle [9]. The effect on insulin-stimulated glucose transport into muscle is also rapid and detectable after a 4-h incubation in the presence of indinavir (shorter incubation times were not tested). The 40% inhibition at 5 μM in isolated muscle is comparable to the 34% decline in glucose disposal we observed in the present study after a 1200 mg oral dose, and the 20% decrease reported by us previously with a dose of 800 mg three times daily [7]. Our findings in humans, therefore, are consistent and compatible with the observations made in vitro.

The concentrations of indinavir at which we conducted our study (mean Cmax 9.4 μM, AUC 13.5 μM⋅h) closely resemble those observed in pharmacokinetic studies of healthy volunteers (Cmax, 11.7 μM; AUC, 23.15 μM⋅h) [20]. Drug concentrations are important and may account for some of the discrepancies among published studies. For example, in vitro studies using indinavir at near-therapeutic concentrations of 10 μM or less for short incubations times (1 h) in both cultured cells [8] and isolated tissue [9] suggest that the mechanism of this effect is due directly to rapid blockade of the GLUT-4 transporters. At these concentrations, indinavir caused no defects in signaling pathways, particularly the phosphoinositide-3 kinase or protein kinase B phosphorylation in 3T3-L1 preadipocytes. A similar finding was reported by Caron et al. using 3T3-F442 preadiocytes, where incubation for up to 8 days in the presence of indinavir at 15 μM (10 μg/ml) did not alter tyrosine phosphorylation [21]. However, when used at supra-therapeutic concentrations of 100 μM for 48 h, indinavir impaired insulin signaling in HepG2 heptaoma cells [22]. Similarly another PI, nelfinavir, impaired insulin stimulation of protein kinase B phosphorylation [23]in vitro but only after 18 h of incubation at concentrations of ≥ 20 μM, nearly fourfold its Cmax of 5.2–5.6 μM in humans [24]. This effect was not observed at lower nelfinavir concentrations (≤ 10 μM) that are in the therapeutic range.

Our findings in human volunteers confirm that the metabolic defect caused by indinavir is rapid and detectable within minutes of achieving standard pharmacologic plasma concentrations of the drug. This strongly suggests a direct mechanism rather than a secondary effect on insulin signaling leading to an impaired ability to inhibit lipolysis. Consistent with this theory, we observed that free fatty acid levels were not acutely increased during euglycemic, hyperinsulinemic clamp and the suppressive effects of hyperinsulinemia on free fatty acid levels did not diminish following indinavir administration. This observation is further reinforced by our earlier published finding that free fatty acid levels were not increased even after 4 weeks of indinavir therapy [7]. Finally, the bulk of the change in glucose disposal rate was due to a decline in the rate of non-oxidative glucose disposal, the latter reflecting an acute decrease in the rate of glucose storage in muscle and adipocytes. Our findings in humans, therefore, are compatible with the hypothesis that the mechanism by which indinavir decreases insulin-stimulated glucose disposal may be a direct block in the uptake of glucose through the GLUT-4 transporter. Clinically, decreases in this order of magnitude in the rate of muscle glycogen synthesis and insulin-stimulated glucose disposal have been shown to contribute significantly to the development and pathophysiology of type II diabetes mellitus [25].

Although the first metabolic defect caused by PI to appear is inhibition of insulin-stimulated glucose disposal, probably through a blockade of the GLUT-4 transporter, other metabolic effects cannot be ruled out. For example, long-term exposure (30 days) to indinavir at concentrations of 15 μM inhibits preadipocyte differentiation presumably by altering the nuclear localization of the sterol regulatory element-binding protein-1 [22]. However, the effects of glucose deprivation due to long-term blockade of GLUT-4 by indinavir in these cell lines remains unclear. Thus, it is conceivable that with long-term exposure, additional metabolic effects beyond the effect on GLUT-4, such as hypertriglyceridemia, adipocyte de-differentiation and changes in body composition, may follow. Future studies are needed to determine the dose dependence and time-course of the effects of indinavir and other PI drugs in humans.

Recent insights in animal nutrition and fuel storage suggest that GLUT-4 may be more than a passive glucose transporter [26]. The data implicate a role for these transporters in the communication about nutritional status, fuel processing and storage between the muscle and adipose tissue. For example, selective knock-out of the GLUT-4 gene from fat cells results in a degree of insulin resistance similar to that seen with a muscle-specific knock-out [27]. Furthermore, the expression of this transporter is tissue specific and regulated by dietary intake [28]. This might explain how GLUT-4 could play an important role in regulating energy storage in adipose tissue. It is not known whether the longer term complications seen in HIV-infected patients (e.g. body fat redistribution) are manifestations of long-term GLUT-4 blockade or are due to other independent mechanisms. However, changes in body fat distribution have been reported in HIV-infected patients not on therapy with a PI, suggesting that blockade of GLUT-4 cannot be the sole mechanism accounting for these changes [29].

We have shown that the effect of indinavir on insulin-stimulated glucose disposal in vivo is rapid and of the same magnitude as that observed after 4 weeks. Recent data from animal studies suggest that this effect on glucose metabolism is also acutely reversible. Rats infused with indinavir developed insulin resistance, which reversed rapidly within 4 h of discontinuation of indinavir [30]. The rapid onset of the effects of indinavir and other PI have practical implications for studies of PI-induced insulin resistance. If the morning dose of a PI is omitted before measurement of fasting glucose and insulin, a lower effect may be seen, as PI levels will be in the trough range. For PI that are to be taken with meals (e.g. nelfinavir, ritonavir and lopinavir) holding the drug before study may be common. Consistent dosing is needed to understand the comparative effects of PI and timing of PI ingestion may explain some differences between studies. The delay in peak plasma concentration may also contribute to more profound effects seen in certain metabolic studies such as oral glucose tolerance testing, where the peak plasma levels may coincide with the critical 2-h time point. In the present study, we did not assess the acute effects of a single dose of indinavir on more conventional measures of insulin resistance such as fasting glucose and insulin levels. However, we have previously reported induction of insulin resistance using fasting glucose and insulin after 4 weeks of treatment with indinavir at 800 mg three times daily, with dosing before measurements [7]. In that study, healthy HIV-negative volunteers had an average of 20% decrease in insulin-stimulated glucose disposal. The magnitude of decrease in insulin sensitivity using the clamp method coincided with an approximate 34% increase in fasting insulin levels and a 47% increase in insulin resistance index by homeostasis model assessment.

It should be noted that we have studied only one PI and our data may not be applicable to all drugs in this class. However, in vitro data using other PI suggest that this may represent a common mechanism. We studied men only; metabolic effects might be different in pre- and postmenopausal women, although there is no reason a priori to suspect that this will prove to be the case given the expression of the GLUT-4 gene.

In summary, our study suggests that the earliest and most direct effect of treatment with indinavir on glucose metabolism is a decrease in insulin-stimulated glucose utilization. The effect is rapid and can be detected at pharmacologic plasma concentrations of indinavir well within the therapeutic range commonly observed in patients. The bulk of the change in glucose disposal rate comes from an acute decrease in the rate of non-oxidative glucose disposal (i.e. storage rate). These findings are compatible with the hypothesis that a mechanism by which indinavir causes insulin resistance is by direct blockade of the glucose transporter GLUT-4. Insights from these studies may provide the basis for designing a new generation of PI drugs that do not perturb glucose metabolism. Future human studies are needed to assess whether these effects are common to other PI and how they might contribute to other observed metabolic and body composition changes reported in patients with HIV.

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The authors thank B. Chang, J. Hirai, M. Pang, and the GCRC nursing staff for technical assistance. Crixivan and Crixivan-Placebo were kindly provided by Merck & Co. Rahway, New Jersey, USA.

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Hicks, C; Currier, J; Sax, P; Sherer, R; Wanke, C
AIDS Patient Care and Stds, 17(5): 221-233.

Metabolic complications associated with HIV protease inhibitor therapy
Nolan, D
Drugs, 63(): 2555-2574.

HIV Clinical Trials
Update on HIV lipodystrophy
Kravcik, S
HIV Clinical Trials, 5(3): 152-167.

Journal of Infection
Prevalence of diabetes mellitus and dyslipidemia among antiretroviral naive patients co-infected with hepatitis C virus (HCV) and HIV-1 compared to patients without co-infection
Visnegarwala, F; Chen, L; Raghavan, S; Tedaldi, E
Journal of Infection, 50(4): 331-337.
Antiviral Therapy
Effects of metformin or gemfibrozil on the lipodystrophy of HIV-infected patients receiving protease inhibitors
Martinez, E; Domingo, P; Ribera, E; Milinkovic, A; Arroyo, JA; Conget, I; Perez-Cuevas, JB; Casamitjana, R; de Lazzari, E; Bianchi, L; Montserrat, E; Roca, M; Burgos, R; Arnaiz, JA; Gatell, JM
Antiviral Therapy, 8(5): 403-410.

Antiviral Therapy
Intracellular disposition and metabolic effects of zidovudine, stavudine and four protease inhibitors in cultured adipocytes
Janneh, O; Haggard, P; Tjia, JF; Jones, SP; Khoo, SH; Maher, B; Back, DJ; Pirmohamed, M
Antiviral Therapy, 8(5): 417-426.

European Journal of Medical Research
Appendix to the German-Austrian HIV therapeutic guidelines: Strategies for treating morphological and metabolic alterations under anfiretroviral treatment
Mauss, S; Behrens, G; Walker, UA
European Journal of Medical Research, 11(2): 47-57.

European Journal of Endocrinology
Switching to unboosted atazanavir improves glucose tolerance in highly pretreated HIV-1 infected subjects
Guffanti, M; Caumo, A; Galli, L; Bigoloni, A; Galli, A; Dagba, G; Danise, A; Luzi, L; Lazzarin, A; Castagna, A
European Journal of Endocrinology, 156(4): 503-509.
Arquivos Brasileiros De Endocrinologia E Metabologia
Prevalence of HIV-associated lipodystrophy in Brazilian outpatients: Relation with metabolic syndrome and cardiovascular risk factors
Diehl, LA; Dias, JR; Paes, ACS; Thomazini, MC; Garcia, LR; Cinagawa, E; Wiechmann, SL; Carrilho, AJF
Arquivos Brasileiros De Endocrinologia E Metabologia, 52(4): 658-667.

AIDS Reader
Hormonal contraception in HIV-positive women
Womack, J; Williams, A
AIDS Reader, 18(7): 372-+.

International Journal of Obesity
Severe insulin resistance contrasting with mild anthropometric changes in the adipose tissue of HIV-infected children with lipohypertrophy
Beregszaszi, M; Jaquet, D; Levine, M; Ortega-Rodriguez, E; Baltakse, V; Polak, M; Levy-Marchal, C
International Journal of Obesity, 27(1): 25-30.
Journal of Clinical Endocrinology & Metabolism
Insulin sensitivity and beta-cell function in protease inhibitor-treated and -naive human immunodeficiency virus-infected children
Bitnun, A; Sochett, E; Dick, PT; To, T; Jefferies, C; Babyn, P; Forbes, J; Read, S; King, SM
Journal of Clinical Endocrinology & Metabolism, 90(1): 168-174.
Annual Review of Medicine
Cardiovascular risks of antiretroviral therapies
Mondy, K; Tebas, P
Annual Review of Medicine, 58(): 141-155.
Bmc Complementary and Alternative Medicine
Pharmacokinetic and metabolic effects of American ginseng (Panax quinquefolius) in healthy volunteers receiving the HIV protease inhibitor indinavir
Andrade, ASA; Hendrix, C; Parsons, TL; Caballero, B; Yuan, CS; Flexner, CW; Dobs, AS; Brown, TT
Bmc Complementary and Alternative Medicine, 8(): -.
Expert Review of Anti-Infective Therapy
Trends in the European HIV/AIDS epidemic: a perspective from Italy
Madeddu, G; Rezza, G; Mura, MS
Expert Review of Anti-Infective Therapy, 7(1): 25-36.
Scandinavian Journal of Infectious Diseases
Long term adverse effects related to nucleoside reverse transcriptase inhibitors: Clinical impact of mitochondrial toxicity
Maagaard, A; Kvale, D
Scandinavian Journal of Infectious Diseases, 41(): 808-817.
Jaids-Journal of Acquired Immune Deficiency Syndromes
Cardiovascular risk factors in HIV-infected patients
Carr, A
Jaids-Journal of Acquired Immune Deficiency Syndromes, 34(): S73-S78.

Potential roles for uncoupling proteins in HIV lipodystrophy
Nolan, D; Pace, C
Mitochondrion, 4(): 185-191.
Metabolic syndrome and hyperlipidemia in HIV-positive patients
Behrens, GMN
Herz, 30(6): 458-466.
New England Journal of Medicine
Medical progress - Cardiovascular risk and body-fat abnormalities in HIV-infected adults
Grinspoon, S; Carr, A
New England Journal of Medicine, 352(1): 48-62.

Skeletal muscle insulin signaling defects downstream of phosphatidylinositol 3-kinase at the level of Akt are associated with impaired nonoxidative glucose disposal in HIV lipodystrophy
Haugaard, SB; Andersen, O; Madsbad, S; Frosig, C; Iversen, J; Nielsen, JO; Wojtaszewski, JFP
Diabetes, 54(): 3474-3483.

American Journal of Physiology-Endocrinology and Metabolism
Insulin sensitivity is preserved despite disrupted endothelial function
Shankar, SS; Considine, RV; Gorski, JC; Steinberg, HO
American Journal of Physiology-Endocrinology and Metabolism, 291(4): E691-E696.
Medecine Et Maladies Infectieuses
Choice of the initial treatment in HIV1 infected patients
Martin, IP
Medecine Et Maladies Infectieuses, 37(): 767-772.

Diabetes Mellitus, Preexisting Coronary Heart Disease, and the Risk of Subsequent Coronary Heart Disease Events in Patients Infected With Human Immunodeficiency Virus The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D Study)
Worm, SW; De Wit, S; Weber, R; Sabin, CA; Reiss, P; El-Sadr, W; Monforte, AD; Kirk, O; Fontas, E; Dabis, F; Law, MG; Lundgren, JD; Friis-Moller, N
Circulation, 119(6): 805-U75.
American Journal of Physiology-Cell Physiology
Indinavir impairs protein synthesis and phosphorylations of MAPKs in mouse C2C12 myocytes
Hong-Brown, LQ; Brown, CR; Lang, CH
American Journal of Physiology-Cell Physiology, 287(5): C1482-C1492.
Jaids-Journal of Acquired Immune Deficiency Syndromes
Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: Recommendations of an International AIDS Society-USA panel
Schambelan, M; Benson, CA; Carr, A; Currier, JS; Dube, MP; Gerber, JG; Grinspoon, SK; Grunfeld, C; Kotler, DP; Mulligan, K; Powderly, WG; Saag, MS
Jaids-Journal of Acquired Immune Deficiency Syndromes, 31(3): 257-275.

Annals of Internal Medicine
Metabolic effects of rosiglitazone in HIV lipodystrophy - A randomized, controlled trial
Hadigan, C; Yawetz, S; Thomas, A; Havers, F; Sax, PE; Grinspoon, S
Annals of Internal Medicine, 140(): 786-794.

Cancer Research
HIV protease inhibitors block Akt signaling and radiosensitize tumor cells both in vitro and in vivo
Gupta, AK; Cerniglia, GJ; Mick, R; McKenna, WG; Muschel, RJ
Cancer Research, 65(): 8256-8265.
Future Lipidology
Cellular mechanisms of lipodystrophy induction by HIV protease inhibitors
Zhou, HP; Pandak, WM; Hylemon, PB
Future Lipidology, 1(2): 163-172.
Emergency Medicine Clinics of North America
Metabolic and Hepatobiliary Side Effects of Antiretroviral Therapy (ART)
Lugassy, DM; Farmer, BM; Nelson, LS
Emergency Medicine Clinics of North America, 28(2): 409-+.
Annual Review of Medicine
HIV-associated lipodystrophy: Pathogenesis, prognosis, treatment, and controversies
Koutkia, P; Grinspoon, S
Annual Review of Medicine, 55(): 303-317.
American Heart Journal
Indinavir impairs endothelial function in healthy HIV-negative men
Shankar, SS; Dube, MP; Gorski, JC; Klaunig, JE; Steinberg, HO
American Heart Journal, 150(5): -.
ARTN 933.e2
Jaids-Journal of Acquired Immune Deficiency Syndromes
Insulin resistance and diabetes mellitus associated with antiretroviral use in HIV-infected patients: Pathogenesis, prevention, and treatment options
Tebas, P
Jaids-Journal of Acquired Immune Deficiency Syndromes, 49(): S86-S92.

Acta Clinica Belgica
Disorders of glucose metabolism in human immunodeficiency virus-infected patients
Benhalima, K; Mathieu, C; Van Wijngaerden, E
Acta Clinica Belgica, 63(4): 227-234.

Journal of Clinical Epidemiology
Hierarchical modeling gave plausible estimates of associations between metabolic syndrome and components of antiretroviral therapy
Young, J; Glass, TR; Bernasconi, E; Rickenbach, M; Furrer, H; Hirschel, B; Tarr, PE; Vernazza, P; Battegay, M; Bucher, HC
Journal of Clinical Epidemiology, 62(6): 632-641.
Naunyn-Schmiedebergs Archives of Pharmacology
Direct interference of HIV protease inhibitors with pancreatic beta-cell function
Dufer, M; Neye, Y; Krippeit-Drews, P; Drews, G
Naunyn-Schmiedebergs Archives of Pharmacology, 369(6): 583-590.
International Journal of Std & AIDS
A review of the aetiology of dyslipidaemia and hyperlipidaemia in patients with HIV
Moyle, G
International Journal of Std & AIDS, 16(): 14-20.

Journal of Clinical Investigation
Impaired glucose phosphorylation and transport in skeletal muscle cause insulin resistance in HIV-1-infected patients with lipodystrophy
Behrens, GMN; Boerner, AR; Weber, K; van den Hoff, J; Ockenga, J; Brabant, G; Schmidt, RE
Journal of Clinical Investigation, 110(9): 1319-1327.
Experimental and Clinical Endocrinology & Diabetes
The HIV protease inhibitor indinavir impairs glycogen synthesis in HepG2 hepatoma cells
Schutt, M; Meier, M; Jost, MM; Klein, HH
Experimental and Clinical Endocrinology & Diabetes, 111(1): 16-20.

Medizinische Klinik
The HIV protease inhibitor-induced insulin resistance syndrome
Schutt, M; Meier, M; Klein, HH
Medizinische Klinik, 98(5): 271-276.

Journal of Clinical Endocrinology & Metabolism
Regulation of adiponectin in human immunodeficiency virus-infected patients: Relationship to body composition and metabolic indices
Tong, Q; Sankale, JL; Hadigan, CM; Tan, G; Rosenberg, ES; Kanki, PJ; Grinspoon, SK; Hotamisligil, GS
Journal of Clinical Endocrinology & Metabolism, 88(4): 1559-1564.
Scandinavian Journal of Infectious Diseases
Impact of switching antiretroviral therapy on lipodystrophy and other metabolic complications: A review
Hansen, BR; Haugaard, SB; Iversen, J; Nielsen, JO; Andersen, O
Scandinavian Journal of Infectious Diseases, 36(4): 244-253.
Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides
Dube, MP; Parker, RA; Tebas, P; Grinspoon, SK; Zackin, RA; Robbins, GK; Roubenoff, R; Shafer, RW; Wininger, DA; Meyer, WA; Snyder, SW; Mulligan, K
AIDS, 19(): 1807-1818.

Journal of Midwifery & Womens Health
Hormonal contraception and HIV-positive women: Metabolic concerns and management strategies
Womack, J; Richman, S; Tien, PC; Grey, M; Williams, A
Journal of Midwifery & Womens Health, 53(4): 362-375.
Acta Physiologica Scandinavica
Cellular mechanisms of insulin resistance, lipodystrophy and atherosclerosis induced by HIV protease inhibitors
Rudich, A; Ben-Romano, R; Etzion, S; Bashan, N
Acta Physiologica Scandinavica, 183(1): 75-88.

Journal of Clinical Endocrinology & Metabolism
Approach to the human immunodeficiency virus-infected patient with lipodystrophy
Brown, TT
Journal of Clinical Endocrinology & Metabolism, 93(8): 2937-2945.
Low CD4+ T-cell count as a major atherosclerosis risk factor in HIV-infected women and men
Kaplan, RC; Kingsley, LA; Gange, SJ; Benning, L; Jacobson, LP; Lazar, J; Anastos, K; Tien, PC; Sharrett, R; Hodis, HN
AIDS, 22(): 1615-1624.

Jornal De Pediatria
Lipodystrophy in children and adolescents with acquired immunodeficiency syndrome and its relationship with the antiretroviral therapy employed
Sarni, ROS; de Souza, FIS; Battistini, TRB; Pitta, TS; Fernandes, AP; Tardini, PC; Fonseca, FLA; dos Santos, VP; Lopez, FA
Jornal De Pediatria, 85(4): 329-334.
Clinical Infectious Diseases
Prospective, intensive study of metabolic changes associated with 48 weeks of amprenavir-based antiretroviral therapy
Dube, MP; Qian, DJ; Edmondson-Melancon, H; Sattler, FR; Goodwin, D; Martinez, C; Williams, V; Johnson, D; Buchanan, TA
Clinical Infectious Diseases, 35(4): 475-481.

Journal of Virology
Antiretroviral Therapy in the Clinic
Tsibris, AMN; Hirsch, MS
Journal of Virology, 84(): 5458-5464.
Clinical impact of HIV-related lipodystrophy and metabolic abnormalities on cardiovascular disease
Behrens, GMN; Meyer-Olson, D; Stoll, M; Schmidt, RE
AIDS, 17(): S149-S154.

Metabolism-Clinical and Experimental
Lipodystrophy in human immunodeficiency virus patients impairs insulin action and induces defects in beta-cell function
Andersen, O; Haugaard, SB; Andersen, LB; Friis-Moller, N; Storgaard, H; Volund, A; Nielsen, JO; Iversen, J; Madsbad, S
Metabolism-Clinical and Experimental, 52(): 1343-1353.
Antiviral Therapy
Contribution of nucleoside-analogue reverse transcriptase inhibitor therapy to lipoatrophy from the population to the cellular level
Nolan, D; Hammond, E; James, I; McKinnon, E; Mollal, S
Antiviral Therapy, 8(6): 617-626.

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.
Cardiovascular Toxicology
Severe impairment of endothelial function with the HIV-1 protease inhibitor indinavir is not mediated by insulin resistance in healthy subjects
Dube, MP; Gorski, JC; Shen, CY
Cardiovascular Toxicology, 8(1): 15-22.
Journal of Antimicrobial Chemotherapy
Metabolic consequences and therapeutic options in highly active antiretroviral therapy in human immunodeficiency virus-1 infection
Samaras, K
Journal of Antimicrobial Chemotherapy, 61(2): 238-245.
HIV Medicine
British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2005)
Gazzard, B
HIV Medicine, 6(): 1-61.

HIV Medicine
Indinavir/ritonavir 800/100mg bid and efavirenz 600mg qd in patients failing treatment with combination nucleoside reverse transcriptase inhibitors: 96-week outcomes of HIV-NAT 009
Boyd, MA; Siangphoe, U; Ruxrungtham, K; Duncombe, CJ; Stek, M; Lange, JMA; Cooper, DA; Phanuphak, P
HIV Medicine, 6(6): 410-420.

Current Pharmaceutical Design
Understanding and avoiding antiretroviral adverse events
Shibuyama, S; Gevorkyan, A; Yoo, U; Tim, S; Dzhangiryan, K; Scott, JD
Current Pharmaceutical Design, 12(9): 1075-1090.

Antiretroviral therapy exposure and incidence of diabetes mellitus in the Women's Interagency HIV Study
Tien, PC; Schneider, MF; Cole, SR; Levine, AM; Cohen, M; DeHovitz, J; Young, M; Justman, JE
AIDS, 21(): 1739-1745.

Antiviral Therapy
The effect of tenofovir disoproxil fumarate on whole-body insulin sensitivity, lipids and adipokines in healthy volunteers
Randell, PA; Jackson, AG; Zhong, LJ; Yale, K; Moyle, GJ
Antiviral Therapy, 15(2): 227-233.
Archives of Disease in Childhood
Metabolic abnormalities and body composition of HIV-infected children on Lopinavir or Nevirapine-based antiretroviral therapy
Arpadi, S; Shiau, S; Strehlau, R; Martens, L; Patel, F; Coovadia, A; Abrams, EJ; Kuhn, L
Archives of Disease in Childhood, 98(4): 258-264.
Journal of Cellular Biochemistry
Indinavir and nelfinavir inhibit proximal insulin receptor signaling and salicylate abrogates inhibition: Potential role of the NFkappa B pathway
Ismail, WIW; King, JA; Anwar, K; Pillay, TS
Journal of Cellular Biochemistry, 114(8): 1729-1737.
The protease inhibitor combination lopinavir/ritonavir does not decrease insulin secretion in healthy, HIV-seronegative volunteers
Pao, VY; Lee, GA; Taylor, S; Aweeka, FT; Schwarz, J; Mulligan, K; Schambelan, M; Grunfeld, C
AIDS, 24(2): 265-270.
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Agent and cell-type specificity in the induction of insulin resistance by HIV protease inhibitors
Ben-Romano, R; Rudich, A; Török, D; Vanounou, S; Riesenberg, K; Schlaeffer, F; Klip, A; Bashan, N
AIDS, 17(1): 23-32.

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Zidovudine/lamivudine contributes to insulin resistance within 3 months of starting combination antiretroviral therapy
Blümer, RM; van Vonderen, MG; Sutinen, J; Hassink, E; Ackermans, M; van Agtmael, MA; Yki-Jarvinen, H; Danner, SA; Reiss, P; Sauerwein, HP
AIDS, 22(2): 227-236.
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American Journal of Therapeutics
Antiretroviral Therapy With Heart
Randell, P; Moyle, G
American Journal of Therapeutics, 16(6): 579-584.
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Current Opinion in Infectious Diseases
Cardiovascular disease and HIV infection: host, virus, or drugs?
Martínez, E; Larrousse, M; Gatell, JM
Current Opinion in Infectious Diseases, 22(1): 28-34.
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JAIDS Journal of Acquired Immune Deficiency Syndromes
Insulin Sensitivity in Multiple Pathways Is Differently Affected During Zidovudine/Lamivudine-Containing Compared With NRTI-Sparing Combination Antiretroviral Therapy
van Vonderen, MG; Blümer, RM; Hassink, EA; Sutinen, J; Ackermans, MT; van Agtmael, MA; Yki-Jarvinen, H; Danner, SA; Serlie, MJ; Sauerwein, HP; Reiss, P
JAIDS Journal of Acquired Immune Deficiency Syndromes, 53(2): 186-193.
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JAIDS Journal of Acquired Immune Deficiency Syndromes
Effects of Growth Hormone on Abnormal Visceral Adipose Tissue Accumulation and Dyslipidemia in HIV-Infected Patients
Kotler, DP; Muurahainen, N; Grunfeld, C; Wanke, C; Thompson, M; Saag, M; Bock, D; Simons, G; Gertner, JM; Serostim in Adipose Redistribution Syndrome Study Group,
JAIDS Journal of Acquired Immune Deficiency Syndromes, 35(3): 239-252.

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Prevalence and Pathogenesis of Diabetes Mellitus in HIV-1 Infection Treated With Combined Antiretroviral Therapy
Samaras, K
JAIDS Journal of Acquired Immune Deficiency Syndromes, 50(5): 499-505.
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Danoff, A; Shi, Q; Justman, J; Mulligan, K; Hessol, N; Robison, E; Lu, D; Williams, T; Wichienkuer, P; Anastos, K
JAIDS Journal of Acquired Immune Deficiency Syndromes, 39(1): 55-62.

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Changes in Metabolic Profile Among Antiretroviral-Naive Patients Initiating Protease Inhibitor Versus Non-Protease Inhibitor Containing HAART Regimens
Visnegarwala, F; Darcourt, J; Sajja, P; Menon, V; Ong, O; Maldonado, M; White, CA
JAIDS Journal of Acquired Immune Deficiency Syndromes, 33(5): 653-655.

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JAIDS Journal of Acquired Immune Deficiency Syndromes, 37(1): 1111-1124.

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Insulin Resistance in HIV-Infected Men and Women in the Nutrition for Healthy Living Cohort
Gorbach, SL; Spiegelman, D; Jacobson, DL; Wanke, C; Jones, CY; Wilson, IB; Greenberg, AS; Shevitz, A; Knox, TA
JAIDS Journal of Acquired Immune Deficiency Syndromes, 40(2): 202-211.

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The Acute Effects of HIV Protease Inhibitors on Insulin Suppression of Glucose Production in Healthy HIV-Negative Men
Lee, GA; Schwarz, J; Patzek, S; Kim, S; Dyachenko, A; Wen, M; Mulligan, K; Schambelan, M; Grunfeld, C
JAIDS Journal of Acquired Immune Deficiency Syndromes, 52(2): 246-248.
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Direct Comparison of the Acute In Vivo Effects of HIV Protease Inhibitors on Peripheral Glucose Disposal
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JAIDS Journal of Acquired Immune Deficiency Syndromes, 40(4): 398-403.

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Antiretroviral Therapy Exposure and Insulin Resistance in the Women's Interagency HIV Study
Tien, PC; Schneider, MF; Cole, SR; Levine, AM; Cohen, M; DeHovitz, J; Young, M; Justman, JE
JAIDS Journal of Acquired Immune Deficiency Syndromes, 49(4): 369-376.
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Nuclear Medicine Communications
Evaluation of glucose uptake by skeletal muscle tissue and subcutaneous fat in HIV-infected patients with and without lipodystrophy using FDG-PET
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Back to Top | Article Outline

HIV protease inhibitors; indinavir; insulin resistance; glucose transport; metabolic complications; diabetes; lipodystrophy; HIV; AIDS

© 2002 Lippincott Williams & Wilkins, Inc.


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