Divisions of 4 Infectious Diseases, 5 Diagnostic Radiology, and 6 Nuclear Medicine, 2 Clinical Research Unit II, and 3 Clinical Spectroscopy Unit, San Raffaele Scientific Institute, and 1 International Center for Assessment of the Nutritional Status, Universita' degli Studi di Milano, 20132 Milan, Italy
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Antiretroviral therapy in
human immunodeficiency virus (HIV)-positive patients can induce a
lipodystrophy syndrome of peripheral fat wasting and central adiposity,
dyslipidemia, and insulin resistance. To test whether in this syndrome
insulin resistance is associated with abnormal muscle handling of fatty
acids, 12 HIV-1 patients (8 females/4 males , age = 26 ± 2 yr, HIV duration = 8 ± 1 yr, body mass index = 22.0 ± 1.0 kg/m2, on protease inhibitors and
nucleoside analog RT inhibitors) and 12 healthy subjects were studied.
HIV-1 patients had a total body fat content (assessed by dual-energy
X-ray absorptiometry) similar to that of controls (22 ± 1 vs.
23 ± 2%; P = 0.56), with a topographic fat
redistribution characterized by reduced fat content in the legs
(18 ± 2 vs. 32 ± 3%; P < 0.01) and
increased fat content in the trunk (25 ± 2 vs. 19 ± 2%;
P = 0.03). In HIV-positive patients, insulin
sensitivity (assessed by QUICKI) was markedly impaired (0.341 ± 0.011 vs. 0.376 ± 0.007; P = 0.012). HIV-positive patients also had increased total plasma cholesterol (216 ± 20 vs. 174 ± 9 mg/dl; P = 0.05) and triglyceride
(298 ± 96 vs. 87 ± 11 mg/dl; P = 0.03)
concentrations. Muscular triglyceride content assessed by means of
1H NMR spectroscopy was higher in HIV patients in soleus
[92 ± 12 vs. 42 ± 5 arbitrary units (AU);
P < 0.01] and tibialis anterior (26 ± 6 vs.
11 ± 3 AU; P = 0.04) muscles; in a stepwise
regression analysis, it was strongly associated with QUICKI
(R2 = 0.27; P < 0.0093).
Even if the basal metabolic rate (assessed by indirect calorimetry) was
comparable to that of normal subjects, postabsorptive lipid oxidation
was significantly impaired (0.30 ± 0.07 vs. 0.88 ± 0.09 mg · kg1 · min
1;
P < 0.01). In conclusion, lipodystrophy in HIV-1
patients in antiretroviral treatment is associated with intramuscular
fat accumulation, which may mediate the development of the insulin resistance syndrome.
human immunodeficiency virus
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A SYNDROME CHARACTERIZED by lipodystrophy (peripheral lipoatrophy and truncal fat accumulation), hyperlipemia, and insulin resistance was recently described in human immunodeficiency virus (HIV)-1-infected patients (5). Although the clinical and biochemical picture is rather consistent, little is known about the pathogenic events leading to abnormal fat deposition and insulin resistance in HIV-1-infected patients. The first hypothesis, proposed by Carr et al. (6), suggested a major role of protease inhibitors (PIs) in the induction of hypertriglyceridemia (and insulin resistance), since they can interact with retinoic acid receptors at the liver site (6). This initial hypothesis was subsequently modified by the demonstration of the lipodystrophic syndrome in HIV-1-infected patients, either on other antiretroviral drugs [mainly nucleoside analog reverse transcriptase inhibitors (NRTI); see Refs. 2 and 36] or naive to PIs (25). Thus it seems that both the viral infection per se or combined with different antiretroviral treatments plays a role in the pathogenesis of the lipodystrophic syndrome.
The abnormal fat distribution of HIV-1-infected patients is
characterized by visceral and truncal obesity, adipose tissue atrophy
of the limbs (mainly lower limbs), increment of adipose tissue in the
mammary region, and "buffalo hump" (5). The metabolic alterations characterizing the insulin resistance syndrome include hyperlipemia (mainly hypertriglyceridemia), reduction of high-density lipoprotein (HDL) cholesterol, glucose intolerance, and hyperuricemia (5, 6). Among the most prominent hormone alterations,
increased levels of insulin, C-peptide, prolactin,
erithropoietin, and tumor necrosis factor (TNF)- were
described (9). An abnormal circadian cortisol pattern was
also described (when this is the prevailing hormone alteration, the
term "pseudo-Cushing" syndrome is used; see Ref. 34).
A beneficial effect of growth hormone (GH) administration (indicated
when an absolute or relative GH secretory defect is present) was
suggested (44).
A clear-cut pathogenesis of HIV-1-related lipodystrophy is presently unknown. A disturbance of lipid metabolism (resulting from either the viral infection or the association virus-antiretroviral therapy-genetic background) seems to play a central role in the pathogenesis of the syndrome. The liver has been considered the main organ responsible for the defective lipid metabolism in lipodystrophic HIV-1-infected patients. The present study was undertaken to define a possible role of muscle in the pathogenesis of insulin resistance of HIV-1-related lipodystrophy. In particular, we asked the following questions: 1) is the HIV-1-related lipodystrophy associated with an alteration of whole body energy metabolism and substrates oxidation rate; and 2) is there a metabolic alteration at the skeletal muscle site? Our data indicate an impaired whole body lipid oxidation in HIV-1-infected patients and a strong association between insulin resistance and intramyocellular lipid accumulation.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Subjects.
Twelve HIV-1-infected patients were selected in the population of over
600 patients at the Outpatient Clinic of Metabolic Diseases in the
Division of Infectious Diseases of San Raffaele Hospital. Table
1 represents the anthropometric
parameters and the major clinical and biochemical data of the study
patients. Twelve healthy volunteers, matched for major anthropometric
parameters, were enrolled in the study and served as a control group.
Antiretroviral therapy included both PIs and nucleoside analog reverse
transcriptase inhibitors in all patients. Table
2 outlines the major inclusion and
exclusion criteria followed in the selection of the 12 HIV-1-infected patients. Only patients who were on a stable antiretroviral therapy for
at least 1 yr (both PI and NRTI) and had constant blood CD4 count and viral level for at least 4 mo were enrolled in the study. Patients who had a variation of body weight >10% of total body weight
were excluded from the study. In all patients, fasting glucose and
glycosylated Hb were assessed on day 1 (see
Experimental protocol for details) and were found to be
normal. Previous normal blood glucose measured within 12 wk before the
study allowed us to rule out diabetes mellitus. In addition, all
HIV-1-infected patients received a standard 75-g oral glucose tolerance
test (found normal) on a separate day within 2 wk of the study period. In all patients, 24-h urinary cortisol excretion was assessed in the
24-h urinary volume collected starting at 0800 of the day before
day 1. Triglycerides and total cholesterol were higher in
HIV-1-infected patients than in control patients. The finding of higher
postabsorptive levels of insulin and C-peptide, indicating insulin
resistance, completed the biochemical picture of the lipodystrophic syndrome. All patients could be classified as having a type III, grade 2 lipodystrophy according to the "ART-associated
Lipodystrophy European Comparative Study" group (33).
All patients had increased truncal adiposity, reduced or absent
lower-extremity subcutaneous fat, and hypertriglyceridemia. Both
HIV-1-infected patients and healthy controls were informed of the
possible risks involved in the participation in the present study and
gave their consent. The experimental protocol was approved by the
Ethics Committee of San Raphael Scientific Institute, and written
informed consent was obtained from all patients.
|
|
Experimental protocol. All subjects involved in this protocol were studied on three separate days. The subjects assumed an isocaloric diet in the 4 wk preceding the study, and they did not modify their usual life style. On day 1, they were admitted to the Metabolic Unit of the Department of Medicine of San Raffaele Scientific Institute after an overnight fast (from 2200 of the day before study, only water was allowed). At 0800, a polyethylene catheter was inserted in the antecubital vein of one forearm, as previously described (23). At 0830, a basal blood sample for the measurements of hormones and metabolites was drawn. On day 2, all subjects were readmitted to San Raffaele Hospital at the Division of Diagnostic Radiology, where a 1H NMR-spectroscopy scan was performed between 0700 and 0800 to assess the intramyocellular concentration of triglycerides, as previously described (30). On day 3, all subjects were admitted to the International Center for Assessment of Nutritional Status of the Universita' degli Studi di Milano to perform dual-energy X-ray absorption (DEXA) for the measurement of fat distribution in different body districts. The same day, respiratory gas exchange measurement by means of indirect calorimetry (model Vmax 29; Sensor Medics Italia, Milan, Italy) was started at 0830 after an overnight fast (9-11 h) and continued for ~30 min. The three tests were performed in random order in no more than a 1-wk period in all subjects.
Analytical determinations.
Aliquots of blood for the measurement of metabolite [glucose,
triglycerides, total cholesterol, HDL, low-density lipoprotein (LDL),
and uric acid] levels were placed in heparinized tubes, as previously
described (30). Plasma glucose was measured with a Beckman
glucose analyzer (glucose oxidase). Blood aliquots for insulin,
C-peptide, prolactin, TNF-, and GH were collected in tubes for serum
separation. Plasma insulin was measured with a microparticle enzyme
immunoassay technology with no cross-reactions with proinsulin,
C-peptide, and glucagon (Imx Insulin assay; Abbott Laboratories, Rome,
Italy; see Ref. 30). Free fatty acids (FFA; Table 1) were
collected and measured as previously described (30). Urine
collection (24 h) was performed to quantify cortisol excretion.
Glycosylated Hb, uric acid, TNF-
, urinary cortisol, and insulin-like
growth factor (IGF)-I were not measured in normal subjects. All blood
samples were placed on ice until the plasma or serum was prepared by
centrifugation at 4°C (within 1.5 h of sampling). All plasma and
serum aliquots were frozen at
60°C until later analysis.
Indirect calorimetry.
Indirect calorimetry measurement was performed as previously described
by means of a Vmax 29 Sensor Medics Instrumentation operated in the
canopy/nutritional dilution mode (23). Respiratory exchanges were measured over a 30-min period with the patient resting
in bed in a quiet room with an ambient room temperature ranging between
23 and 25°C. Only parameters obtained in steady-state conditions were
used for final calculations (steady state defined as 3 min of
O2 within 10%, of respiratory quotient
within 5%, and of air flow through the canopy system within 10%).
1H NMR spectroscopy.
1H NMR spectroscopy was performed on a Sigma 1.5 Tesla
scanner (General Electric Medical Systems, Milwaukee, WI) using a
conventional linear extremity coil. High-resolution,
T1-weighted images of the right calf were obtained before
spectroscopic acquisition to localize the voxel of interest for the
1H spectroscopy study. Voxel shimming was executed
to optimize the homogeneity of the magnetic field within the specific
volume of interest. Two 1H spectra were collected from a
15 × 15 × 15 mm3 volume within the soleus and
tibialis anterior muscles. A PRESS pulse sequence (repetition time = 2,000 ms and echo time = 60 ms) was used, and 128 averages were
accumulated for each spectrum, with a final acquisition time of 4.5 min. The water signal was suppressed during the acquisition, since it
would dominate the other metabolite's peak signals of interest. A
third 1H spectrum of a triglyceride solution inside a glass
sphere, positioned within the extremity coil next to the calf, was also
obtained during the same session to have an external standard acquired in the same conditions as the subject's spectra. Postprocessing of the
data, executed with the Sage/IDL software, consisted of high-pass
filtering, spectra apodization, zerofilling, Fourier transformation,
and phasing of the spectra. The integral of the area under the peak was
calculated using a Marquardt fitting with Lorentzian functions of the
peaks of interest. The integral of the methylene signal
(CH2) at 1.35 parts/million was used to calculate
intramyocellular triglyceride content expressed in arbitrary units (AU)
as the ratio to the integral of the peak of the external standard × 1,000 (30, 31).
DEXA. DEXA was performed with a Lunar-DPX-IQ scanner (Lunar, Madison, WI). A different scan mode was chosen with respect to each subject's body size, as suggested by the manufacturer's operator manual. For regional analysis, three-compartment processing was performed in the arms, trunk, and legs (30). Fat content is expressed as kilograms of fat mass and as a percentage of tissues. Because all patients had truncal fat accumulation (rather than pure visceral obesity), the computed tomography scan of the abdomen was not performed.
Insulin action.
Insulin action was assessed using a quantitative insulin sensitivity
check index (QUICKI) (18). QUICKI hinges on the
measurement of fasting insulin and glucose concentrations. It takes
both the logarithm and the reciprocal of the glucose-insulin product
(a, b)
![]() |
Statistical analysis. All data are expressed as means ± SE. Comparisons between the control and the HIV groups were performed with the Student's t-test for unpaired data when appropriate.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Body composition.
Table 3 presents data on absolute and
percent fat composition in HIV-1-infected patients and in healthy
volunteers in different body districts. No difference was observed in
the absolute and percent fat content in the whole body and in the upper
limbs between the two study groups. In contrast, both the absolute
(P = 0.003) and percent (P = 0.002) fat
content in the legs were markedly reduced with respect to the control
group. The absolute (P = 0.02) and percent
(P = 0.02) fat content of the trunk were higher in the
HIV-1-infected patients with respect to controls.
|
Energy metabolism.
Resting energy expenditure (REE) in HIV-1-infected patients was not
statistically different compared with healthy volunteers either in
absolute terms (P = 0.47) or when calculated per
kilogram body weight (P = 0.54) or kilogram lean body
mass (P = 0.21). In contrast, the respiratory quotient,
calculated by dividing the CO2 by the
O2, was markedly increased in
HIV-1-infected patients (0.91 ± 0.02, P = 0.0001)
with respect to healthy volunteers (0.81 ± 0.1), indicating an
impaired lipid oxidation. Accordingly, whole body lipid oxidation
(mg · kg
1 · min
1) was
markedly impaired in HIV-1-infected patients with respect to controls
(0.20 ± 0.06 vs. 0.88 ± 0.09, respectively,
P = 0.00001). The reduction of lipid oxidation was
matched by a complementary increment of glucose oxidation
(mg · kg
1 · min
1) in
HIV-1-infected patients (1.87 ± 0.21, P = 0.003)
with respect to healthy subjects (1.03 ± 0.13; Fig.
1 and Table 3).
|
Intramyocellular triglyceride concentration.
The intramyocellular triglyceride content of the soleus muscle was
significantly increased in HIV-1-infected patients compared with
healthy controls (101 ± 15 vs. 44 ± 5 AU, P = 0.001). Similarly, the triglyceride content of the tibialis anterior
muscle was higher in HIV patients compared with controls (26 ± 6 vs. 11 ± 2 AU, respectively, P = 0.02; Fig.
2).
|
Insulin action.
The QUICKI was lower (P = 0.012) in HIV-1-infected
patients (0.341 ± 0.011) compared with healthy controls
(0.376 ± 0.007). An inverse correlation between insulin action
and intramyocellular triglyceride concentration was shown in the study
subjects (Fig. 3). Gan et al.
(11) found a similar correlation between insulin action
assessed via the clamp and intramyocellular lipid content.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
All patients included in the study were lipodystrophic (Table 2).
In particular, the total body weight and the total percentage of body
fat mass were not statistically different from the control group.
Interestingly, the arm fat percentages were also similar in
HIV-1-infected patients and in healthy subjects, confirming that the
body districts mainly involved are 1) the lower extremities, where the apoptotic process is prominent (1), and
2) the trunk, where the fat accumulation is increased. Both
the antiretroviral drugs and the virus itself have been hypothesized as
possible causes of HIV-1-related lipodystrophy (25). The
complete sequence of events by which PIs lead to insulin resistance,
cause apoptosis, and eventually determine lipodystrophy is
presently still unknown. PIs have two possible mechanisms by which they
induce lipodystrophy and insulin resistance. First, PI drugs have a
direct effect on the retinoic acid receptor (leading to
apoptosis of adipocytes in specific body districts) and on the
lipoprotein receptor-related protein; second, PIs have an indirect
negative effect on insulin action by impairing triglyceride clearance
(5, 6, 32). Because in the present work we did not measure
the lipolytic rate of adipose tissue, we cannot draw any conclusion on
a possible regional difference of PIs on lipolytic rate. In contrast,
NRTI may, possibly, induce lipodystrophy via mitochondrial toxicity. In
addition, non-virus-related mitochondrial toxic myopathies are known to
induce lipid storage inside the skeletal muscle cells (10). Finally, the demonstration of lipodystrophy in
patients naive for antiretroviral drugs (25) or in the
very early stages of disease (4) may support the
possibility that the retrovirus itself may induce the syndrome, without
the concomitance of any drug treatment. Complex interactions are
present among the retroviral infection, PIs, and NRTI drugs. Therefore,
we selected patients on both classes of drugs (PI and NRTI for 1 yr),
having the three known factors possibly involved in the pathogenesis of
the lipodystrophy/insulin resistance syndrome (Table 2).
All patients were hypertriglyceridemic (Tables 1 and 3). No patient had hormone or metabolic factors that, per se, could induce or worsen an altered distribution of body fat or insulin resistance. First, diabetes mellitus was excluded, since hyperglycemia is known to induce insulin resistance. All HIV-1-infected patients had a normal urinary excretion of cortisol and plasma hormone levels in the normal range, excluding a major hormonal alteration leading to truncal adiposity. Interestingly, FFA concentration was not increased as in other forms of lipodystrophy, possibly because of the differential fat distribution between the abdomen (accumulation) and legs (atrophy; Table 1).
All patients were insulin resistant, with comparable glucose levels in the two groups. We made an effort to exclude a number of different diseases (diabetes mellitus, obesity, hyperuricemia, cancer, hereditary diseases, and sepsis) on the basis of known risk factors leading to a reduction of insulin action. We also ruled out a coexisting hyperuricemia by measuring the plasma uric acid concentration (normal in all subjects; Table 1). The normal hormone levels previously discussed excluded a hormonal cause of reduced insulin action, pointing to either the viral infection or the pharmacological interactions of antiretroviral drugs as isolated causes of insulin resistance. A possible mechanism of induction of insulin resistance by PIs was suggested by Murata et al. (27), who recently described a selective inhibition of GLUT4 activity by indinavir (a PI drug), with a normal phosphorylation of the tyrosine residues of insulin receptor and insulin receptor substrate-1.
REE is increased during sepsis (29) or in patients with
advanced acquired immunodeficiency syndrome (37), leading
eventually to cachexia. Our HIV-1-infected population does not show a
significant increase in REE compared with the control group.
Nonetheless, two previous reports demonstrate an increased REE in
HIV-lipodystrophic patients on antiretroviral drug treatment (17,
38). Possible causal links between increased metabolic rate and
either higher TNF- blood levels or resistance to antiretroviral drug
treatment were previously suggested. Shevitz et al. (38)
recently suggested that, although highly active antiretroviral therapy
(HAART) may decrease the metabolic rate by lowering viral load, it
increases the metabolic rate by a distinct, independent, and unknown
mechanism. It is important to note that lipodystrophy itself
(not associated with HIV infection, but with other diseases) may
increase the metabolic rate. We (24) and others (20,
21) have shown increased REE in diabetic patients with partial
or total lipoatrophic diabetes mellitus. Nonetheless, REE was found to
be increased in diseases associated with congenital/acquired,
total/partial lipodystrophy, like Kobberling-Dunningan syndrome
(42), Nasu-Hakola disease (8), and cystic
angiomatosis (3).
It is noteworthy that our patients demonstrate a markedly reduced whole
body lipid oxidation rate (and a complementary increase of carbohydrate
oxidation) compared with the control group (Fig. 1 and Table
4). This finding is somewhat expected in
a cohort of patients hypertriglyceridemic, insulin resistant, and with an impaired clearance of plasma lipids, although it is most consistent in HIV-infected patients treated with antiretroviral drugs. In contrast, an early defect of lipid oxidation was shown in obese and
postobese subjects (26, 35). Once obesity or type 2 diabetes is established, there is not necessarily a decreased lipid
oxidation. A previous report of Hommes et al. (17) found
the lipid oxidation normal to increased in HIV-infected patients not on
HAART, underlining the importance of antiretroviral drugs in the
development of the lipid oxidation defect. Korach et al.
(22) recently showed that only after the institution of
antiretroviral therapy did HIV patients develop a decrease in lipid
oxidation.
|
Both the liver and the skeletal muscle are major sites of lipid
oxidation. It is reasonable to postulate that an impairment of
-oxidation of fatty acids induces triglyceride accumulation at the
organ sites. Liver steatosis (assessed by ultrasound echography) was
detected in all HIV-1-infected patients included in this study (Table
1; and is commonly present in most lipodystrophic patients; see Ref.
16), although this finding might be indicative of a concomitant chronic hepatitis instead of primary hepatic lipid accumulation. For this reason, the report of a higher intramyocellular triglyceride concentration in the HIV-1-infected group is of crucial importance (Fig. 2). This is the first demonstration that
HIV-1-infected patients with lipodystrophy have an increased level of
lipids in the skeletal muscle cells. Because all HIV-1-infected
patients were on both classes of drugs (PIs and nucleoside analog
inverse transcriptase inhibitors), it is impossible to ascribe to one class of drug or to the other the increase of intramyocellular lipid
content. Interestingly, many viral infections cause lipid (either
cholesterol or triglyceride) accumulation in the liver parenchyma
(7), heart (39), or skeletal muscle
(15, 28). Therefore, the retroviral infection per se may
be partially responsible for the higher triglyceride content in the
skeletal muscle. Finally, intramyocellular triglyceride accumulation
was described in other forms of lipodystrophy not characterized by
cytokine production, either in rodent models (12) or in
humans (40). Therefore, the lack of an
HIV-nonlipodystrophic group does not allow us to dissect out the role
of lipodystrophy and of viral infection itself in the development of
intramuscular triglyceride accumulation.
In conclusion, the present data indicate a novel metabolic defect of HIV-1-infected patients treated with HAART, namely an intramyocellular accumulation of triglycerides associated with a reduced whole body lipid oxidation. The intramyocellular lipid concentration inversely correlates with insulin sensitivity. Probably, the retroviral infection in combination with HAART is responsible for the metabolic defect, which is associated with abnormal fat distribution. Recent publications point to a selective impairment of GLUT4 activity by PI drugs (27), and genetic manipulation of GLUT4 expression has shown a role of this protein in adipose tissue metabolism (13, 19, 41). Therefore, on the basis of our results and on in vitro experimental evidence, the use of pharmacological agents selectively enhancing insulin action could be suggested in HIV-1-infected patients (14, 43).
![]() |
ACKNOWLEDGEMENTS |
---|
This work was supported by Progetto Finalizzato del Ministero della Sanita', Italy, Grant no. R.F. 99 Unita' 03 and 04.
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: L. Luzi, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy (E-mail: luzi.livio{at}hsr.it).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published October 8, 2002;10.1152/ajpendo.00391.2001
Received 29 August 2001; accepted in final form 17 September 2002.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Bastard, JP,
Caron M,
Vidal H,
Jan V,
Auclair M,
Vigouroux C,
Luboinski J,
Laville M,
Maachi M,
Girard PM,
Rozenbaum W,
Levan P,
and
Capeau J.
Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance.
Lancet
359:
1026-1031,
2002[Medline].
2.
Brinkman, K,
Smeitink JA,
Romijn JA,
and
Reiss P.
Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy.
Lancet
354:
1112-1115,
1999[ISI][Medline].
3.
Brunzell, JD,
Shankle SW,
and
Bethune JE.
Congenital generalized lipodystrophy accompanied by cystic angiomatosis.
Ann Intern Med
69:
501-516,
1968[ISI][Medline].
4.
Capiluppi, B,
Ciuffreda D,
Sciandra M,
Marroni M,
Tambussi G,
and
Lazzarin A.
Metabolic disorders in a cohort of patients treated with highly aggressive antiretroviral therapies during primary HIV-1 infection.
AIDS
14:
1861-1862,
2000[ISI][Medline].
5.
Carr, A,
Samaras K,
Burton S,
Law M,
Freund J,
Chisholm DJ,
and
Cooper DA.
A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors.
AIDS
12:
F51-F58,
1998[ISI][Medline].
6.
Carr, A,
Samaras K,
Chisholm DJ,
and
Cooper DA.
Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance.
Lancet
351:
1881-1883,
1998[ISI][Medline].
7.
Czaja, AJ,
Carpenter HA,
Santrach PJ,
and
Moore SB.
Host- and disease-specific factors affecting steatosis in chronic hepatitis C.
J Hepatol
29:
198-206,
1998[ISI][Medline].
8.
Deisenhammer, F,
Willeit J,
Schmidauer C,
Kiechl S,
and
Pohl P.
Membranous lipodystrophy (Nasu-Hakola disease).
Nervenarzt
64:
263-265,
1993[ISI][Medline].
9.
Ducobu, J,
and
Payen MC.
Lipids and AIDS.
Rev Med Brux
21:
11-17,
2000[Medline].
10.
Enzi, G.
Multiple symmetric lipomatosis: an updated clinical report.
Medicine
63:
53-64,
1984.
11.
Gan, SK,
Samaras K,
Thompson C,
Kraegen E,
Carr A,
Cooper D,
and
Chisholm D.
Correlations between intramyocellular lipid, visceral fat and insulin sensitivity: a study of HIV positive subjects with and without peripheral lipodystrophy (Abstract).
Diabetes
50:
A315,
2001.
12.
Gavrilova, O,
Marcus-Samuels B,
Graham D,
Kim JK,
Shulman GI,
Castle AL,
Vinson C,
Eckhaus M,
and
Reitman ML.
Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice.
J Clin Invest
105:
271-278,
2000
13.
Gnudi, L,
Shepherd PR,
and
Kahn BB.
Over-expression of GLUT4 selectively in adipose tissue in transgenic mice:implication for nutrient partitioning.
Proc Nutr Soc
55:
191-199,
1996[ISI][Medline].
14.
Hadigan, C,
Corcoran C,
Basgoz N,
Davis B,
Sax P,
and
Grinspoon S.
Metformin in the treatment of HIV lipodystrophy syndrome.
JAMA
284:
472-477,
2000
15.
Hajjar, DP,
Picart F,
and
Pomerantz KB.
Molecular motions and thermotropic phase behavior of triacylglycerols and cholesteryl esters in herpesvirus-infected arterial smooth muscle cells: a deuterium nuclear magnetic resonance study.
Biophys Chem
43:
255-263,
1992[ISI][Medline].
16.
Harbour, JR,
Rosenthal P,
and
Smuckler EA.
Ultrastructural abnormalities of the liver in total lipodystrophy.
Hum Pathol
12:
856-862,
1981[ISI][Medline].
17.
Hommes, MJ,
Romijn JA,
Endert E,
and
Sauerwein HP.
Resting energy expenditure and substrate oxidation in human immunodeficiency virus (HIV)-infected asymptomatic men: HIV affects host metabolism in the early asymptomatic stage.
Am J Clin Nutr
54:
311-315,
1991[Abstract].
18.
Katz, A,
Nambi SS,
Mather K,
Baron AD,
Follmann DA,
Sullivan G,
and
Quon MJ.
Quantitative Insulin Sensitivity Check Index: a simple, accurate method for assessing insulin sensitivity in humans.
J Clin Endocrinol Metab
85:
2402-2410,
2000
19.
Katz, EB,
Stenbit AE,
Hatton K,
De Pinho R,
and
Charron MJ.
Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT 4.
Nature
377:
151-155,
1995[ISI][Medline].
20.
Klein, S,
Jahoor F,
Wolfe RR,
and
Stuart CA.
Generalized lipodystrophy: in vivo evidence for hypermetabolism and insulin-resistant lipid, glucose, and amino acid kinetics.
Metabolism
41:
893-896,
1992[ISI][Medline].
21.
Kobberling, J,
Willms B,
Kattermann R,
and
Creutzfeldt W.
Lipodystrophy of the extremities. A dominantly inherited syndrome associated with lipoatrophic diabetes.
Humangenetik
29:
111-120,
1975[ISI][Medline].
22.
Korach, M,
Leclercq P,
Peronnet F,
and
Leverve X.
Metabolic response to a C-glucose load in human immunodeficiency virus patients before and after antiprotease therapy.
Metabolism
51:
307-313,
2002[Medline].
23.
Luzi, L,
Castellino P,
and
DeFronzo RA.
Insulin and hyperaminoacidemia regulate by a different mechanism leucine turnover and oxidation in obesity.
Am J Physiol Endocrinol Metab
270:
E273-E281,
1996
24.
Luzi, L,
Dozio N,
Battezzati A,
Perseghin G,
Sarugeri E,
Terruzzi I,
and
Spotti D.
Anomalous leucine metabolism in total lipoathrophic diabetes: a possible mechanism of muscle mass hypertrophy.
Acta Diabetol
29:
86-93,
1992[ISI].
25.
Madge, S,
Kinloch-de-Loes S,
Mercey D,
Johnson MA,
and
Weller, IV
Lipodystrophy in patients naive to HIV protease inhibitors.
AIDS
13:
735-737,
1999[ISI][Medline].
26.
McGarry, JD.
Glucose-fatty acid interactions in health, and disease.
Am J Clin Nutr
67:
500S-504S,
1998[Abstract].
27.
Murata, H,
Hruz PW,
and
Mueckler M.
The mechanism of insulin resistance caused by HIV protease inhibitor therapy.
J Biol Chem
275:
20251-20254,
2000
28.
Pearce, PH,
Johnsen RD,
Wysocki SJ,
and
Kakulas BA.
Muscle lipids in Duchenne muscular dystrophy.
Aust J Exp Biol Med Sci
59:
77-90,
1981[ISI][Medline].
29.
Pernerstorfer-Schoen, H,
Schindler K,
Parschalk B,
Schindl A,
Thoeny-Lampert S,
Wunderer K,
Elmadfa I,
Tschachler E,
and
Jilma B.
Beneficial effects of protease inhibitors on body composition and energy expenditure: a comparison between HIV-infected and AIDS patients.
AIDS
13:
2389-2396,
1999[ISI][Medline].
30.
Perseghin, G,
Scifo P,
De Cobelli F,
Pagliato E,
Battezzati A,
Arcelloni C,
Vanzulli A,
Testolin G,
Pozza G,
Del Maschio A,
and
Luzi L.
Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans. A 1H-13C NMR spectroscopy assessment in offspring of type 2 diabetic parents.
Diabetes
48:
1600-1606,
1999[Abstract].
31.
Perseghin, G,
Scifo P,
Pagliato E,
Battezzati A,
Soldini L,
Benedini S,
Testolin G,
Del Maschio A,
and
Luzi L.
Gender factors affect fatty acids-induced insulin resistance in nonobese humans: effects of oral steroidal contraception.
J Clin Endocrinol Metab
86:
3188-3196,
2001
32.
Pihlajamaki, J,
Karjalainen L,
Karhapaa P,
Vauhkonen I,
and
Laakso M.
Impaired free fatty acid suppression during hyperinsulinemia is a characteristic finding in familial combined hyperlipidemia, but insulin resistance is observed only in hypertriglyceridemic patients.
Arterioscler Thromb Vasc Biol
20:
164-170,
2000
33.
Polo M, Galli M, Scientmark T, and Walli R. Proposal for a
clinical and metabolic classification of metabolic and hormone
abnormalities under HAART. In: Int Workshop 2nd on HIV-related
Lipodystrophy, Marrakesh, Morocco, 2000, p. 57-58.
34.
Renard, E,
Fabre J,
Paris F,
Reynes J,
and
Bringer J.
Syndrome of body fat redistribution in HIV-1-infected patients: relationships to cortisol and catecholamines.
Clin Endocrinol (Oxf)
51:
223-230,
1999[ISI][Medline].
35.
Ruderman, NB,
and
Dean D.
Malonyl CoA, long chain fatty acyl CoA and insulin resistance in skeletal muscle.
J Basic Clin Physiol Pharmacol
9:
295-308,
1998[Medline].
36.
Saint-Marc, T,
Partisani M,
Poizot-Martin I,
Bruno F,
Rouviere O,
Lang JM,
Gastaut JA,
and
Touraine JL.
A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy.
AIDS
13:
1659-1667,
1999[ISI][Medline].
37.
Sheehan, LA,
and
Macallan DC.
Determinants of energy intake and energy expenditure in HIV and AIDS.
Nutrition
16:
101-106,
2000[ISI][Medline].
38.
Shevitz, AH,
Knox TA,
Spiegelman D,
Roubenoff R,
Gorbach SL,
and
Skolnik PR.
Elevated resting energy expenditure among HIV-seropositive persons receiving highly active antiretroviral therapy.
AIDS
13:
1351-1357,
1999[ISI][Medline].
39.
Suzuki, H,
Kurihara Y,
Takeya M,
Kamada N,
Kataoka M,
Jishage K,
Ueda O,
Sakaguchi,
Higashi T,
Suzuki T,
Takashima Y,
Kawabe Y,
Cynshi O,
Wada Y,
Honda M,
Kurihara H,
Aburatani H,
Doi T,
Matsumoto A,
Azuma S,
Noda T,
Toyoda Y,
Itakura H,
Yazaki Y,
Kodama T,
A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection.
Nature
386:
292-296,
1997[ISI][Medline].
40.
Szczepaniak, LS,
Babcock EE,
Schick F,
Dobbins RL,
Garg A,
Burns DK,
McGarry JD,
and
Stein DT.
Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo.
Am J Physiol Endocrinol Metab
276:
E977-E989,
1999
41.
Tsu-Shuen Tsao,
Stenbit AE,
J Li,
Houseknecht KL,
Zierath JR,
Katz EB,
and
Charron MJ.
Muscle-specific transgenic complementation of GLUT4-deficient mice.
J Clin Invest
100:
671-677,
1997
42.
Ursich, MJ,
Fukui RT,
Galvao MS,
Marcondes JA,
Santomauro AT,
Silva ME,
Rocha DM,
and
Wajchenberg BL.
Insulin resistance in limb, and trunk partial lipodystrophy (type 2 Kobberling-Dunnigan syndrome).
Metabolism
46:
159-163,
1997[ISI][Medline].
43.
Walli, R,
Michl GM,
Muhlbayer D,
Brinkmann L,
and
Goebel FD.
Effects of troglitazone on insulin sensitivity in HIV-infected patients with protease inhibitor-associated diabetes mellitus.
Res Exp Med (Berl)
199:
253-262,
2000[Medline].
44.
Wanke, C,
Gerrior J,
Kantaros J,
Coakley E,
and
Albrecht M.
Recombinant human growth hormone improves the fat redistribution syndrome (lipodystrophy) in patients with HIV.
AIDS
13:
2099-2103,
1999[ISI][Medline].