ORIGINAL
E n d o c r i n e
ARTICLE
C a r e
The Effect of Strength and Endurance Training on
Insulin Sensitivity and Fat Distribution in Human
Immunodeficiency Virus-Infected Patients with
Lipodystrophy
B. Lindegaard, T. Hansen, T. Hvid, G. van Hall, P. Plomgaard, S. Ditlevsen, J. Gerstoft,
and B. K. Pedersen
The Centre of Inflammation and Metabolism at the Department of Infectious Diseases (B.L., T.Ha., T.Hv., G.v.H., P.P., B.K.P.), the
Copenhagen Muscle Research Centre (B.L., T.Ha., T.Hv., G.v.H., P.P., B.K.P.), and Department of Infectious Diseases (B.L., P.P., J.G.,
B.K.P.), Rigshospitalet, DK-2100 Copenhagen, Denmark; and Department of Mathematical Sciences (S.D.), University of Copenhagen,
DK-2100 Copenhagen, Denmark
Context: Fat redistribution, insulin resistance, and low-grade inflammation characterize HIV-infected patients with lipodystrophy. Currently, no effective therapies exist for the combined treatment of fat redistribution and insulin resistance.
Objective: Our objective was to evaluate the effects of strength and endurance training on insulin
sensitivity and fat distribution in HIV-infected patients with lipodystrophy.
Subjects and Methods: Twenty sedentary HIV-infected men with lipodystrophy were randomly
assigned to supervised strength or endurance training three times a week for 16 wk. The primary
endpoints were improved peripheral insulin sensitivity (euglycemic-hyperinsulinemic clamp combined with isotope-tracer infusion) and body fat composition (dual-energy x-ray absorptiometry
scan). Secondary endpoints included fasting lipids and inflammatory markers.
Results: Insulin-mediated glucose uptake increased with both endurance training (55.7 ⫾ 11 to
63.0 ⫾ 11 ␮mol glucose/kg lean mass䡠min, P ⫽ 0.02) and strength training (49.0 ⫾ 12 to 57.8 ⫾ 18
␮mol glucose/kg lean mass䡠min, P ⫽ 0.005), irrespective of training modality (P ⫽ 0.24). Only
strength training increased total lean mass 2.1 kg [95% confidence interval (CI), 0.8 –3.3], decreased
total fat 3.3 kg (95% CI, ⫺4.6 to ⫺2.0), trunk fat 2.5 kg (95% CI, ⫺3.5 to ⫺1.5), and limb fat 0.75
kg (95% CI, ⫺1.1 to ⫺0.4). Strength training significantly decreased total and limb fat mass to a
larger extent than endurance training (P ⬍ 0.05). Endurance training reduced total cholesterol,
low-density lipoprotein cholesterol, free fatty acids, high-sensitivity C-reactive protein, IL-6, IL-18,
and TNF-␣ and increased high-density lipoprotein cholesterol, whereas strength training decreased triglycerides, free fatty acids, and IL-18 and increased high-density lipoprotein cholesterol
(P ⬍ 0.05 for all measurements).
Conclusion: This study demonstrates that both strength and endurance training improve peripheral insulin sensitivity, whereas only strength training reduces total body fat in HIV-infected patients with lipodystrophy. (J Clin Endocrinol Metab 93: 3860 –3869, 2008)
reatment with highly active combination antiretroviral therapy (HAART) in HIV-infected patients is associated with
lipodystrophy, characterized by sc fat loss, a relative increase in
T
central fat accumulation, and severe metabolic side effects, including dyslipidemia, insulin resistance, and low-grade inflammation (1). These morphological and metabolic abnormalities
0021-972X/08/$15.00/0
Abbreviations: CI, Confidence interval; FFA, free fatty acids; HAART, highly active combination antiretroviral therapy; HDL, high-density lipoprotein; HS-CRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; OGTT, oral glucose tolerance test; Ra, rate of
appearance; Rd, rate of disappearance; 3-RM, three-repetition maximum; VO2max, maximal oxygen consumption.
Printed in U.S.A.
Copyright © 2008 by The Endocrine Society
doi: 10.1210/jc.2007-2733 Received December 11, 2007. Accepted July 3, 2008.
First Published Online July 15, 2008
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J Clin Endocrinol Metab. October 2008, 93(10):3860 –3869
J Clin Endocrinol Metab, October 2008, 93(10):3860 –3869
may contribute to an increased risk of cardiovascular diseases in
HIV-infected patients (2).
In HIV-negative individuals, both endurance and strength
training improve insulin sensitivity (3, 4), but few studies have
compared the two training modalities, and conflicting results
exist (5– 8).
In HIV-infected patients with lipodystrophy, evidence is lacking with regard to an effect of both strength training and endurance training on insulin sensitivity because previous studies applied indirect methods (9 –13). Endurance training alone (9, 14)
or combined with strength training (10, 15, 16) decreases trunk
and visceral fat in HIV-infected patients with lipodystrophy.
However, the effect of strength training has been examined in
only two studies with conflicting results (12, 17).
We conducted a randomized study in HIV-infected patients
with lipodystrophy to evaluate the individual effects of strength
training and endurance training on 1) insulin sensitivity using a
combined euglycemic-hyperinsulinemic clamp and stable isotope tracer method, 2) body composition, 3) lipid profile, and
4) inflammation. Our study design also allowed us to compare
the two training modalities.
Subjects and Methods
Participants
Thirty-nine HIV-positive men were recruited from the outpatient
clinic of the Department of Infectious Diseases (Rigshospitalet, Copenhagen, Denmark) between February 2005 and March 2006. Participants
underwent a medical examination, standard blood tests, a 2-h 75-g oral
glucose tolerance test (OGTT), and a maximal oxygen consumption
(VO2max) test after 12 h of fasting to determine eligibility. Inclusion
criteria were 18 – 65 yr, stable HAART for at least 3 months before
enrollment, untrained defined by VO2max (according to Ref. 18), lipodystrophy [defined by the presence of peripheral lipoatrophy with at least
one moderate sign of fat loss in face, arms, buttocks, or legs based on a
physical examination by a single investigator (B.L.) using a validated
questionnaire developed by Carr et al. (19)], dyslipidemia [triglycerides
⬎1.7 mmol/liter and/or high-density lipoprotein (HDL)-cholesterol
⬍0.9 mmol/liter], and suppressed viral load (⬍20 copies/ml). Exclusion
criteria were severe cardiovascular diseases, arthritis, severe neuropathy,
opportunistic infections that required hospitalization within the last 6
wk, diabetes (fasting glucose ⱖ7 mmol/liter or 2-h glucose ⬎11 mmol/
liter after an OGTT), or concurrent therapy with antidiabetic agents,
anticoagulants, or any hormones.
Fifteen age- and VO2max-matched HIV-seronegative healthy men
served as controls for baseline measurement.
HIV infection and antiretroviral therapy-related characteristics are
shown in Table 2. None of the patients changed any of the antiretroviral
agents during the study period.
Clinical research protocol
Written and informed consent was obtained from all participants
according to the requirements from the local ethical committee (KF 01262/04) and the Helsinki Declaration II. All measurements were performed after a 24-h abstention from strenuous exercise and a 12-h fast.
At baseline and 8 and 16 wk, body composition was measured by dualenergy x-ray absorptiometry scan (Lunar Prodigy, version 8.8; GE Medical Systems, Madison, WI) (19) and VO2max and strength tests were
performed. At baseline and after 16 wk, blood sampling and a euglycemic
clamp were performed. The participants were randomized to endurance
training or strength training after the clamp procedure.
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Strength testing
Strength testing was performed using a three-repetition maximum
(3-RM) during six exercises: leg curl, pull-down, seated leg press, chest
press, seated rows, and leg extension.
VO2max
An incremental exercise to volitional fatigue was performed between
0800 and 1000 h on a cycle ergometer (Monark 839E; Monark Ltd,
Varberg, Sweden). VO2max was measured with an indirect calorimetric
system (Moxus modular VO2 system; AEI Technologies, Pittsburgh, PA)
using a two-way non-rebreathing valve (Hans Rudolph, Inc., Kansas
City, MO), which recorded data every 15 sec. Based on the pre-VO2max
test, a protocol was designed so that VO2max was reached within 8 –12
min of exercise start (20). Exhaustion was defined by two of the following: respiratory exchange ratios more than 1.10, VO2 reached a plateau,
and/or repetitions per minute less than 60 in more than 10 sec.
Euglycemic-hyperinsulinemic clamp combined with
stable isotope infusion
Diet was registered 2 d before the clamp, and participants were advised to ingest the same diet at the end-of-study visit. Subjects were
admitted at 0800 h to the laboratory 46 – 48 h after the VO2max test and
after a 12-h overnight fast (including HAART). A euglycemic-hyperinsulinemic clamp combined with glucose stable isotope technique was
undertaken as described previously (21). In brief, after obtaining baseline
blood samples to determine background glucose enrichment, a primed
16-␮mol/kg constant infusion (0.22 ␮mol/kg䡠min) of [6,6-2H2]glucose
(Cambridge Isotopes Laboratories, Inc., Cambridge, MA) was maintained for 5 h to determine glucose kinetics. The clamp was initiated 2.5 h
after the start of the isotope infusion (basal condition) and continued for
2.5 h (adapted after Ref. 22). Insulin (Actrapid; Novo Nordisk Insulin,
Bagsværd, Denmark), 100 IU/ml, was infused at a rate of 50 mU/m2䡠min
(initiated with a two-step priming dose of 200 mU/m2䡠min for 5 min
followed by 100 mU/m2䡠min for 5 min). Blood glucose was maintained
at 5.5 mmol/liter by infusion of 20% glucose enriched to 2.5% with
[6,6-2H2]glucose (23). The infusion of [6,6-2H2]glucose was decreased
by 75% of basal infusion rate during insulin-stimulated condition to
steadily maintain the plasma glucose enrichment by accounting for the
expected decline in hepatic glucose production. Arterialized blood samples were obtained every 10 min during the last 30 min of the basal and
insulin-stimulated conditions to determine plasma glucose concentrations and tracer-to-tracee ratio. Venous blood samples were obtained at
0, 30, 60, 90, 120, 130, 140, and 150 min during the basal condition. All
blood samples were drawn into tubes containing EDTA, centrifuged, and
stored at ⫺80 C until analyzed.
Training protocol
Training was performed in a public fitness center, all sessions were
supervised, and the heart rate was continuously monitored (Heart Rate
Watch; Polar, Kempele, Finland). The subjects trained three times per
week for 16 wk. All programs contained a 5-min warm-up.
The endurance training consisted of eight different programs with 35
min of interval training. Based on a regression between VO2 and heart
rate, the participants trained at a heart rate corresponding to the desired
VO2max. The intensity varied from 50 –100% of VO2max. The first 8 wk,
the mean intensity was targeted at 65% of VO2max and the last 8 wk, it
was 75% of VO2max.
The strength training consisted of eight exercises (leg curl, pull-down,
seated leg press, chest press, seated rows, leg extension, abdominal
crunch, and back extension) in resistance training machines (LifeFitness)
for 45– 60 min. The number of repetitions and sets changed every week
(Table 1), and the resting interval was 60 –120 sec. The 1-RM was calculated as 106% of the 3-RM results (24).
Compliance was noted at each training day, and if subjects missed a
training day, a make-up was made.
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Lindegaard et al.
Training and Insulin Sensitivity in HIV
J Clin Endocrinol Metab, October 2008, 93(10):3860 –3869
TABLE 1. Resistance training program overview
Week
Exercise
1–2
3– 4
5– 6
7– 8
9 –10
11
12
13–16
Sets
Repetitions
Workloads (%)
3
12
50
3
12
60
3
10
70
4
10
70
4
8
80
4
10
70
4
10
75
4
8
80
Workloads in percentages are of the calculated 1-RM based on the 3-RM tests.
Laboratory analysis
Lipids and inflammatory markers for each subject were measured at
eight (0, 30, 60, 90, 120, 130, 140, and 150 min) and five (0, 30, 60, 90, and
120 min) time points, respectively, during the basal condition of the clamp
procedure. Plasma concentration of free fatty acids [(FFA) (NEFA-C kit;
Wako Chemical Inc., Neuss, Germany)] was determined using an automatic
analyzer (Cobas Fara, Roche, Basel, Switzerland). The plasma concentration of IL-18, TNF-␣, IL-6, and insulin was determined by ELISA (25). Total
cholesterol, HDL-cholesterol, low-density lipoprotein (LDL)-cholesterol,
triglycerides, and glucose were determined using standard laboratory procedures. CD4⫹ cell counts were calculated by flow cytometry and HIV RNA
copies were measured by the Amplicor HIV Monitor (Roche Molecular
Systems, Branchburg, NJ) (lower limit of detection, 20 copies/ml).
Enrichment of glucose was determined with the use of liquid chromatography-mass spectrometry (23).
Calculations
A physiological and isotopic steady state was achieved during the last
30 min of the basal and the insulin-stimulated conditions, so the rates of
appearance (Ra) and disappearance (Rd) of glucose were calculated as the
tracer infusion rate divided by the tracer to-tracee ratio as described (21).
Glucose Ra and Rd are expressed per kilogram body weight (micromoles
per kilogram body weight per minute) or per kilogram lean mass (micromoles per kilogram per lean mass per minute) to correct for changes
in kg lean mass.
(SAS Institute Inc., Cary, NC) was used. Data are presented as mean ⫾
SD if not otherwise stated. The data analyses, including baseline characteristics, were performed only for those patients who completed the
training protocol.
Results
Baseline characteristics
Of 39 patients recruited, 24 fulfilled the inclusion criteria, but
four declined to participate. Consequently, 20 patients were randomized to either strength training (n ⫽ 10) or endurance training (n ⫽ 10). Two patients, assigned to the endurance training,
withdrew from the study because of severe back pain (n ⫽ 1) and
psychiatric problems (n ⫽ 1) (Fig. 1). Compliance with the training session was 98.8 ⫾ 2.0% in the strength group and 95.8 ⫾
3.5% in the endurance group.
Energy intake and energy expenditure analysis
The patients were instructed to maintain their habitual diet. Mean daily
energy intake and expenditure were determined by registration of food intake and activity for 3 d (including one weekend day) in the beginning and
the end of the training period. The data were analyzed by a software program (DanKost Sport; Dansk Catering Center A/S, Herlev, Denmark).
Statistics
Insulin, triglycerides, FFA, HDL-cholesterol, LDL-cholesterol, and
cytokines were natural log-transformed to achieve an approximate normal distribution and equal variance. Baseline characteristics and glucose
kinetics for basal and insulin-stimulated conditions between training
groups and between HIV-infected patients and healthy controls and for
changes from baseline between training groups were compared with
unpaired t test or Pearson’s ␹2 test. Changes within groups in energy
parameters, in glucose kinetics for basal and insulin-stimulated conditions, and in ⌬-values (relative change from basal to insulin-stimulated
condition) were compared with paired t test. Changes within groups
(before and after training) and between groups (strength and endurance)
in body composition, inflammatory markers, and lipids were assessed by
a linear mixed model (PROC MIXED), where a random subject-specific
component was introduced to adjust for the interindividual variations.
The different time points for lipid and inflammatory markers were entered as a continued variable. The effect of time for body composition
values was estimated using a categorical variable (0, 8, or 16 wk). The
model allowed for an interaction term between time and group. Likelihood ratio tests were applied to assess statistical significance. The fit of
the general linear model was evaluated by testing the residuals for normality and by inspection of the residual plots. Correlations were evaluated by Pearson’s product-moment correlation. For the analyses, SAS 9.1
FIG. 1. Patients flow diagram. A total of 39 HIV-infected patients with
lipodystrophy were recruited from the outpatient clinic. Of those, 24 fulfilled the
inclusion criteria and four declined to participate. Consequently, 20 patients were
included in the study. After study start, two withdrew from the endurance group
due to psychiatric problems and back pain.
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TABLE 2. Baseline characteristics of patients and healthy controls at entry
Endurance group
(n ⴝ 8)
Age (yr)
Duration of HIV infection (yr)
Duration of antiretroviral therapy (yr)
CD4⫹ cell (cells/␮l)
LogHIV RNA (copies/ml)
Antiretroviral use
NNRTI-based HAART/
PI-based HAART/
NNRTI-, PI-based
HAART regime, no.
Current NRTI use, no. (%)
Lamivudine, no. (%)
Zidovudine, no. (%)
Stavudine, no. (%)
Tenofovir/emtricitabine, no. (%)
Abacavir, no. (%)
Current PI use, no. (%)
Current NNRTI use, no. (%)
Physical activity parameters
VO2max (LO2/min)
Upper-and lower body
strength (kg)
Body composition
Body mass index (kg/m2)
Weight (kg)
Waist (cm)
Fat mass (kg)
Trunk fat mass (kg)
Trunk fat percentage (%)
Limb fat mass (kg)
Limb fat percentage (%)
Trunk-to-limb fat ratio
Lean mass (kg)
Metabolic parameters
Total cholesterol (mmol/liter)
HDL-C (mmol/liter)
LDL-C (mmol/liter)
Triglycerides (mmol/liter)
Glucose (mmol/liter)
Insulin (pmol/liter)a
HOMA-IRa
Insulin sensitivity
Ra (␮mol glucose/kg䡠min)b
Basal
Clamp
⌬
Rd (␮mol glucose/kg䡠min)
Basal
Clamp
⌬
Glucose tolerance
Glucose area under the
curve (mmol/liter䡠min)
Insulin area under the
curve (pmol/liter䡠min)a
53.1 (8.4)
14 (7.3)
9.0 (4.6)
530 (274)
1.30 (0.05)
3/5/0
Strength group
(n ⴝ 10)
45.9 (8.0)
16 (12.2)
10.3 (3.8)
596 (196)
1.38 (0.16)
Healthy controls
(n ⴝ 15)
P value, endurance
group vs. strength
group
P value, HIV
patients vs.
healthy
47.5 (6.1)
0.09
0.5
0.3
0.5
4/5/1
8 (100)
6 (75)
4 (50)
0 (0)
3 (37.5)
3 (37.5)
5 (62.5)
3 (37.5)
10 (100)
9 (90)
6 (60)
1 (10)
1 (10)
4 (40)
6 (60)
5 (50)
2.5 (0.4)
79.8 (13.6)
2.2 (0.5)
81.0 (17.6)
2.5 (0.6)
77.2 (3.4)
0.22
0.87
24.0 (3.1)
78.4 (10.0)
94.7 (5.9)
15.3 (5.2)
10.8 (4.1)
70.3 (4.4)
3.9 (1.2)
26.2 (4.1)
2.8 (0.60)
59.9 (5.5)
23.4 (2.5)
72.5 (9.2)
94.5 (5.9)
13.5 (4.8)
9.7 (3.6)
71.5 (8.2)
3.4 (1.7)
24.8 (8.0)
3.3 (0.61)
56.2 (6.4)
23.7 (1.9)
76.9 (7.4)
90 (5.7)
15.7 (4.4)
8.9 (3.0)
56.1(5.2)
6.2 (1.5)
40.2 (4.9)
1.4 (0.29)
58.2 (5.2)
0.65
0.21
0.35
0.47
0.53
0.71
0.45
0.66
0.38
0.18
0.98
0.5
0.5
0.4
0.3
⬍0.0001
⬍0.0001
⬍0.0001
⬍0.001
0.9
4.63 (0.64)
1.51 (0.32)
3.3 (0.6)
0.76 (0.24)
5.2 (0.3)
26 (18 –31)
1.1 (0.76 – 0.3)
0.9
0.19
0.46
0.91
0.83
0.29
0.73
0.001
0.049
0.11
⬍0.0001
0.2
0.0001
0.002
5.7 (0.5)
1.06 (0.2)
3.8 (0.6)
2.3 (1.2)
5.4 (0.5)
42 (30 – 65)
1.7 (1.4 –2.6)
5.6 (1.2)
1.3 (0.5)
3.6 (0.3)
2.6 (1.9)
5.5 (1.0)
47 (39 –75)
2.0 (1.4 –2.9)
14.3 (0.49)
5.9 (2.0)
8.3 (2.06)
14.1 (1.6)
6.8 (1.8)
7.3 (2.1)
11.8 (2.0)
4.0 (2.5)
7.8 (1.9)
0.84
0.35
0.34
0.0002
0.004
0.9
14.3 (0.49)
43.0 (10.6)
28.8 (10)
14.1 (1.6)
38.0 (9.2)
23.8 (9.4)
11.8 (2.0)
48.6 (8.4)
36.81 (7.14)
0.84
0.30
0.31
0.0002
0.01
0.0015
778 (113)
924 (94)
670 (126)
0.12
0.004
0.27
⬍0.001
56880 (16230 –90420)
56055 (47970 – 67800)
23115 (15240 –29670)
Data are presented as mean (SD) or as median (interquartile ranges), as indicated, when data were log-transformed. Baseline comparisons for the HIV patients are all
P ⬎ 0.05 by t test. ⌬ , Differences between clamp and basal values; HOMA-IR, homeostatic model assessment for insulin resistance; NNRTI, nonnucleoside reverse
transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.
a
Median (interquartile range).
b
Ra and Rd of glucose during a euglycemic-hyperinsulinemic clamp performed in both HIV patients and healthy controls.
At baseline, there were no differences between groups in clinical or biochemical characteristics (Tables 2 and 3). The patients
were included on the basis of moderate lipoatrophy. All except
one participant in the strength group had also at least one sign of
fat accumulation. Compared with 15 healthy age-matched and
VO2max-matched men, the HIV-infected patients had reduced
limb fat mass, a lower percentage of fat in the limb, an increased
percentage of fat in the trunk, and an increased trunk-limb ratio.
Variable
36.5 (4.5)
2.84 (0.51)
86.0 (12.7)
5.4 (5.1–5.6)
45 (18 –72)
5.78 (5.53– 6.33)
1.05 (0.88 –1.26)
3.45 (3.07–3.90)
2.04 (1.54 –2.7)
403 (355– 487)
1.82 (0.76 – 4.36)
1.6 (1.2–2.1)
1.22 (0.88 –1.68)
340 (294 –394)
13.5 (2.6)
52.6 (5.1)
32.4 (5.2)
1.7 (3.3)
12160 (2438)
5.4 (5.1–5.6)
59 (32– 86)
5.93 (5.53– 6.33)
0.96 (0.8 –1.15)
3.64 (3.23– 4.10)
2.04 (1.54 –2.7)
436 (384 – 494)
2.42 (1.01–5.80)
1.8 (1.4 –2.3)
1.45 (1.05–2.01)
373 (322– 432)
13.5 (3.1)
49.7 (5.7)
33.5 (6.0)
3.3 (4.5)
12097 (3151)
After training
31.9 (3.8)
2.50 (0.41)
79.8 (13.6)
Before training
⫺1.1 (⫺9.3–7.1)
⫺1.6 (⫺6.2–3.0)
62.5 (⫺1742–1868)
⫺0.02 (⫺2.2–2.2)
⫺2.9 (⫺11.1–5.4)
0.69
0.60
0.9
0.98
0.45
⬍0.0001
0.009
0.010
⬍0.0001
0.017
⫺32.8 (⫺57.6, ⫺6.2)
⫺0.6 (⫺0.83 to ⫺0.39)
⫺0.19 (⫺0.34 to ⫺0.06)
⫺0.23 (⫺0.45 to ⫺0.05)
⫺32.6 (⫺45.9 –17.8)
0.9
36.3 (8.7)
3.0 (3.9)
12561 (3015)
15.3 (1.7)
45.6 (7.6)
1.54 (1.0 –2.37)
1.3 (0.99: 1.7)
1.21 (0.95–1.55)
338 (279 – 411)
579 (480 –700)
2.1 (1.53–2.87)
3.09 (2.62–3.65)
1.18 (0.88 –1.57)
⬍0.0001
0.0001
5.5 (5.0 –5.9)
56 (28 – 84)
5.7 (5.11– 6.29)
31.1 (4.6)
2.22 (0.49)
81.0 (17.6)
Before training
0.9
0.4
0.0023
0.0046
0.0029
0.0044
P value
0.005 (⫺0.08 – 0.09)
⫺0.18 (⫺0.27 to ⫺0.09)
0.09 (0.06(0.12)
0.004 (⫺0.09 – 0.1)
⫺14 (⫺51–22)
⫺0.16 (⫺0.26 to ⫺0.06)
4.6 (1.9 to 7.3)
0.34 (0.15 to 0.51)
6.3 (2.7 to 9.8)
Change (95% CI)
32.7 (6.4)
6.4 (7.6)
12398 (3655)
18.4 (2.8)
42.5 (8.4)
1.65 (1.07–2.54)
1.4 (1.1–1.9)
1.24 (0.97–1.59)
326 (268 –396)
505 (418 – 610)
1.72 (1.25–2.36)
3.25 (2.76 –3.84)
1.22 (0.91–1.64)
5.4 (4.9 –5.8)
70 (42–98)
5.68 (5.09 – 6.27)
32.5 (3.7)
2.30 (0.36)
105.3 (20)
After training
⫺3.6 (⫺8.8 –1.6)
3.4 (⫺4.8 –11.7)
⫺163 (⫺3342–3017)
3.1 (1.3– 4.9)
⫺3.1 (⫺12.5– 6.2)
0.11 (⫺0.18 – 0.35)
0.11 (⫺0.0004 – 0.21)
0.03 (⫺0.18 – 0.21)
⫺12.8 (⫺23.3 to ⫺2.7)
⫺7 ⫺74.3 (⫺123 to ⫺20.9)
0.18
0.23
0.9
0.0018
0.38
0.44
0.051
0.74
0.029
0.008
⬍0.001
⫺0.38 (⫺0.58 – 0.19)
0.52
0.88
0.79
0.23
0.30
0.39
0.16
0.39
0.42
0.06
0.91
0.18
0.005
0.52
b
0.77
0.64
0.55
0.22
0.61
0.87
0.0068
0.3
0.4
0.81
0.28
0.37
⬍0.0001
P value
0.16 (0.07– 0.25)
0.05 (0.01– 0.08)
⫺0.07 (⫺0.2– 0.05)
14 (⫺19 – 49)
⫺0.02 (⫺0.16 – 0.12)
1.39 (⫺1.4 to 4.2)
0.08 (⫺0.11 to 0.28)
24.3 (19.1 to 29.5)
Change (95% CI)
P-value,
baseline,
betweengroups
0.52
0.23
0.8
0.017
0.26
0.001
0.0018
0.09
0.4
0.66
0.0003
⬍0.0001
0.013
0.4
0.2
0.13
0.076
0.046
⬍0.0001
P-value,
change,
betweengroups
Mean changes (95% CI) and estimates (95% CI).
One outlier was due to an increase in LDL-cholesterol after strength training. After exclusion of the outlier, the mean change (95% CI) was 0.04 (⫺0.46 – 0.63) mmol/liter.
a
b
Training and Insulin Sensitivity in HIV
Plasma samples were obtained on the day of the euglycemic clamp. Data are presented as mean (SD) and mean changes (95% CI) and estimates (95% CI), as indicated. HOMA-IR, Homeostatic model assessment for insulin
resistance.
Physical fitness
VO2max (ml O2/kg䡠min)
VO2max (liters O2/min)
3-RM for six muscle
groups (kg)
Metabolic parameters
Glucose (mmol/liter)a
Insulin (␳mol/liter)a
Total cholesterol
(mmol/liter)a
HDL-cholesterol (mmol/
liter)a
LDL-cholesterol (mmol/
liter)a
Triglycerides
(mmol/liter)a
FFA (␮mol/liter)a
Inflammatory parameters
HS-CRPa
TNF-␣ (pg/ml)a
IL-6 (pg/ml)a
IL-18 (pg/mL)a
Energy parameters
% energy from protein
% energy from
carbohydrate
% energy from fat
% energy from alcohol
Energy expenditure (kJ)
Strength training (n ⴝ 10)
Lindegaard et al.
Endurance training (n ⴝ 8)
TABLE 3. The effect of endurance and strength training on physical fitness, metabolic, inflammatory, and energy parameters in HIV-infected patients with lipodystrophy
3864
J Clin Endocrinol Metab, October 2008, 93(10):3860 –3869
J Clin Endocrinol Metab, October 2008, 93(10):3860 –3869
Although insulin resistance was not an inclusion criteria,
HIV-infected patients had increased plasma insulin and glucose
and insulin areas under the curves during an OGTT (Table 2).
During basal conditions, HIV-infected patients had increased glucose Rd and Ra compared with healthy controls
(Table 1). Glucose Ra during insulin-stimulated condition was
higher in HIV-patients compared with controls, but the ⌬Ra
did not differ between groups. Glucose Rd during insulinstimulated condition and ⌬Rd were lower in HIV-patients
compared with controls.
Effect of strength and endurance training on insulin
sensitivity
During basal (Table 2) and insulin-stimulated conditions,
plasma insulin and glucose were unchanged with both training
modalities [plasma insulin during the insulin-stimulated condition: endurance training, 518 pmol/liter (95% CI, 480 to 572) to
573 pmol/liter (95% CI, 465 to 700), P ⫽ 0.13; strength training:
514 pmol/liter (95% CI, 464 to 570) to 481 pmol/liter (95% CI,
454 to 616), P ⫽ 0.36].
jcem.endojournals.org
3865
Training did not influence glucose Ra (Fig. 2A) and glucose Rd
(Fig. 2B) during basal conditions. Glucose Ra was not influenced
by training during the insulin-stimulated condition.
Glucose Rd increased during insulin-stimulated condition
with both endurance training (⬃15.6%; 43.03 ⫾ 10.6 to 49.7 ⫾
10 ␮mol glucose/kg body weight䡠min, P ⫽ 0.005) and strength
training (⬃25.0%; 38.0 ⫾ 9.2 to 47.6 ⫾ 15 ␮mol glucose/kg
body weight䡠min, P ⫽ 0.003), irrespective of training modality
(P ⫽ 0.24). ⌬Rd increased also significantly with both endurance
training (⬃22.7%; 28.8 ⫾ 10 to 35.3 ⫾ 10.5 ␮mol glucose/kg
body weight䡠min, P ⫽ 0.008) and strength training (⬃42.6%;
23.8 ⫾ 9.4 to 34.0 ⫾ 15 ␮mol glucose/kg body weight䡠min P ⫽
0.002), irrespective of training modality (P ⫽ 0.26).
When Rd was expressed by lean body mass, the increases in
insulin-stimulated glucose Rd (endurance training: 55.7 ⫾ 14 to
63.0 ⫾ 11 ␮mol glucose/kg lean body mass䡠min, ⬃13.6%, P ⫽
0.02; strength training: 49.0 ⫾ 12 to 57.8 ⫾ 18 ␮mol glucose/kg
lean body mass䡠min, ⬃18%, P ⫽ 0.002) and ⌬Rd (endurance
training: 37.0 ⫾ 12.5 to 44.7 ⫾ 11.5 ␮mol glucose/kg lean body
mass䡠min, ⬃20.8%, P ⫽ 0.019; strength training: 30.8 ⫾ 12 to
FIG. 2. Glucose Ra (A) and Rd (B) expressed as micromoles per kilogram body weight per minute and Glucose Ra (C) and Rd (D) expressed as micromoles per kilogram
lean body mass per minute before and after 16 wk of endurance and strength training. Basal indicates no insulin infusion, and clamp indicates 50 mU/m2䡠min insulin
infusion. Data are presented as mean (SD). *, P ⬍ 0.05; **, P ⬍ 0.01 for insulin-stimulated Rd before and after 16 wk of training within each group. †, P ⬍ 0.001; ††,
P ⬍ 0.0001 clamp vs. basal stage.
3866
Lindegaard et al.
Training and Insulin Sensitivity in HIV
41.3 ⫾ 17.8 ␮mol glucose/kg lean body mass䡠min, ⬃34%, P ⫽
0.0018) were still significant.
⌬Rd achieved after both training modalities was comparable
to that of the untrained controls [mean difference (95% confidence interval, CI), ⫺1.51 (⫺9.2 to 6.2) ␮mol glucose/kg body
weight䡠min endurance training vs. controls (P ⫽ 0.68), ⫺2.8
(⫺12.1 to 6.4) ␮mol glucose/kg body weight䡠min strength training vs. controls, respectively, P ⫽ 0.53).
Effect of strength and endurance training on body
composition
Strength training decreased body weight, increased lean body
mass [estimate (95% CI) 2.06 (0.8 to 3.3) kg], decreased total fat
[⫺3.3 (⫺4.6 to ⫺2.0) kg], trunk fat [⫺2.50 (⫺3.5 to ⫺1.5) kg],
and limb fat mass [⫺0.75 (⫺1.1 to ⫺0.4) kg], whereas endurance
training led to no differences (Fig. 3). Strength training decreased
total fat mass (P ⫽ 0.023) and limb fat mass (P ⫽ 0.003) to a
larger extent than endurance training.
Effect of strength and endurance training on physical
fitness
Endurance training increased VO2max by 14.4% (P ⬍ 0.01)
with no difference after strength training (Table 3). Strength
J Clin Endocrinol Metab, October 2008, 93(10):3860 –3869
training increased strength by 30% (P ⬍ 0.0001) and endurance training increased strength by 7.8% (P ⫽ 0.01). The
increase was more pronounced after strength training than
after endurance training (P ⬍ 0.0001) (Table 2).
Effect of strength and endurance training on lipid
profile
Total cholesterol, LDL-cholesterol, and FFA decreased and
HDL-cholesterol increased after endurance training, whereas triglycerides and FFA decreased and LDL- and HDL-cholesterol increased after strength training (Table 3). The increase in LDL-cholesterol was due to one outlier with very low baseline values. After
exclusion of the outlier, LDL-cholesterol did not change after
strength training (P ⫽ 0.29).
Effect of strength and endurance training on
inflammatory markers
Plasma high-sensitivity C-reactive protein (HS-CRP),
TNF-␣, IL-6, and IL-18 decreased after endurance training,
but only plasma IL-18 decreased after strength training
(Table 3).
FIG. 3. Changes in body composition. Estimate changes (95% CI) in body weight (A), total lean mass (B), total fat mass (C), trunk fat mass (D) and limb fat mass (E)
before, after 8 wk, and after 16 wk of endurance training and strength training. Training effect within groups and between groups was estimated using a mixed
model. **, P ⬍ 0.01; ***, P ⬍ 0.0001 within strength group. #, P ⬍ 0.05; ##, P ⬍ 0.01 between groups.
J Clin Endocrinol Metab, October 2008, 93(10):3860 –3869
Effect of strength and endurance training on energy
intake
The total energy intake and carbohydrate and fat intake were
unchanged with training. The protein intake increased significantly after strength training. Energy expenditure did not change
over time in either group (Table 3).
Correlation between changes in body composition and
insulin sensitivity
Change in ⌬Rd correlated with changes in limb lean mass after
strength training (r ⫽ 0.85; P ⫽ 0.0018) but not after endurance
training (r ⫽ ⫺0.038; P ⫽ 0.92). There was no correlation between change in fat mass and change in ⌬Rd (strength group: r ⫽
⫺0.52, P ⫽ 0.12; endurance group: r ⫽ 0.21, P ⫽ 0.61).
Discussion
The major findings of the present study were that both
strength training and endurance training improved insulinmediated glucose uptake, but only strength training, and not
endurance training, caused a reduction in total fat mass. Both
training modalities were tolerated well by the participants.
The obtained level of peripheral insulin sensitivity after training was comparable to the level found in untrained agematched HIV-negative controls in the present study and to
that achieved in HIV-negative individuals without (26) or
with insulin resistance after both training modalities (6, 27,
28). Previous studies in HIV-infected patients did not report
significant findings on insulin sensitivity after endurance
training alone or combined with strength training, probably
due to the use of indirect measurements (homeostatic model
assessment for insulin resistance, 2-h glucose) (9 –12).
A strength training-induced improvement in insulin sensitivity has previously been ascribed to an increase in lean body mass
(29, 30). However, we found that an increase in insulin-stimulated glucose uptake, before correction for the change in lean
body mass, represents an increase of 42.6% after strength training and 34% after correction for the increase in lean body mass.
Therefore, the increase in insulin-stimulated glucose uptake is
not solely mediated by increased muscle mass. This is in agreement with other studies (6, 26 –28).
The strength training group appeared to have an increased
protein intake, a fact that potentially may have led to an effect on
muscle mass (31).
Our study is the first to compare the effect of the two training
modalities in HIV-infected patients, and only few studies exist in
HIV-negative individuals (5– 8, 30). Two studies apply the clamp
technique and find an increase in insulin sensitivity after endurance training in nonobese healthy young women (30) but an
increase in insulin sensitivity after both training modalities in
elderly men (8). Using indirect methods, strength training increases insulin sensitivity in all studies (5–7, 32), whereas
endurance training has an effect only in some studies (5, 7, 32).
Training did not enhance hepatic insulin sensitivity in contrast to the findings by Shojaee-Maradie et al. (33). The discrepancy may be explained by the use of different insulin doses.
jcem.endojournals.org
3867
Body weight did not change after endurance training, but
decreased after strength training despite an increase in lean body
mass. The weight reduction was due to a decrease in total fat and
in particular to a decrease in trunk fat of approximately 2 kg.
This finding is in contrast to Yarasheski et al. (12) despite a
similar training program. We are unable to explain this discrepancy. Of note, however, is that the patients in our study had more
pronounced lipodystrophy with both more advanced lipoatrophy and more central fat accumulation compared with the patients in the study by Yarasheski et al. (12).
Surprisingly, endurance training did not alter trunk fat in
contrast to other studies in HIV-negative individuals (3, 34). In
HIV-infected patients, endurance training was found to decrease
total fat mass in one study (14) but not in another (9), although
visceral fat was reduced (9). Unfortunately, we did not measure
visceral fat, and although trunk fat is likely to reflect intraabdominal fat, small changes in visceral fat cannot be detected by
dual-energy x-ray absorptiometry scan. Our study indicates that a
major loss of trunk fat is not required to improve insulin sensitivity
after endurance training, which adds to previous reports (27, 35).
Insulin resistance in HIV-infected patients with lipodystrophy is believed to be a result of the reduction in peripheral sc fat
(36). Although strength training induced a minor decrease in sc
fat, the improved metabolism of these patients suggests an overall beneficial effect of strength training on body composition.
HIV-infected patients with lipodystrophy are characterized
by decreased HDL-cholesterol levels and increased plasma levels
of triglycerides and FFA. The increase in plasma FFA is due to
increased lipolysis from adipose tissue (37, 38) and an inadequate lipid oxidation, although lipid oxidation is increased (37).
Interestingly, both modes of training influenced the lipid profile,
but in different manners. Endurance training had beneficial effects on both HDL- and LDL-cholesterols, whereas strength
training increased HDL-cholesterol. Changes in HDL-cholesterol after endurance training are in accordance with the literature regarding HIV-negative individuals (34). To our surprise,
we did not see any reduction in triglycerides after endurance
training, in contrast to a reduction after strength training as
previously reported (12). It remains unclear why changes in triglycerides were evident in the strength training group only. However, an increase in muscle mass may enhance triglyceride clearance from the circulation as proposed by Yarasheski et al. (12).
During standardized exercise, HIV-infected patients with lipodystrophy are characterized by mitochondrial dysfunction (39),
and this has been proposed to represent one of the underlying
mechanisms for dyslipidemia in HIV-infected patients with lipodystrophy (40). Therefore, the effect of endurance training on
mitochondrial biogenesis and lipid oxidation (41) may not be
achieved in HIV-infected patients with lipodystrophy. Furthermore, a recent study showed that HIV-infected patients receiving
HAART have a blunted lipolytic response and lipid oxidation in
skeletal muscle in response to moderate exercise probably due to
a failure to mobilize FFA from the adipose tissue stores (42). This
impairment may explain the lack of a reduction in triglycerides
and in trunk fat mass in response to endurance training in our
study.
Our study is the first to investigate the effect on inflammatory
3868
Lindegaard et al.
Training and Insulin Sensitivity in HIV
markers in response to training in HIV-infected patients. Both
endurance and strength training induced a decrease in plasma
IL-18, whereas endurance training also decreased other inflammatory markers (TNF-␣, IL-6, and HS-CRP). The finding that
both training modalities had marked effects on insulin sensitivity
might point to a possible pathogenetic effect of IL-18, more than
that of other cytokines. An antiinflammatory effect of endurance
training in HIV-infected patients with lipodystrophy adds to previous studies in other groups of patients (43, 44). Because TNF-␣
negatively regulates insulin signaling and whole-body glucose
uptake in humans (23), the reduction in plasma TNF-␣ in the
present study may be related to the increased insulin-mediated
glucose uptake.
Strength training, however, had no effect on HS-CRP,
TNF-␣, and IL-6, in accordance with previous studies (27, 45),
suggesting that at least this training mode may exert its beneficial
effect on glucose metabolism independently of an antiinflammatory effect.
Our study has several limitations. The study lacks a sedentary
control group to adjust for co-intervention of starting a training
regime in a health center, and it includes a small number of
patients. It was difficult to recruit more participants because
many patients already performed strength training; however, we
obtained the desired primary and secondary endpoints and
found differences between strength and endurance training in fat
mass, lipid profile, and inflammatory markers. A small n-value
may have resulted in inadequate power to determine baseline
differences. The endurance training group was 7 yr older than the
strength training group, but this was not significant due to small
group sizes.
In conclusion, we have demonstrated that both endurance
training and strength training increase insulin sensitivity in HIVinfected patients with lipodystrophy, whereas only strength
training reduces trunk fat mass. On the other hand, several epidemiological studies in persons without HIV infection demonstrate that a high fitness level offers protection against cardiovascular diseases and premature mortality (46). Therefore,
we suggest that an appropriate exercise program should include strength training as well as endurance training to reduce
the risk of cardiovascular diseases in HIV-infected patients
with lipodystrophy.
Acknowledgments
We thank the subjects for their participation in this study. Ruth Rousing,
Hanne Willumsen, Carsten Nielsen, and Flemming Jessen are thanked
for their excellent technical help. The Danish HIV-Cohort is thanked for
providing us with HIV-related data.
Address all correspondence and requests for reprints to: Birgitte
Lindegaard, Centre of Inflammation and Metabolism, Rigshospitalet–7641, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Email:
[email protected].
The Centre of Inflammation and Metabolism is supported by a grant
from Danish National Research Foundation (02-512-55). The Copenhagen Muscle Research Centre is supported by grants from the Copenhagen Hospital Corp., the University of Copenhagen, and the Faculties
of Science and of Health Sciences at this University. The study was further
J Clin Endocrinol Metab, October 2008, 93(10):3860 –3869
supported by the Danish Medical Research Council (22-04-0588), the
Lundbeck Foundation, the Danish AIDS Foundation, the Novo Nordisk
Foundation, Direktør Emil Hertz og Hustru Inger Hertz⬘ Fond, Direktør
Jacob Madsen og Hustru Olga Madsens Fond, Fonden for Lægevidenskabens Fremme, Kong Christian den Tiendes Fond, Brødrene Hartmanns Fond, and Ragnhild Ibsens Legat.
Disclosure Statement: The authors have nothing to disclose.
References
1. Grinspoon S, Carr A 2005 Cardiovascular risk and body-fat abnormalities in
HIV-infected adults. N Engl J Med 352:48 – 62
2. Friis-Moller N, Sabin CA, Weber R, D’Arminio MA, El Sadr WM, Reiss P,
Thiebaut R, Morfeldt L, De Wit S, Pradier C, Calvo G, Law MG, Kirk O,
Phillips AN, Lundgren JD 2003 Combination antiretroviral therapy and the
risk of myocardial infarction. N Engl J Med 349:1993–2003
3. Snowling NJ, Hopkins WG 2006 Effects of different modes of exercise training
on glucose control and risk factors for complications in type 2 diabetic patients:
a meta-analysis. Diabetes Care 29:2518 –2527
4. Braith RW, Stewart KJ 2006 Resistance exercise training: its role in the prevention of cardiovascular disease. Circulation 113:2642–2650
5. Smutok MA, Reece C, Kokkinos PF, Farmer C, Dawson P, Shulman R, DeVaneBell J, Patterson J, Charabogos C, Goldberg AP 1993 Aerobic versus strength
training for risk factor intervention in middle-aged men at high risk for coronary heart disease. Metabolism 42:177–184
6. Eriksson J, Tuominen J, Valle T, Sundberg S, Sovijarvi A, Lindholm H,
Tuomilehto J, Koivisto V 1998 Aerobic endurance exercise or circuit-type
resistance training for individuals with impaired glucose tolerance? Horm
Metab Res 30:37– 41
7. Smutok MA, Reece C, Kokkinos PF, Farmer CM, Dawson PK, DeVane J,
Patterson J, Goldberg AP, Hurley BF 1994 Effects of exercise training modality
on glucose tolerance in men with abnormal glucose regulation. Int J Sports Med
15:283–289
8. Ferrara CM, Goldberg AP, Ortmeyer HK, Ryan AS 2006 Effects of aerobic and
resistive exercise training on glucose disposal and skeletal muscle metabolism
in older men. J Gerontol A Biol Sci Med Sci 61:480 – 487
9. Thoni GJ, Fedou C, Brun JF, Fabre J, Renard E, Reynes J, Varray A, Mercier
J 2002 Reduction of fat accumulation and lipid disorders by individualized
light aerobic training in human immunodeficiency virus infected patients with
lipodystrophy and/or dyslipidemia. Diabetes Metab 28:397– 404
10. Dolan SE, Frontera W, Librizzi J, Ljungquist K, Juan S, Dorman R, Cole ME,
Kanter JR, Grinspoon S 2006 Effects of a supervised home-based aerobic and
progressive resistance training regimen in women infected with human immunodeficiency virus: a randomized trial. Arch Intern Med 166:1225–1231
11. Robinson FP, Quinn LT, Rimmer JH 2007 Effects of high-intensity endurance
and resistance exercise on HIV metabolic abnormalities: a pilot study. Biol Res
Nurs 8:177–185
12. Yarasheski KE, Tebas P, Stanerson B, Claxton S, Marin D, Bae K, Kennedy M,
Tantisiriwat W, Powderly WG 2001 Resistance exercise training reduces hypertriglyceridemia in HIV-infected men treated with antiviral therapy. J Appl
Physiol 90:133–138
13. Driscoll SD, Meininger GE, Lareau MT, Dolan SE, Killilea KM, Hadigan CM,
Lloyd-Jones DM, Klibanski A, Frontera WR, Grinspoon SK 2004 Effects of
exercise training and metformin on body composition and cardiovascular indices in HIV-infected patients. AIDS 18:465– 473
14. Smith BA, Neidig JL, Nickel JT, Mitchell GL, Para MF, Fass RJ 2001 Aerobic
exercise: effects on parameters related to fatigue, dyspnea, weight and body
composition in HIV-infected adults. AIDS 15:693–701
15. Jones SP, Doran DA, Leatt PB, Maher B, Pirmohamed M 2001 Short-term
exercise training improves body composition and hyperlipidaemia in HIVpositive individuals with lipodystrophy. AIDS 15:2049 –2051
16. Roubenoff R, Weiss L, McDermott A, Heflin T, Cloutier GJ, Wood M,
Gorbach S 1999 A pilot study of exercise training to reduce trunk fat in
adults with HIV-associated fat redistribution. AIDS 13:1373–1375
17. Roubenoff R, McDermott A, Weiss L, Suri J, Wood M, Bloch R, Gorbach S
1999 Short-term progressive resistance training increases strength and lean
body mass in adults infected with human immunodeficiency virus. AIDS 13:
231–239
18. Astrand I, Astrand PO, Hallback I, Kilbom A 1973 Reduction in maximal
oxygen uptake with age. J Appl Physiol 35:649 – 654
19. Carr A, Emery S, Law M, Puls R, Lundgren JD, Powderly WG 2003 An
objective case definition of lipodystrophy in HIV-infected adults: a case-control study. Lancet 361:726 –735
J Clin Endocrinol Metab, October 2008, 93(10):3860 –3869
20. Buchfuhrer MJ, Hansen JE, Robinson TE, Sue DY, Wasserman K, Whipp BJ
1983 Optimizing the exercise protocol for cardiopulmonary assessment.
J Appl Physiol 55:1558 –1564
21. Lindegaard B, Frosig C, Petersen AM, Plomgaard P, Ditlevsen S, Mittendorfer
B, van Hall G, Wojtaszewski JF, Pedersen BK 2007 Inhibition of lipolysis
stimulates peripheral glucose uptake but has no effect on endogenous glucose
production in HIV lipodystrophy. Diabetes 56:2070 –2077
22. DeFronzo RA, Tobin JD, Andres R 1979 Glucose clamp technique: a method
for quantifying insulin secretion and resistance. Am J Physiol 237:E214 –E223
23. Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR,
Pedersen BK 2005 Tumor necrosis factor-␣ induces skeletal muscle insulin
resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. Diabetes 54:2939 –2945
24. Brzycki M 1993 Strength testing: predicting a one-rep max from reps-tofatigue. The Journal of Physical Education, Recreation & Dance 64:88 –90
25. Lindegaard B, Keller P, Bruunsgaard H, Gerstoft J, Pedersen BK 2004 Low
plasma level of adiponectin is associated with stavudine treatment and lipodystrophy in HIV-infected patients. Clin Exp Immunol 135:273–279
26. Miller JP, Pratley RE, Goldberg AP, Gordon P, Rubin M, Treuth MS, Ryan AS,
Hurley BF 1994 Strength training increases insulin action in healthy 50- to
65-yr-old men. J Appl Physiol 77:1122–1127
27. Klimcakova E, Polak J, Moro C, Hejnova J, Majercik M, Viguerie N, Berlan
M, Langin D, Stich V 2006 Dynamic strength training improves insulin
sensitivity without altering plasma levels and gene expression of adipokines
in subcutaneous adipose tissue in obese men. J Clin Endocrinol Metab
91:5107–5112
28. Holten MK, Zacho M, Gaster M, Juel C, Wojtaszewski JF, Dela F 2004
Strength training increases insulin-mediated glucose uptake, GLUT4 content,
and insulin signaling in skeletal muscle in patients with type 2 diabetes. Diabetes 53:294 –305
29. Yki-Jarvinen H, Koivisto VA 1983 Effects of body composition on insulin
sensitivity. Diabetes 32:965–969
30. Poehlman ET, Dvorak RV, DeNino WF, Brochu M, Ades PA 2000 Effects of
resistance training and endurance training on insulin sensitivity in nonobese,
young women: a controlled randomized trial. J Clin Endocrinol Metab 85:
2463–2468
31. Tipton KD, Elliott TA, Cree MG, Wolf SE, Sanford AP, Wolfe RR 2004
Ingestion of casein and whey proteins result in muscle anabolism after resistance exercise. Med Sci Sports Exerc 36:2073–2081
32. Polak J, Moro C, Klimcakova E, Hejnova J, Majercik M, Viguerie N, Langin
D, Lafontan M, Stich V, Berlan M 2005 Dynamic strength training improves
insulin sensitivity and functional balance between adrenergic ␣2A and ␤
pathways in subcutaneous adipose tissue of obese subjects. Diabetologia
48:2631–2640
33. Shojaee-Moradie F, Baynes KC, Pentecost C, Bell JD, Thomas EL, Jackson
NC, Stolinski M, Whyte M, Lovell D, Bowes SB, Gibney J, Jones RH, Umpleby
jcem.endojournals.org
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
3869
AM 2007 Exercise training reduces fatty acid availability and improves the
insulin sensitivity of glucose metabolism. Diabetologia 50:404 – 413
Fletcher GF, Balady G, Blair SN, Blumenthal J, Caspersen C, Chaitman B,
Epstein S, Sivarajan Froelicher ES, Froelicher VF, Pina IL, Pollock ML 1996
Statement on exercise: benefits and recommendations for physical activity
programs for all Americans. A statement for health professionals by the Committee on Exercise and Cardiac Rehabilitation of the Council on Clinical Cardiology, American Heart Association. Circulation 94:857– 862
Dengel DR, Pratley RE, Hagberg JM, Rogus EM, Goldberg AP 1996 Distinct
effects of aerobic exercise training and weight loss on glucose homeostasis in
obese sedentary men. J Appl Physiol 81:318 –325
Mynarcik DC, McNurlan MA, Steigbigel RT, Fuhrer J, Gelato MC 2000
Association of severe insulin resistance with both loss of limb fat and elevated
serum tumor necrosis factor receptor levels in HIV lipodystrophy. J Acquir
Immune Defic Syndr 25:312–321
Sekhar RV, Jahoor F, White AC, Pownall HJ, Visnegarwala F, RodriguezBarradas MC, Sharma M, Reeds PJ, Balasubramanyam A 2002 Metabolic
basis of HIV-lipodystrophy syndrome. Am J Physiol Endocrinol Metab 283:
E332–E337
Hadigan C, Borgonha S, Rabe J, Young V, Grinspoon S 2002 Increased rates
of lipolysis among human immunodeficiency virus-infected men receiving
highly active antiretroviral therapy. Metabolism 51:1143–1147
Chapplain JM, Beillot J, Begue JM, Souala F, Bouvier C, Arvieux C, Tattevin
P, Dupont M, Chapon F, Duvauferrier R, Hespel JP, Rochcongar P,
Michelet C 2004 Mitochondrial abnormalities in HIV-infected lipoatrophic patients treated with antiretroviral agents. J Acquir Immune Defic
Syndr 37:1477–1488
Oh J, Hegele RA 2007 HIV-associated dyslipidaemia: pathogenesis and treatment. Lancet Infect Dis 7:787–796
Menshikova EV, Ritov VB, Toledo FG, Ferrell RE, Goodpaster BH, Kelley
DE 2005 Effects of weight loss and physical activity on skeletal muscle
mitochondrial function in obesity. Am J Physiol Endocrinol Metab 288:
E818 –E825
Cade WT, Reeds DN, Mittendorfer B, Patterson BW, Powderly WG, Klein S,
Yarasheski KE 2007 Blunted lipolysis and fatty acid oxidation during moderate exercise in HIV-infected subjects taking HAART. Am J Physiol Endocrinol Metab 292:E812–E819
Goldhammer E, Tanchilevitch A, Maor I, Beniamini Y, Rosenschein U, Sagiv
M 2005 Exercise training modulates cytokines activity in coronary heart disease patients. Int J Cardiol 100:93–99
Kondo T, Kobayashi I, Murakami M 2006 Effect of exercise on circulating
adipokine levels in obese young women. Endocr J 53:189 –195
Rall LC, Roubenoff R, Cannon JG, Abad LW, Dinarello CA, Meydani SN
1996 Effects of progressive resistance training on immune response in aging
and chronic inflammation. Med Sci Sports Exerc 28:1356 –1365
Blair SN, Cheng Y, Holder JS 2001 Is physical activity or physical fitness more
important in defining health benefits? Med Sci Sports Exerc 33:S379 –S399