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Exercise Training Rapidly Increases Hepatic

Insulin Extraction in NAFLD
ADITHYA HARI1, CIARÀN E. FEALY2, CHRISTOPHER L. AXELROD5, JACOB M. HAUS3, CHRIS A. FLASK1,
ARTHUR J. MCCULLOUGH4, and JOHN P. KIRWAN1,5
1
Case Western Reserve University, Cleveland, OH; 2Nutrition and Movement Sciences, Maastricht University, Maastricht, The
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NETHERLANDS; 3Human Bioenergetics Laboratory, University of Michigan, Ann Arbor, MI; 4Department of Gastroenterology
and Hepatology, Cleveland Clinic, Cleveland, OH; and 5Integrated Physiology and Molecular Medicine Laboratory, Pennington
Biomedical Research Center, Baton Rouge, LA

ABSTRACT
HARI, A., C. E. FEALY, C. L. AXELROD, J. M. HAUS, C. A. FLASK, A. J. MCCULLOUGH, and J. P. KIRWAN. Exercise Training
Rapidly Increases Hepatic Insulin Extraction in NAFLD. Med. Sci. Sports Exerc., Vol. 52, No. 7, pp. 1449–1455, 2020. Purpose: We aimed
to determine the immediacy of exercise intervention on liver-specific metabolic processes in nonalcoholic fatty liver disease. Methods: We
undertook a short-term (7-d) exercise training study (60 min·d−1 treadmill walking at 80%–85% of maximal heart rate) in obese adults
(N = 13, 58 ± 3 yr, 34.3 ± 1.1 kg·m−2, >5% hepatic lipid by 1H-magnetic resonance spectroscopy). Insulin sensitivity index was estimated
by oral glucose tolerance test using the Soonthorpun model. Hepatic insulin extraction (HIE) was calculated as the molar difference in area
under the curve (AUC) for insulin and C-peptide (HIE = 1 − (AUCInsulin/AUCC-Pep)). Results: The increases in HIE, V̇O2max, and insulin
sensitivity index after the intervention were 9.8%, 9.8%, and 34%, respectively (all, P < 0.05). Basal fat oxidation increased (pre: 47 ±
6 mg·min−1 vs post: 65 ± 6 mg·min−1, P < 0.05) and carbohydrate oxidation decreased (pre: 160 ± 20 mg·min−1 vs post: 112 ± 15 mg·min−1,
P < 0.05) with exercise training. After the intervention, HIE correlated positively with adiponectin (r = 0.56, P < 0.05) and negatively with
TNF-α (r = −0.78, P < 0.001). Conclusions: By increasing HIE along with peripheral insulin sensitivity, aerobic exercise training rapidly re-
verses some of the underlying physiological mechanisms associated with nonalcoholic fatty liver disease, in a weight loss-independent man-
ner. This reversal could potentially act through adipokine-related pathways. Key Words: AEROBIC EXERCISE TRAINING, NAFLD,
HEPATIC INSULIN EXTRACTION

N
onalcoholic fatty liver disease (NAFLD), character-
ized by excessive accumulation of fat in the liver, is
commonly associated with obesity-related comorbid-
ities such as type 2 diabetes, dyslipidemia, and metabolic syn-
drome. It is estimated that the incidence of NAFLD in the
United States is approximately 25% of the adult population
(1). The natural history of NAFLD includes a slow progression
from simple steatosis (hepatocyte ballooning) to steatohepatitis
(steatosis + inflammation) and then a faster progression toward
fibrosis, cirrhosis, and, in a more limited number of cases,
Address for Correspondence: John P. Kirwan, Ph.D., F.A.C.S.M., Pennington
Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808;
E-mail: John.Kirwan@pbrc.edu.
Submitted for publication August 2019.
Accepted for publication December 2019.
0195-9131/20/5207-1449/0
MEDICINE & SCIENCE IN SPORTS & EXERCISE®
Copyright © 2020 by the American College of Sports Medicine.
DOI: 10.1249/MSS.0000000000002273
hepatocellular carcinoma (2). The severity of NAFLD and its
progression toward cirrhosis and liver failure are associated
with escalating risk toward atherogenesis and cardiovascular
disease (3,4). Slowing down, or possibly reversing, the pro-
gression of NAFLD to advanced fibrosis has an immense po-
tential to reduce the societal cardiovascular and general health
risk burden.
There are no effective and safe pharmacological agents for
treating NAFLD (5), as metformin and thiazolidinediones have
been shown to improve liver histology only after inflammation
sets in (commonly referred to as nonalcoholic steatohepatitis,
or NASH). Previously, it was reported that bariatric surgery in-
duced long-term improvements in liver histology in patients
with grade 3 obesity and NASH (6,7). Interestingly, the long-
term effectiveness of bariatric surgery for improving liver pa-
thology was predicted by early improvements in whole-body
insulin sensitivity. Weight loss (~5% to 10%) achieved by a
combination of physical activity and hypocaloric diet is the
mainstay of therapy for NAFLD and NASH (5). However,
the amount weight loss achieved, even in a tightly regulated

1449

Copyright © 2020 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
 setting, is highly variable (8). In this study, we sought to deter-
mine whether short-term aerobic exercise training could mani-
fest metabolic improvement in liver-related outcomes.
The liver plays a critical role in maintaining peripheral insu-
lin concentrations relative to insulin secretion by regulating the
first-pass metabolism of insulin, a phenomenon known as “he-
patic insulin extraction” (HIE). In healthy adults, ~50% to 80%
of secreted insulin (in the portal vein) is extracted and cleared
by hepatocytes (9). Meier et al. (9) found that both the amount
of insulin secreted in a pulsatile fashion and the amplitude of the
pulsatile peak were positively correlated with hepatic insulin
clearance and delivery of insulin to the circulation. Incretins,
like GLP-1, can also theoretically influence HIE primarily by
modulating the degree of insulin secretion. Although the pres-
ence of hepatic insulin resistance is established in NAFLD
(10), the relationship with liver fat content is strongly debated
(11,12). Understanding these intricate relationships is important
BASIC SCIENCES
to devise targeted therapies to manage NAFLD. In this study, we
explored whether HIE is related to liver fat content and/or periph-
eral insulin resistance. Second, we evaluated whether HIE is
modulated by aerobic exercise, independent of weight loss.
METHODS
The recruitment and methods have been previously described
(13) (Fig. 1). Briefly, 13 obese, sedentary adults (age, 58 ± 3.4 yr;
body mass index, 34.3 ± 1.1 kg·m−2) with radiographically
confirmed NAFLD (>5% intrahepatic lipid (IHL) content)
were enrolled into a short-term, 7-d exercise intervention. Af-
ter obtaining informed consent, individuals underwent a med-
ical screening, physical examination, oral glucose tolerance
test (OGTT), and blood analyses including a lipid panel and
liver enzymes to estimate hepatic function. The exclusion
criteria included individuals with any active disease condition,
use of medications known to affect study outcomes, individual
alcohol consumption >20 g·d−1 for men and >10 g·d−1 for
women, ongoing exercise or weight loss programs, any con-
traindications to exercise (as detected during a 12-lead elec-
trocardiogram exercise test), and postmenopausal status or
hormonal replacement therapy in women. This study was
approved by Cleveland Clinic Institutional Review Board.
FIGURE 1—Schematic of study design. Procedures are listed according to the chronological sequence of the day.
1450 Official Journal of the American College of Sports Medicine
Copyright © 2020 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
All participants signed informed consent forms before study
participation.
Cardiorespiratory fitness. Physical activity levels were
estimated using the Minnesota Leisure Time Physical Activity
Questionnaire (14). The subjects were deemed sedentary if
they expended <300 kcal·d−1 of energy through their leisure
time activity. An incremental graded treadmill exercise test
was conducted to determine the participant’s maximal oxygen
consumption (V̇O2max) as previously reported (15). Expired
air was continuously sampled using an automated sampler
(Jaeger Oxycon Pro; Viasys, Yorba Linda, CA). Heart rate
was continuously captured during each exercise session. Max-
imal heart rate was used to prescribe exercise intensity during
the exercise training sessions (Polar Electro Inc., Woodbury,
NY). The test was deemed satisfactory if ≥3 of the following
criteria were attained: 1) a respiratory quotient of >1.10, 2) self-
determined fatigue, 3) heart rate at <10 bpm of age-predicted
maximum, and (4) plateau in oxygen consumption with increasing
workloads. Participants abstained from coffee and alcohol
consumption for 12 and 48 h, respectively, before exercise testing.
Body composition. Height and body weight were mea-
sured using standard techniques. Whole-body fat distribution
was measured by dual-energy x-ray absorptiometry (Lunar
model iDXA, Madison, WI).
Aerobic exercise intervention. Study participants com-
pleted 60 min of supervised aerobic exercise on a treadmill at
~85% of HRmax daily for seven consecutive days. They were
instructed to maintain current diet during this intervention period.
Substrate metabolism. After an overnight fast, partici-
pants were admitted to the Clinical Research Unit, rested
for ~30 min, and indirect calorimetry was conducted to esti-
mate energy expenditure and substrate metabolism. Exhaled
air was continuously sampled for ~15 min using an automated
system under a ventilated hood until steady state was achieved.
Energy expenditure, and rates of carbohydrate and fat oxidation
were calculated as previously described (16).
Glucose metabolism. After indirect calorimetry, a stan-
dard 75-g OGTT was performed at ~8:00 AM before and after
the 7-d exercise intervention. An intravenous catheter was
placed in an antecubital vein and secured with a saline lock.
After the baseline draws, the glucose drink was consumed
http://www.acsm-msse.org
and whole-blood samples were drawn in plastic tubes contain-
ing EDTA at 30, 60, 90, 120, and 180 min after ingestion. In-
cremental area under the curve (iAUC) was calculated using
the trapezoidal equation after baseline correction. Insulin sensitiv-
ity index (ISI) was estimated using the Soonthorpun model (17):
h i
1:9
 BW  FPG þ 520− 1:9
Uglu
6 18  BW  AUCglu − 1:8
ISIðOGTTÞ ¼
ðAUCins  BWÞ
Here, BW is the body weight in kilograms; AUCglu, area under
the glucose curve after glucose load for 3 h; Uglu, urinary loss
of glucose; and AUCins, area under the insulin curve for 3 h
during the OGTT. HIE was calculated from molar areas under
the insulin and C-peptide curves and expressed as fold change
relative to baseline (18). Hepatic insulin resistance index (HIRI)
was estimated as the product of AUCgluc and AUCins during the
first 30 min of the test (19). The C-peptide-genic index, which
is the increase in the peripheral C-peptide concentration rel-
at the laboratory at ~6:00 AM. A body-array magnetic reso-
nance imaging coil with center aligning to the participants’
spine and shoulders was affixed using Velcro straps. Partici-
pants were placed in a prone position and head first into the
scanner on a memory foam mattress to further minimize respi-
ratory artifact. To accurately scan the liver, an 8-cm3 voxel
 1000
was placed within the right posterior lobe of the participants’
liver, and magnetic resonance spectra with and without water
suppression were acquired with a single-voxel PRESS acqui-
sition (repetition time, 5000 ms; echo time, 30 ms) (20). Final
data were Fourier-transformed, filtered, baseline-corrected, and
phased. The diagnosis of NAFLD was confirmed if IHL was >5%.
Statistical analyses. Normality of the data was deter-
mined using the Shapiro–Wilk test. Continuous variables are
expressed as mean and SEM for parametric measures, and me-
dian and interquartile ranges for nonparametric measures. Cat-
egorical variables are expressed as percentages. Differences

ative to increase in glucose concentration within 30 min of
oral glucose loading, was calculated from [ΔC-peptide(30–0)/
ΔGlucose(30–0)] (19).
Plasma analyses. Plasma glucose was determined at the
time of testing using a YSI 2300 STAT Plus (Yellow Springs,
OH). The remaining plasma was immediately stored at −80°C.
Plasma insulin concentrations were determined using a radioim-
munoassay (Millipore, Billerica, MA). Plasma C-peptide was
measured using enzyme-linked immunosorbent assay (ELISA;
Linco Research, St. Charles, MO). Plasma free fatty acid
concentrations were determined using a colorimetric assay
(Wako Pure Chemical Industries, Richmond, VA). GLP-1
and HMW adiponectin were measured through the 120-min
time point of the OGTT using commercially available ELISA
kits (Millipore, St. Charles, MO). MNC-derived TNF-α was
determined via high-sensitivity ELISA (R&D Systems,
Minneapolis, MN).
Liver scans. IHL content was measured by 1H-magnetic
resonance spectroscopy on a 3-T magnetic resonance system
(Siemens Sonata, Erlangen, Germany), before and after the ex-
ercise intervention. After an overnight fast, the subjects arrived
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between the preintervention and postintervention groups were
analyzed for statistical significance using paired Student t-tests
(parametric), and Wilcoxon signed rank test (nonparametric)
for continuous variables and χ2 test for categorical variables.
α was assumed at 0.05. Effect size was calculated using
Cohen’s D formula as the difference in the means divided by
the SD of the difference. With the current paired sample size
of 13, effect size of 0.84, SD of 0.075, and α of 5%, the cal-
culated power for our primary outcome of HIE was >95%.
Correlation analyses were performed using Pearson’s and
Spearman methods, and the association between biochemical
and anthropometric parameters was evaluated using multivar-
iate linear regression, with and without subgroup analysis, af-
ter power transformation. All graphical and descriptive statistical
analyses were performed using R Studio, version 1.1.453.
RESULTS
Data from a subset of the individuals included herein have
been previously reported (13,21); this secondary analysis is
focused on HIE and hepatic insulin resistance. Participant

TABLE 1. Participant characteristics.

Parameters Prestudy Poststudy P
Age (yr) 57.5 ± 3.6 — —
Weight (kg) 97 ± 4 96 ± 4 0.63
Body fat (%) 44.9 ± 1.7 44.6 ± 1.6 0.19
V̇O2max (mL·kg−1·min−1) 23.6 ± 1.7 25.7 ± 1.7 0.005
FPG (mM) 5.9 ± 0.3 5.7 ± 0.2 0.66
iAUC glucose (180 min) 66.9 ± 16.3 52.9 ± 14.5 0.002
Fasting plasma insulin (pM) 149.1 ± 18.1 126.4 ± 12.1 0.04
iAUC insulin (180 min) 111,908 ± 14,841.2 80,166.7 ± 10,407.7 0.005
Fasting C-peptide (nM) 962.1 ± 126.5 832.0 ± 91.4 0.08
iAUC C-peptide (180 min) 25,8510 ± 30,971 229,320 ± 30,186 0.41
Fasting GLP-1 (pg·mL−1) 11.7 ± 2.6 10.1 ± 2.8 0.03
iAUC GLP-1 (180 min) 18,32.3 ± 369.2 15,39.9 ± 313.3 0.004
Adiponectin (ng·mL−1) 3513 ± 653 3659 ± 767 0.58
TNF-α (pg·L−1) 1963 ± 241 2639 ± 500 0.58
Liver triglyceride content (%) 14.0 ± 2.9 14.1 ± 2.2 0.7
Hepatic polyunsaturated fat fraction (%) 0.4 ± 0.08 0.5 ± 0.07 0.02
Carbohydrate oxidation rate (g·min−1) 0.16 ± 0.02 0.11 ± 0.02 0.006
Lipid oxidation rate (g·min−1) 0.05 ± 0.007 0.07 ± 0.005 0.07
Data are presented as mean ± SE.
FPG, fasting plasma glucose.

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FIGURE 2—Profiles and AUC for glucose, insulin, C-peptide, and GLP-1 during the OGTT. a.u.: arbitrary units. *Postintervention vs preintervention,
P < 0.05.

characteristics are shown in Table 1. Blood and metabolic screen-
ing data revealed that subjects were prediabetic with a fasting
blood glucose concentration of 5.9 ± 0.3 mM and met the diag-
nostic criteria for hepatic steatosis based on IHL measured with
magnetic resonance spectroscopy (average, 14% ± 9%).
The 7-d aerobic exercise training prescription induced a
9.8% ± 3.1% increase in V̇O2max (P < 0.01), and 20.7% ± 6.5%
and 21.5% ± 10.4% decrease in the iAUC for glucose and in-
sulin after the glucose load (P < 0.05), respectively (Fig. 2).
There was no change in body weight or body fat percentage
after the exercise program. Although fasting glucose concentration
and C-peptide did not change with exercise training, peripheral in-
sulin concentrations decreased significantly (11.9% ± 4.3%,
P < 0.05). There was also an 11.5% ± 4.2% and 13.5% ± 3.9%
(P < 0.05) decrease in fasting and iAUC for GLP-1 after the exer-
cise intervention, respectively (Fig. 2). Other plasma metabolic and
biochemical parameters did not significantly change.
HIE and ISIOGTT increased significantly (9.8% ± 3.2% and
49.2% ± 14.7%, respectively; P < 0.05). HIRI decreased by
4.0% ± 18% from baseline (P < 0.05) (Fig. 3). The C-peptide-
genic index trended toward a decrease; however, this was not sta-
tistically significant (pre: 721.6 ± 222.5 pM·mM−1 vs post:
489.6 ± 90.5 pM·mM−1, P = 0.17). There was a 63.5% ± 32.9%
increase in hepatic polyunsaturated lipid content (P < 0.05), al-
though the saturated fat percentage and the triglyceride content
did not differ for these participants. Whole-body fasting carbohy-
drate oxidation rate decreased by 28.2% ± 8.1% (P < 0.01).
Correlation analyses. At baseline, a higher HIE percent-
age correlated with a lower HIRI, higher peripheral insulin
sensitivity, lower hepatic saturated fat percentage, and higher
plasma HDL concentration (r = −0.5, 0.67, −0.48, and 0.6, re-
spectively; all, P < 0.05; Fig. 4). The change in HIE correlated
significantly with the change in peripheral insulin sensitivity
and the change in peak glucose concentration after OGTT
(r = −0.69 and 0.61, respectively; P < 0.05; Fig. 5). After the
intervention, HIE correlated positively with adiponectin
(r = 0.56, P < 0.05) and negatively with plasma TNF-α con-
centration (r = −0.78, P < 0.001).

FIGURE 3—Differences in OGTT-derived indices of HIE, HIRI, and ISI before and after the exercise intervention. *Postintervention vs preintervention,
P < 0.05.

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DISCUSSION
NAFLD is a complex disease that arises from a combination
of reduced insulin sensitivity (both hepatic and peripheral),
hyperinsulinemia, and their related downstream metabolic ef-
fects. There is conflicting evidence that HIE is associated with
liver fat content, owing to differences in methodologies used
and study populations (11,18,22). In this study, we found that
lower HIE was significantly associated with a higher saturated
fraction of liver fat. The positive association of plasma HDL
with HIE was further increased by its interaction with body
weight (adjusted R2 = 0.3 vs 0.58, P < 0.05), potentially
through ApoA-1 (23), which suggests a central role for insulin
dynamics in the development and the progression of NAFLD.
ApoA-1 is the major protein component of HDL and is found
to have an inverse relationship with hepatic fat content. De- FIGURE 5—Link between the change in HIE and change in peak glucose
creased HIE, and thus prevailing hyperinsulinemia, promotes concentration at 90 min after exercise intervention.
insulin resistance (24,25) (Fig. 4). More recently, Viskochil

et al. (26) described elevations in plasma insulin concentra-
tions after a 7-d increase in sedentary time owing to dynamic
reductions in total HIE (AUC). Hence, exploiting a therapeutic
option, which can independently affect each of these compo-
nents in a dose-dependent and time-dependent manner, should
seemingly result in a robust treatment response.
The American Association for the Study of Liver Diseases
treatment guidelines recommend exercise as the most impor-
tant component of treatment for NAFLD (5). The physiologi-
cal adaptations to exercise are multifactorial; however, to date,
the independent effects of exercise on NAFLD have not been
isolated from concomitant weight loss. Our study provides ev-
idence that aerobic exercise training quickly reverses some of
the underlying pathophysiological derangements of NAFLD,
even before the weight-loss phase sets in. These effects may
BASIC SCIENCES
be due to discrete and interdependent increments in HIE, and
peripheral and hepatic insulin sensitivity (27). The associa-
tions between changes in HIE and peripheral and hepatic insu-
lin resistance support our working hypothesis. Given that
skeletal muscle is the largest insulin responsive organ in the
body, it stands to reason that the change in skeletal muscle in-
sulin sensitivity may be contributing to the change in HIE. Al-
though the short-term exercise intervention used in this study
did not significantly reduce liver triglyceride content or change
percentage of saturated fat, small but likely clinically important
changes were predicted by the interaction between changes in
HIE and V̇O2max. Our findings are in agreement with Utzschneider
et al. (11), who compared HIE in NAFLD and non-NAFLD
subjects and determined that HIE was not related to liver fat
but instead was related to peripheral insulin resistance.

FIGURE 4—Relationship between baseline HIE and HIRI (A), ISI (B), hepatic saturated fat (in percent; C), and plasma HDL concentration (D) at baseline.
Solid line represents regression line, whereas the dashed lines represent the 95% confidence intervals.

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 Exercise is known to independently change both glucose and
insulin kinetics (28). Fasting plasma glucose and C-peptide
concentrations did not change after the intervention. However,
the insulin concentrations required to maintain blood glucose
levels decreased significantly, indicating the important contri-
bution of increased HIE to maintaining overall glucose ho-
meostasis. In support, we observed that the overall change in
HIE correlated positively with change in the peak glucose con-
centration (90 min after OGTT; Fig. 5, change in HIE and glu-
cose), a measure that also contributes significantly to reduced
cardiovascular disease risk (29).
As previously published (30), there was a decrease in fasting
and total circulating GLP-1 with short-term exercise training
in these patients. However, we did not observe any significant
statistical associations between changes in HIE and GLP-1 and
any significant change in insulin secretion based on the C-
peptide-genic index. This suggests that exercise-induced im-
BASIC SCIENCES
provements in glucose homeostasis in people with NAFLD
are potentially due to an early increase in HIE and are indepen-
dent of modulations of the GLP-1/insulin-secretion pathway.
The distinct changes in GLP-1 may eventually contribute to
sustained improvements in the capacity to secrete insulin. Fur-
thermore, the significant relationship between HIE and
adiponectin (r = 0.6) and TNF-α (r = −0.78) after exercise in-
tervention highlights the contribution of HIE to a metaboli-
cally healthy and lower systemic inflammatory milieu. These
effects may be mediated through circulating free fatty acid
concentrations, which could directly reduce HIE independent
of prevailing glucose concentrations (31).
First-pass extraction of insulin is ~50% to 80%, and is pre-
dominately driven by the liver (32), followed by the kidney at
~20% (33). In the liver, HIE involves binding and internaliza-
tion via receptor-mediated endocytosis and later degradation
by insulin-degrading enzyme (IDE) via lysosome proteolysis
(34). Hyperinsulinemia has been implicated to reduce HIE
by insulin-receptor saturation (35), although it was recently
counterargued that acute changes in HIE are essential for
dampening systemic insulin oscillations relative to pulsatile
insulin secreted from β-cells (9). Kirwan et al. (36) have previ-
ously shown that acute exercise increases HIE in untrained
adults, which may be attributed to increased expression of he-
patic IDE (37). Kurauti et al. (37) found that exercise can in-
crease the expression and activity of IDE at least via IL-6
(myokine)–mediated transduction and activation of STAT3
in the liver. Long-term aerobic exercise training increases
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1454 Official Journal of the American College of Sports Medicine
Copyright © 2020 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
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CONCLUSIONS
In conclusion, we found that the pathophysiology contribut-
ing to NAFLD is quickly reversed by 7 d of aerobic exercise
training. Even in the absence of weight loss, exercise reduced
hyperinsulinemia through an increase in HIE and, concomi-
tantly, muscle and liver insulin sensitivity. These effects were
independent of changes in fasting and aggregate plasma incretin
concentrations. Changes in total GLP-1 and adiponectin sensi-
tivity may add more potency to the effectiveness of longer-
term exercise in these patients. Our findings further strengthen
the rationale for the use of exercise in managing NAFLD.
The authors wish to thank the research volunteers for their out-
standing dedication and effort, and the staff of the Clinical Research
Unit who helped with the implementation of the study and assisted with
data collection.
This research was supported by National Institutes of Health Grant
R01-AG-12834 (J. P. K) and was supported in part by the National Insti-
tutes of Health National Center for Research Resources, CTSA-1UL1-
RR-024989, and the Case Center for Imaging Research, Case Western
Reserve University, Cleveland, OH.
The authors declare that they have no conflict of interest. The results
of this study are presented clearly, honestly, and without fabrication,
falsification, or inappropriate data manipulation. The authors report that
results of the present study do not constitute endorsement by the
American College of Sports Medicine.
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