Journal of Diabetes Research

Journal of Diabetes Research / 2016 / Article

Review Article | Open Access

Volume 2016 |Article ID 2868652 | https://doi.org/10.1155/2016/2868652

Martin Röhling, Christian Herder, Theodor Stemper, Karsten Müssig, "Influence of Acute and Chronic Exercise on Glucose Uptake", Journal of Diabetes Research, vol. 2016, Article ID 2868652, 33 pages, 2016. https://doi.org/10.1155/2016/2868652

Influence of Acute and Chronic Exercise on Glucose Uptake

Academic Editor: Thomas J. Hawke
Received23 Nov 2015
Revised31 Jan 2016
Accepted03 Feb 2016
Published16 Mar 2016

Abstract

Insulin resistance plays a key role in the development of type 2 diabetes. It arises from a combination of genetic predisposition and environmental and lifestyle factors including lack of physical exercise and poor nutrition habits. The increased risk of type 2 diabetes is molecularly based on defects in insulin signaling, insulin secretion, and inflammation. The present review aims to give an overview on the molecular mechanisms underlying the uptake of glucose and related signaling pathways after acute and chronic exercise. Physical exercise, as crucial part in the prevention and treatment of diabetes, has marked acute and chronic effects on glucose disposal and related inflammatory signaling pathways. Exercise can stimulate molecular signaling pathways leading to glucose transport into the cell. Furthermore, physical exercise has the potential to modulate inflammatory processes by affecting specific inflammatory signaling pathways which can interfere with signaling pathways of the glucose uptake. The intensity of physical training appears to be the primary determinant of the degree of metabolic improvement modulating the molecular signaling pathways in a dose-response pattern, whereas training modality seems to have a secondary role.

1. Introduction

Insulin resistance plays a key role in the development of type 2 diabetes and is caused by genetic predisposition and environmental and lifestyle factors including physical inactivity and poor nutrition habits [1]. These risk factors also contribute to obesity, which is a major determinant of glucometabolic impairment and systemic subclinical inflammation [2]. Physical activity, as cornerstone in the prevention and treatment of diabetes, has marked acute and chronic effects on the regulation of glucose uptake and on inflammatory processes [3, 4]. The glucometabolic impairment in type 2 diabetes results from alterations of different signaling pathways modulating glucose uptake comprising insulin- and exercise-induced signaling pathways. However, during exercise, glucose uptake is normal or near normal [5], pointing to an insulin-independent activation of relevant signaling pathways mediating exercise-induced glucose uptake. An insulin-resistant state is also associated with changes in immunological and hormonal cross talk involving interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), or adiponectin. These cytokines and adipokines are part of inflammatory processes and immune defense and can also affect molecular signaling pathways modulating glucose uptake. Behavioral interventions as well as unstructured physical activity have been shown to positively influence inflammatory processes, which was accompanied by improvements in glucose uptake [6, 7].

Physical exercise is distinguished primarily in resistance training and endurance training. Endurance training imposes a high-frequency (repetition), low-power output demand on muscular contraction, whereas resistance exercise imposes a low-frequency, high-resistance demand [8]. These two traditional modalities can also be performed as high-intensity training (HIT). This training form comprises alternating cycles of intensive and extensive phases involving endurance training, also known as high-intensity interval training (HIIT), and resistance training or the supramaximal exercise form of sprint interval training (SIT) [9, 10].

The overarching aim of this review is to summarize the mechanisms and molecular signaling pathways mediating glucose uptake as well as related changes in the release of immune mediators upon acute and chronic exercise exposure. Furthermore, we aim to assess the role of training intensity and training modality for the modulation of the aforementioned processes.

2. Search Strategy and Evaluation of Data

We searched PubMed/MEDLINE without language restriction from database inception until January 20, 2016, using the following search terms: “signaling OR pathway OR GLUT4 OR glucose OR inflammation OR inflammatory OR cytokine” AND “exercise OR training OR endurance exercise OR resistance exercise OR contraction”. Reference lists of review articles and all included articles identified by the search were also examined for other potentially eligible studies. The search was limited to human and animal studies. Duplicates were removed. Search results for relevant intervention studies are summarized in Table 1 and shown in detail in Tables 2, 3, 4, and 5.


Metabolic factorAcute trainingChronic trainingExercise characteristics (intensity, modality)References

Proximal insulin signaling (IRS-1, PI3-K, PDK, αPKC)↑↑Moderate-to-intensive exercise for untrained and high-intensity exercise for trained individuals, independent of modality[1222]

AMPK↑↑↑↑Dose-response pattern, independent of modality[8, 2331]

Ca2+-calmodulin axis↑↑↑↑Dose-response pattern, independent of modality[8, 27, 3135]

mTOR/S6K↑↑↑↑Dose-response pattern, independent of modality [29, 3646]

Downstream targets: AS160, TBC1D1, Rac1Dose-response pattern for AS160 and Rac1, independent of modality[16, 4760]

IKK/NF-κB pathway↑↕↓↓Dose-response pattern, independent of modality[2, 6177]

Inflammasome pathway↓↓Dose-response pattern, independent of modality[2, 7880]

JNK/MAPK pathway↑↑↓↓Dose-response pattern, independent of modality[6769, 8185]

AdiponectinIntense exercise, independent of modality[3, 5, 53, 8694]

↑↑/↓↓, consistent findings in animal models and humans; ↑/↓, preliminary evidence from animal models and/or humans; —, no impact; animal studies showed no effects; increase in skeletal muscle and increase/decrease in adipose tissue; αPKC, atypical PKC; AMPK, AMP-activated protein kinase; AS160, Akt substrate of 160 kDa; Ca, calcium; CaMKII, Ca2+/calmodulin-dependent protein kinase 2; IRS-1, insulin receptor substrate 1; IKK/NF-κB, IκB kinase/nuclear factor kappa B; JNK, C-Jun N-terminal kinase; MAPK, mitogen-activated protein kinases; mTOR/S6K, mammalian target of rapamycin/ribosomal S6 kinase; PDK, phosphoinositide-dependent kinase; PI3-K, phosphoinositide 3-kinase; Rac1, ras-related C3 botulinum toxin substrate 1; TBC1D1, TBC1 domain family member 1.

ReferenceStudy population, Age, yearsTraining modalityType of sportTraining frequencyAcute/chronic exerciseTraining intensityTissue & conditionTime since the last exercise bout, hChanges in glucose uptake and related molecular signaling

Cusi et al., 2000 [12]9 untrained obese CON,
10 untrained T2D
44 ± 4 

42 ± 3
ETCycling60 minAcute65%  Muscle & insulin-stimulated (clamp)24 h after exerciseIncrease of insulin receptor (+60% in obese CON, +34% in T2D) and IRS-1 tyrosine phosphorylation (+20% in T2D)

Howlett et al., 2006 [15]7 untrained CON24 ± 2ETCycling60 minAcute75%  Muscle & insulin-stimulated (clamp)Immediately after exercise, and at 30 and 120 minutes of clampIncrease of insulin-stimulated IRS-2 signaling (IRS-2-associated PI3–kinase activity) after exercise

Perseghin et al., 1996 [13]10 untrained lean offspring T2D,
8 untrained CON
33 ± 3 

29 ± 2
ETStair-climbing machine45 minAcute65%  Muscle & insulin-stimulated (clamp)48 h after exerciseIncrease of glucose disposal by 35% in the offspring and 41% in CON

Wojtaszewski et al., 2000 [21]7 trained CON22 ± 1ETOne-leg-exercise60 minAcute18–23%  Muscle & insulin-stimulated (clamp)After 7, 15, 60, 120, 150 min of exerciseNo change in proximal insulin signaling, but exercise induced increase of glucose uptake up to 2-to-4-fold higher compared to rested leg

Musi et al., 2001 [24]7 untrained lean T2D,
8 untrained CON
53 ± 3 

49 ± 1
ETCycling45 minAcute70% of MuscleDuring and immediately after exerciseSimilar protein expression of AMPK α1, α2, and β1 in muscle of T2D, compared with CON, increase of AMPKα2 activity (2.7-fold) after exercise

Gibala et al., 2009 [28]6 trained CON23 ± 2HITCycling20 minAcute4 × 30 s “all-out” sprintMuscleImmediately and 3 h after exerciseIncrease of AMPK (30%), AMPKα1 (20%), and AMPKα2 (80%) phosphorylation

Sriwijitkamol et al., 2007 [25]8 CON,
8 obese CON,
12 T2D
45 ± 3 
44 ± 4 
53 ± 3
ETCycling40 minAcute50–70%  MuscleDuring and immediately after exerciseAMPK activity only improved in lean CON in a dose-response manner

Benziane et al., 2008 [26]9 untrained CON23 ± 2ETCycling60 minAcute164 W (intense)MuscleImmediately and 3 h after exerciseIncrease of AMPK (16.0-fold) and mTOR (2.0-fold) phosphorylation after exercise and abrogation of AMPK phosphorylation and mTOR phosphorylation after 3 h of exercise

Egan et al., 2010 [27]8 sedentary CON25 ± 1ETCyclingn.r.Acute40/80%  
(400 kcal)
MuscleImmediately, 3 h and 19 h after exerciseIncrease of AMPK (2.8-fold) and CaMKII (84%) phosphorylation immediately after high-intensity but not low-intensity exercise

Rose et al., 2006 [34]8 trained CON25 ± 1ETCycling90 minAcute67%  MuscleAt rest and after 1, 10, 30, 60, and 90 min of exerciseIncrease of CaMKII activity during exercise depending on exercise duration (2-fold)

Rose et al., 2006 [34]10 trained CON25 ± 2ETCycling30 minAcute35%, 60%, 85%  MuscleImmediately and 30 min after exerciseIncrease of CaMKII phosphorylation during exercise depending on exercise intensity (1 to 3-fold)

Combes et al., 2015 [35]9 trained CON22 ± 5ET/HITCycling30 min/30 × 1 minAcute70% of MuscleImmediately and 3 h after exerciseIncrease of CaMKII phosphorylation by 2.7-fold after HIT compared to continuous exercise (same work rate)

Fujita et al., 2007 [44]6 untrained CON70 ± 2ETTreadmill walking45 minAcute70% of Muscle & insulin-stimulated (clamp)20 h after exerciseIncrease of mTor activity (5.0-fold) after 20 h of rest under insulin stimulation

Camera et al., 2010 [39]8 trained CON29 ± 2ETCycling60 minAcute70%  MuscleImmediately, 15, 30, and 60 min after exerciseIncrease of mTOR phosphorylation (100%) that peaked 30–60 min after exercise termination, workload (660 kcal)

Camera et al., 2010 [39]8 trained CON28 ± 2RTLeg extension8 × 5 repetitionsAcute80% 1-RMMuscleImmediately, 15, 30, and 60 min after exerciseIncrease of mTOR phosphorylation (100%) that peaked 30–60 min after exercise termination, workload (130 kcal)

Mascher et al., 2011 [43]16 untrained CON23 ± 2 
25 ± 1
ETOne-leg cycling60 minAcute65–70%   of one legMuscleImmediately, 90 and 180 min after exerciseTime-dependent increase of mTOR phosphorylation after 180 min of recovery by 60% compared to resting situation

Pugh et al., 2015 [45]10 untrained CON21 ± 1RTLeg extension4 × 8 repetitionsAcute70% 1-RMMuscle2 h and 6 h after exerciseNo change of mTOR after RT alone

Pugh et al., 2015 [45]10 untrained CON21 ± 1RT + HITLeg extension + cycling4 × 8 repetitions + 20 minAcute70% 1-RM + 10 times 1 min 
90%  
Muscle2 h and 6 h after exerciseRT + HIT: increase of mTOR phosphorylation by 30% compared to resistance training alone

Dreyer et al., 2006 [40]11 untrained CON27 ± 2RTLeg extension10 × 10 repetitionsAcute70% 1-RMMuscleDuring and 2 h after exerciseIncrease of AMPK phosphorylation (50%) until 1 h after exercise and progressive increase of mTOR phosphorylation up to 100% at 2 h after exercise

Deshmukh et al., 2006 [16]9 trained CON29 ± 6ETCycling60 minAcute70%  MuscleImmediately after exerciseIncrease of Akt (80%) and AS160 (100%) phosphorylation in endurance trained young athletes after exercise

Deshmukh et al., 2006 [16]9 trained CON29 ± 6RTIsokinetic leg extension8 × 5 repetitionsAcuteMaximal voluntary isokinetic leg extensionsMuscleImmediately after exerciseNo change of Akt and AS160 in endurance trained young athletes after exercise

Treebak et al., 2007 [55]30 trained CON26 ± 1ETCycling20 min, 
2 min, 
30 sec
Acute222 W 
376 W 
666 W
MuscleImmediately after exerciseNo change in AS160 phosphorylation in all 3 study arms

Treebak et al., 2007 [55]8 trained CON25 ± 1ETCycling90 minAcute67%  MuscleImmediately after exerciseIncrease of AS160 phosphorylation (120%)

Treebak et al., 2009 [56]12 trained CON26 ± 1ETOne-leg-exercise60 minAcute80% of Muscle4 h after exerciseIncrease of AS160 phosphorylation in exercised leg by 20–40%

Sylow et al., 2014 [58]9 CONn.r.ETInclined walking45 minAcute69%  MuscleImmediately after exerciseIncrease of Rac1 activity by 38% in m. soleus and 52% in m. gastrocnemius; increase of p-Rac1-Ser71 phosphorylation by 39% in m. soleus and by 20% in m. gastrocnemius

Vendelbo et al., 2014 [54]8 trained CON26 ± 4ETCycling60 minAcute65%  Muscle30 min and 4 h after exerciseIncrease of AS160 and TBC1D1 phosphorylation 30 min after exercise

O’Gorman et al., 2006 [19]7 obese CON,
8 obese T2D
48 ± 4 
45 ± 2
ETCycling60 minAcute 
short term (7 days)
75%  Muscle & insulin-stimulated (clamp)16 h after exerciseIncrease of glucose disposal by 36% in T2D, but not CON, no change in proximal signaling

Wadley et al., 2007 [20]8 untrained CON24 ± 1ETCycling60 minAcute 
short-term (7 days)
75%  Muscle & insulin-stimulated (clamp)24 h after exerciseNo change of insulin receptor & IRS-1 tyrosine phosphorylation after either acute or short-term training

Frøsig et al., 2007 [95]8 trained CON25 ± 1ETOne-legged knee extensor apparatus60–120 minShort-term (21 days)70–85% peak work loadMuscle & insulin-stimulated (clamp)Immediately, 10 and 120 min under insulin after exerciseIncrease of Akt1/2 and AS160 protein content by 55% and 25%, but, under insulin stimulation, no exercise effect

Perseghin et al., 1996 [13]10 untrained lean offspring T2D,
8 untrained CON
33 ± 3 

29 ± 2
ETStair-climbing machine4 × 45 minChronic 
(6 weeks)
65%  Muscle & insulin-stimulated (clamp)48 h after exerciseIncrease of glucose uptake by 76% in offspring and 58% in CON

Holten et al., 2004 [96]10 untrained overweight T2D,
7 untrained CON
62 ± 3 

61 ± 3
RTLeg training program3 × 30 minChronic 
(6 weeks)
50% 1-RM - 70–80% 1-RMMuscle & insulin-stimulated (clamp)16 h after exercise40% increase in GLUT4 protein content in T2D, no change in CON; increase of protein content of insulin receptor by 19% (CON) and 21% (T2D), increase of PKB-α/β (Akt1/2) protein content by 22% (CON) and 12% (T2D)

Consitt et al., 2013 [52]21 sedentary CON18–84ETRunning3 × 60 minChronic (10 weeks)75%  Muscle & insulin-stimulated (clamp)40 h after exerciseIncrease of whole-body insulin action and insulin-stimulated AS160 phosphorylation after exercise by 60% in young and 75% in insulin resistant CON

Consitt et al., 2013 [52]22 sedentary CON20–82RTUpper and lower body3 × 45 minChronic (10 weeks)12-RMMuscle & insulin-stimulated (clamp)40 h after exerciseIncrease of whole-body insulin action and insulin-stimulated AS160 phosphorylation after exercise by 75% in young & old individuals

Vissing et al., 2013 [29]24 untrained CON23 ± 1ET/HITCycling3 × 40 minChronic (10 weeks)65%–90% of MuscleImmediately, 15, 30, 60, and 120 min after exerciseIncrease of AMPK phosphorylation by 44% after ET

Vissing et al., 2013 [29]24 untrained CON23 ± 1RT3 leg-exercises3 × 8 × 5 repetitionsChronic (10 weeks)4-5-RMMuscleImmediately, 15, 30, 60, and 120 min after exerciseIncrease of AMPK phosphorylation by 10% and increase of mTOR/p70SK6 phosphorylation after 2 h up to 22 h by 91%–281%

Nitert et al., 2012 [33]13 sedentary CON (positive family history (FH+))37 ± 4ETCycling/aerobic exercise3 × 60 minChronic (26 weeks)n.r.Muscle48 h after exerciseDecrease of DNA methylation of genes of calcium signaling pathway after exercise in individuals with FH+

Stuart et al., 2010 [38]6 sedentary CON 37 ± 3ETCycling30–70 minChronic (6 weeks)70%–85% of Muscle40–48 h after exerciseIncrease of GLUT4 by 66% and phosphor-mTOR by 83%

Data are given as mean ± SD for age; all changes given in the table were statistically significant; 1-RM, one repetition maximum; AMPK, AMP-activated protein kinase; AS160, Akt substrate of 160 kDa; Ca, calcium; CaMKII, Ca2+/calmodulin-dependent protein kinase 2; CON, controls; ET, endurance training; HIT, high-intensity interval training, maximum heart rate, IRS-1/2, insulin receptor substrate 1/2; mTOR, mammalian target of rapamycin (C1 complex 1 & C2 complex 2); n.r., not reported; PDK, phosphoinositide-dependent kinase; PI3-K, phosphoinositide 3-kinase; PKB, protein kinase B; Rac1, ras-related C3 botulinum toxin substrate 1; RM, repetition maximum; RT, resistance training; T2D, type 2 diabetes; TBC1D1, TBC1 domain family member 1; , maximum oxygen consumption, , maximum Watt.

ReferenceAnimals, Age, weekTraining modalityType of sportTraining frequencyAcute/chronic exerciseTraining intensityTissue & conditionTime since the last exercise bout, hChanges in glucose uptake-related molecular signaling

Treadway et al., 1989 [17]Male Sprague-Dawley ratsn.r.ETTreadmill running45 minAcute18 m/minInsulin stimulated muscleImmediately after exerciseNo effect on insulin binding, basal and insulin-stimulated receptor autophosphorylation, or basal and insulin-stimulated exogenous kinase activity

Goodyear et al., 1995 [18]Male Sprague-Dawley ratsn.r.ESContractionn.r.AcuteTraining duration, 500 ms; pulse rate, 100 Hz; duration, 0.1 ms at 1–3 VInsulin stimulated muscleImmediately after contraction phaseDecrease of insulin-stimulated tyrosine phosphorylation and PI3-kinase activity (20%), no effect of exercise without insulin

Sakamoto et al., 2002 [50]Male Sprague-Dawley ratsn.r.ESContractionn.r.AcuteTraining rate, 1/s; train duration, 500 ms; pulse rate, 100 Hz; duration, 0.1 ms at 2–5 VMuscleImmediately after contraction phaseIncrease of Akt Ser473 phosphorylation after 5 min (3-fold) and decrease to +23% after 30 min

Wojtaszewski et al., 1999 [51]Male muscle-specific insulin receptor knockout mice9-10ETTreadmill running60 minAcute22 m/min with 10% inclineInsulin stimulated muscleImmediately after exerciseIncrease of insulin-stimulated glucose transport without improvement of proximal insulin signaling, but increase of Akt phosphorylation (6.0-fold)

Castorena et al., 2014 [49]Male Wistar rats (LFD and HFD)n.r.ETSwimming4 × 30 minAcuten.r.Insulin stimulated muscleImmediately and 3 h after exercise phaseIncrease of AS160 immediately (2.0–2.5-fold) and after 3 h (3-fold, in LFD)

Bruss et al., 2005 [57]Male Wistar ratsn.r.ESContractionn.r.AcuteTraining rate, 2/min; training duration, 10 s; pulse rate, 100 Hz; duration, 0.1 ms at 2–5 VMuscleImmediately after contraction phaseIncrease of AS160 phosphorylation (3.7-fold)

Fujii et al., 2005 [97]Muscle-specific transgenic knockout of α2 subunits of AMPK mice10–16ESContraction10 minAcuteTraining rate, 1/min; training duration, 10 s; pulse rate, 100 Hz; duration, 0.1 ms at 100 VMuscleImmediately after contraction phaseNear normal glucose uptake (−13%) in KO mice

Jeppesen et al., 2013 [98]Muscle specific knockout of LKB1 mice16–20ETTreadmill running24 minAcute12.5 m/minMuscleImmediately after contraction phaseNormal glucose uptake in LKB1 deficient mice

Lefort et al., 2008 [99]Muscle-specific transgenic knockout of α2 subunits of AMPK micen.r.ESContraction2 minAcuteTraining rate, 1/s; training duration, 500 ms; pulse rate, 100 Hz; at 30 VMuscleImmediately after contraction phaseNo change of AMPK activity after contraction, but increase of glucose uptake by 50% compared to CON mice

Sakamoto et al., 2005 [100]Muscle specific knockout of LKB1 micen.r.ESContraction5 minAcuteTraining rate, 1/s; training duration, 200 ms; pulse rate, 50 Hz; duration, 0.1 ms at 2–5 VMuscleImmediately after contraction phaseReduced glucose uptake in LKB1 deficient mice

Thomson et al., 2008 [41]Fischer 344 × Brown Norway male rats32ESContraction22 minAcute10 sets 6 contractions for 3 sMuscleImmediately and 20, and 40 min after contraction phaseIncrease of AMPK activity and inhibition of mTOR signaling

Katta et al., 2009 [36]12 male lean normal Zucker rats, 12 male young obese Syndrome × Zucker rats10ESn.r.22 minAcute10 sets of 6 contractionsMuscleImmediately, 1 h and 3 h after exerciseIncrease of mTOR phosphorylation (Ser2448, 63%) and p70S6K (Thr389, 37%) compared to lean normal Zucker rats

Sylow et al., 2013 [101]Female C57BL/6 mice12–16ETTreadmill running50%–70% maximal running speed 30 minAcute16 m/min 
22 m/min
MuscleImmediately after exerciseIncrease of Rac1 activity by 44%/50%/100% after 40%/50%/70% of maximal speed

Witczak et al., 2007 [102]Female ICR mice8ESContraction15 minAcuten.r.Muscle45 min after contractionNo change in insulin-stimulated glucose uptake in calmodulin-binding domain-mutant mice, decrease of contraction-stimulated glucose uptake in calmodulin-binding domain-mutant mice

Witczak et al., 2010 [103]Female ICR mice6–8ESContraction10 minAcuteTraining rate, 1/min; training duration, 10 s; pulse rate, 100 pulses/s; duration, 0.1 ms; volts, 100 VMuscle45 min after contractionDecrease of contraction-induced muscle glucose uptake (30%)

Edgett et al., 2013 [46]Female Sprague-Dawley ratsn.r.ETTreadmill running120 minAcute15 m/min + 5 m/min every 5 minMuscleImmediately and 3 h after exerciseTime-dependent increase of mTOR mRNA by 44% after 180 min of recovery

Edgett et al., 2013 [46]Female Sprague-Dawley ratsn.r.ESContraction120 minChronic (7 days)n.r.MuscleImmediately and 3 h after exerciseIncrease of mTOR phosphorylation by 74% after 7 days of ES

Calegari et al., 2011 [31]20 male Wistar rats8ETTreadmill running5–60 minChronic (8 weeks)5 m/min–30 m/minPancreatic islets24 h after exerciseIncrease of AMPK phosphorylation (100%) and CaMKII phosphorylation (+50%)

Luo et al., 2013 [30]Male Sprague-Dawley rats18–20RTLadder climbing with weights3 × 10 repetitionsChronic (9 weeks)10% per week increase of additional weightMuscle48 h after exerciseIncrease of both total and phosphorylated AMPK compared to sedentary control

Ritchie et al., 2014 [53]Male wild-type (WT, C57BL/6J) mice, adiponectin knockout (AdKO, B6.129-Adipoqtm1Chan/J) mice12ETTreadmill running3 × 45–60 minChronic (8 weeks)20–32 m/minInsulin stimulated muscle48 h after exerciseIncrease in total AS160 phosphorylation from AdKO (44%) compared to WT mice (28%);  
no differences in total GLUT4 protein content

All changes given in the table were statistically significant; AMPK, AMP-activated protein kinase; AS160, Akt substrate of 160 kDa; Ca, calcium; CaMKII, Ca2+/calmodulin-dependent protein kinase 2; CON, controls; DIO, diet-induced obesity; ES, electrical stimulation; ET, endurance training; GLUT4, glucose transporter 4; HFD, high fed diet; LFD, low fed diet; LKB-1, liver kinase B1; mTOR, mammalian target of rapamycin (C1 complex 1 & C2 complex 2); n.r., not reported; PI3-K, phosphoinositide 3-kinase; Rac1, ras-related C3 botulinum toxin substrate 1; RT, resistance training; SK6, serine kinase 6; T2D, type 2 diabetes; TBC1D1, TBC1 domain family member 1.

ReferenceStudy population, Age, yearsTraining modalityType of sportTraining frequencyAcute/chronic exerciseTraining intensityTissue & conditionTime since the last exercise bout, hChanges in cytokines and related inflammatory signaling

Lancaster et al., 2005 [64]11 trained CON25 ± 1ETCycling90 minAcute65%   + 34°C radiationPlasmaImmediately and 2 h after exerciseIncrease in IL-6 plasma levels in response to LPS stimulation after exercise

Leggate et al., 2010 [73]11 trained CON22 ± 4ETCycling60 minAcute62%  
(matched work)
PlasmaImmediately, 1.5, 6 and 23 h after exerciseIncrease of soluble interleukin-6 receptor complex after continuous ET (126%)

Leggate et al., 2010 [73]11 trained CON22 ± 4HITCycling4 min work/2 min restAcute88%  
(matched work)
PlasmaImmediately, 1.5, 6 and 23 h after exerciseIncrease of soluble interleukin-6 receptor complex plasma levels (159%) and increase of IL-6 plasma levels (2.5-fold) immediately after HIT

Lyngsø et al., 2002 [70]9 CON24 ± 1ETCycling60 minAcute60%  PlasmaDuring, immediately and 3 h after exerciseIncrease of IL-6 plasma levels (17-fold) during and 30 min after exercise

Keller et al., 2001 [104]6 untrained CON26 ± 4ETTwo-legged knee extensor apparatus180 minAcute60% of maximum workload of 2 minPlasmaImmediately, 30, 60, 90 and 180 min after exerciseIncrease of IL-6 and TNF-α plasma levels immediately and 2 h after exercise

Febbraio et al., 2004 [105]6 trained CON24 ± 1ETCycling120 minAcute40%  
70%  
PlasmaDuring (every 30 min), immediately, 60 and 120 min after exerciseIncrease of IL-6 plasma levels at 70% of 60 min after exercise, no change at 40% of

Ostrowski et al., 1998 [72]16 trained CON31 ± 2ETMarathon42.2 kmAcuten.r.PlasmaImmediately and 2 h after exerciseIncrease of IL-6 (62.0-fold), IL-1 receptor antagonist (23.0-fold), TNF-α (2.0-fold), and IL-1β (1.5-fold) plasma levels immediately after exercise

Ostrowski et al., 1999 [106]10 trained CON28 ± 5ETMarathon42.2 kmAcuten.r.PlasmaImmediately, and every 30 min until 4 h after exerciseIncrease of IL-6 plasma levels (128.0-fold) peaked immediately after exercise and increase of IL-1 receptor antagonist (39.0-fold), TNF-α (2.0-fold), and IL-1β (2-fold) plasma levels peaked 1 h after exercise

Starkie et al., 2001 [107]5 trained CONn.r.ETMarathon150–200 minAcuten.r.PlasmaImmediately, 2 h and 24 h after exerciseIncrease of IL-6 and TNF-α plasma levels

Oliveira and Gleeson, 2010 [65]9 trained CON25 ± 5ETCycling90 minAcute75%  PlasmaImmediately, 2 and 4 h after exerciseDecrease of monocyte TLR4 protein content expression immediately (32%) and 1 h (45%) after exercise

Galpin et al., 2012 [84]9 trained CONn.r.RTDynamic pull exercise15 sets × 3 repetitionsAcute85% 1-RMMuscleDuring and immediately after exerciseIncrease of MAPK (3-fold) and JNK (2.4-fold) phosphorylation

Suzuki et al., 2000 [108]16 trained CONn.r.ETMarathonn.r.Acuten.r.PlasmaImmediately after exerciseIncrease of IL-6 and IL-1 receptor antagonist plasma levels by 100-fold, decrease of IL-2 by 32% after exercise

Boppart et al., 2000 [83]14 trained CON32 ± 2ETMarathon42.2 kmAcuten.r.MuscleImmediately, 1 day, 3 days and 5 days after exerciseIncrease of JNK activity immediately after exercise (5-fold), but diminished in the following days

Aronson et al., 1998 [82]8 CON30 ± 12ETCycling60 minAcute70%  MuscleImmediately after exerciseIncrease of JNK activity immediately after exercise (6-fold)

Punyadeera et al., 2005 [87]10 trained CON23 ± 1ETCycling120 minAcute50%  Plasma & muscleImmediately and 2 h after exerciseNo change in adiponectin plasma levels and adiponectin receptor expression in muscle

Jürimäe et al., 2006 [86]8 trained CON63 ± 1ETRowing6.5 kmAcute76%  PlasmaImmediately and 30 min after exerciseIncrease of adiponectin plasma levels (15%) 30 min after exercise

Fatouros et al., 2005 [93]50 untrained CON65–78RTWeight machine3 × 60 minChronic (24 weeks)3-4 sets of 4–12 repetitions with 45–85% of 1-RMPlasma48 h after exerciseIncrease of adiponectin plasma levels in high-intensity group (60%) and medium-intensity group (18%), still elevated in HI group after 24 weeks of detraining (32%)

Kriketos et al., 2004 [88]19 sedentary obese CON37 ± 1ETBrisk walking/jogging4-5 × 40 minChronic (10 weeks)55–70%  Plasma48 h after exerciseIncrease of adiponectin plasma levels by 230%

Lim et al., 2008 [89]36 CON (young),
38 CON (middle-aged)
22 ± 3 

60 ± 6
ETCycling3 × 60 minChronic (10 weeks)70%  PlasmaImmediately after exerciseIncrease of adiponectin plasma levels in young (20%) and middle-aged women (27%)

Kondo et al., 2006 [92]8 untrained obese CON,
8 lean untrained CON
18 ± 1 

18 ± 2
ETWalking/jogging4-5 × 30 minChronic (28 weeks)60–70% HRR 
(400–500 kcal)
PlasmaImmediately after exerciseIncrease of adiponectin plasma levels in obese CON (75%) and no change in lean CON; 
decrease of TNFα plasma levels in obese CON (37%) and no change in lean CON

Rodriguez-Miguelez et al., 2014 [66]16 untrained CON70 ± 1RTLeg press, pec deck, biceps curl2 × 3 sets per 3 exercises 
8–12 repetitions
Chronic (8 weeks)50–80% 1-RMPlasma5-6 days after trainingDecrease of TLR2 and TLR4 protein content expression and no change in TNF-α protein content; 
upregulation of IL-10 mRNA und protein content after exercise

O’Leary et al., 2006 [90]16 untrained obese CON63 ± 1ETRunning/cycling5 × 60 minChronic (12 weeks)85%  Plasma18 h after exerciseNo change in adiponectin plasma levels

Kadoglou et al., 2007 [78]30 untrained T2D57 ± 7ETWalking, running, cycling4 × 45–60 minChronic (16 weeks)50–85%  Plasma48 h after exerciseDecrease of IL-6 (33%) and IL-18 (40%) plasma levels in T2D after exercise

Leick et al., 2007 [79]13 untrained obese CON,
16 untrained CON
36 ± 4 

25 ± 1
ETCycling 

Rowing
90–120 min  

3 × 30 min
Acute 

Chronic (8 weeks)
60–70%  

>70%  
Adipose tissueImmediately, 2 and 10 h after exercise 
48 h after exercise
No change of IL-18 mRNA expression after acute exercise in each time point; 
decrease of IL-18 mRNA (20%) in adipose tissue after exercise

Sriwijitkamol, et al., 2006 [63]8 untrained CON,
6 untrained T2D
36 ± 3 

45 ± 3
ETCycling4 × 45 minChronic (8 weeks)70%  Muscle24–36 h after exerciseIncrease in IκBα und IκBβ protein in CON and T2D (50%) and decrease of TNFα protein content in T2D (40%)

Gray et al., 2009 [109]24 untrained CON49 ± 9ETCommunity-based walking5 timesChronic (12 weeks)>3000 steps per dayPlasman.r.No change in IL-6, TNF-α and hs-CRP plasma levels

Data are given as mean ± SD for age; all changes given in the table were statistically significant; CON, controls; ET, endurance training; HI, high-intensity; HIT, high-intensity interval training, maximum heart rate, HRR, heart rate reserve; hs-CRP, high-sensitive C-reactive protein; IκBα/β, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha/beta; IL-2, interleukin 2; IL-6, interleukin 6; IL-10, interleukin 10; IL-18, interleukin 18; JNK, C-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; mRNA, messenger RNA; n.r., not reported; RM, one repetition maximum; RT, resistance training; T2D, type 2 diabetes; TLR2, Toll-like receptor 2, TLR4, Toll-like receptor 4, TNF-α, tumor necrosis factor alpha; , maximum oxygen consumption; , maximum Watt.


ReferenceAnimals, Age, weekTraining modalityType of sportTraining frequencyAcute/chronic exerciseTraining intensityTissue & conditionTime since the last exercise bout, hChanges in cytokines and related inflammatory signaling

Oliveira et al., 2011 [69]Male Wistar rats with HFD8ETSwimming2 × 180 minAcuteAdditional weight of 5% of body weightAdipose, muscle & hepatic tissue2, 16, 24, and 36 h after exerciseDecrease in TLR4 mRNA and protein expression in all tissues and reduction in JNK and IKKβ phosphorylation in adipose, muscle & hepatic tissue;
decrease of TNF-α and IL-6 mRNA levels in all tissues

Castellani et al., 2015 [74]Male untrained C57BL/6J mice,
trained male C57BL/6J mice
10

14
ETTreadmill running120 minAcute15 m/min–19 m/min (50% maximal running speed)Adipose tissue & plasmaImmediately and 4 h after exerciseIncrease of IL-6 and IL-6 Rα protein expression (3-fold) after exercise, more pronounced in trained mice compared to untrained mice

Whitham et al., 2012 [81]Male untrained C57BL/6 mice (CON),
male untrained C57BL/6 mice with JNK-KO (JNK-KO)
n.r.ETTreadmill running30–60 minAcute0.22–0.25 m/sMuscleImmediately and 30 min after exerciseIncrease of muscle IL-6 mRNA expression 30 min after exercise in CON;
no change of muscle IL-6 mRNA expression 30 min after exercise in JNK-KO

Macpherson et al., 2015 [75]Male untrained C57BL/6J mice fed with HFD7ETTreadmill running120 minAcute15 m/min - 5% inclineAdipose tissueImmediately and 2 h after exerciseIncrease of MCP-1 mRNA (2-fold) immediately after exercise and increase of IL-6, MCP-1 (10-fold) and IL-10 (5-fold) mRNA after 2 hours

Kawanishi et al., 2013 [62]12 male C57BL/6J mice with HFD, 12 C57BL/6J mice with ND4ETTreadmill running5 × 60 minChronic (16 week)15 m/min–20 m/minAdipose tissue & liver72 h after exerciseHigher levels of TNFα mRNA (4.0-fold) and IL-6 mRNA (2.5-fold) in HFD sedentary mice compared to ND mice after chronic exercise

Cho et al., 2016 [94]10 untrained C57BL/6 mice with HFD15HITTreadmill running40 minChronic (8 weeks)10–17 m/minMuscleImmediately after exercisePrevention of downregulation of AdipoR1 expression caused by HFD

Ritchie et al., 2014 [53]Male wild-type (WT, C57BL/6J), adiponectin knockout (AdKO, B6.129-Adipoqtm1Chan/J) mice12ETTreadmill running3 × 45–60 minChronic (8 weeks)5 × 20–32 m/minMuscle48 h after exerciseIncrease in total AS160 from AdKO (44%) compared to WT mice (28%);
no differences in total GLUT4

da Luz et al., 2011 [67]Obese DIO ratsn.r.ETSwimming5 × 60 minChronic (8 weeks)Additional weight of 5% of body weightAdipose tissue & hepatic tissueImmediately after exerciseDecrease of JNK, IκB, and NF-κB activity and protein expression and increase of IRS-1, insulin receptor, and Akt phosphorylation after chronic exercise in adipose and hepatic tissue

Medeiros et al., 2011 [68]Obese Wistar rats with HFDn.r.ETSwimmingn.r.Chronic (12 weeks)n.r.Adipose tissuen.r.Increase in Akt (2.3-fold) and Foxo1 (1.7-fold) phosphorylation, reduction in phospho-JNK (1.9-fold), NF-kB (1.6-fold) and PTP-1B (1.5-fold) protein expression, and increase in mTOR (1.7-fold), p70S6k (1.9-fold), and 4E-BP1 phosphorylation (1.4-fold) after exercise training

Oliveira et al., 2011 [69]Male Wistar rats with HFD8ETSwimming5 × 60 minChronic (8 weeks)Additional weight of 5% of body weightAdipose, muscle & hepatic tissue24 and 36 h after exerciseDecrease in TLR4 mRNA and protein expression and reduction of JNK and IKKβ phosphorylation in adipose, muscle & hepatic tissue;
Increase of insulin-stimulated IRS-1 and insulin receptor and Akt phosphorylation,
decrease of TNFα and IL-6 mRNA level in all tissues

Passos et al., 2015 [85]Male Sprague-Dawley rats with HFD5-6ETTreadmill running5 × 60 minChronic (8 weeks)15–25 m/minPlasmaImmediately after exerciseDecrease in JNK activation and total JNK level in HFD compared to sedentary HFD

Mardare et al., 2016 [80]Male C57BL/6 mice10ETTreadmill running5 × 30 minChronic (10 weeks)80%  Serum & adipose tissue72 h after exerciseDecrease of IL-18 and TNF-α expression in adipose tissue

Mardare et al., 2016 [80]Male C57BL/6 mice10RTIsometric strength training5 × 3 min with 3 setsChronic (10 weeks)n.r.Serum & adipose tissue72 h after exerciseDecrease of IL-18 serum levels

All changes given in the table were statistically significant; CON, controls; DIO, diet-induced obesity; ES, electrical stimulation; ET, endurance training; GLUT4, glucose transporter 4; HFD, high fed diet; HI, high-intensity; HIT, high-intensity interval training; hs-CRP, high-sensitive C-reactive protein; IκBα/β, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha/beta; IL-6, interleukin 6; IL-6 Rα, interleukin 6 receptor α; IL-10, interleukin 10; IRS-1, insulin receptor substrate 1; JNK, C-Jun N-terminal kinase; MCP-1, monocyte chemotactic protein 1; mRNA, messenger RNA; ND, normal diet; NF-κB, nuclear factor kappa; n.r., not reported; RT, resistance training; TNF-α, tumor necrosis factor alpha; TLR4, Toll-like receptor 4.

The current literature does not provide a clear definition for acute or chronic effects of training [11]. The training effect is influenced by the time period between termination of the last bout of exercise and measurement as well as by training intensity [4]. Measurements of training effects within a time period of 0–72 h after exercise termination can show acute effects, even in a chronic training process, which makes it difficult to distinguish between acute and chronic training effects. In this review, we define the effect of chronic training as the sum of all training sessions, according to previous work [4].

3. Effect of Exercise on Molecular Signaling Cascades

3.1. Insulin Receptor Substrate 1 (IRS-1)/Phosphatidylinositol 3-Kinase (PI3-K) and Akt/Protein Kinase B (Akt/PKB) Pathways

In conditions of rest, insulin regulates glucose transport into the muscle due to activation of a protein signaling cascade. After binding of insulin to its receptor, the insulin receptor is autophosphorylated. Insulin receptor substrate 1 (IRS-1) binds to the phosphorylated tyrosine residues of the insulin receptor and is subsequently phosphorylated by the tyrosine kinase of the insulin receptor. Binding of IRS-1 to the p85 subunit of phosphatidylinositol 3-kinase (PI3-K) results in activation of a PI3-K-dependent pathway comprising phosphoinositide-dependent kinase (PDK) and atypical protein kinase C (αPKC) [110]. Key downstream molecules modulating translocation of glucose transporter type 4 (GLUT4) to the plasma membrane comprise, besides Akt/protein kinase B (Akt/PKB), Ras-related C3 botulinum toxin substrate 1 (Rac1), the TBC1 domain family member 1 (TBC1D1), or the Akt substrate of 160 kDa (AS160) [32, 110, 111] (Figure 1).

In type 2 diabetes patients, despite a normal amount of GLUT4 transporters [112], insulin fails, in general, to induce adequate insulin signaling as assessed by IRS-1 tyrosine phosphorylation, Akt/PKB activity, and translocation of GLUT4 to the cell membrane [113116].

Exercise activates the insulin-signaling pathways, facilitating GLUT4 expression and translocation to the cell membrane. The effects of acute and chronic exercise on glucose uptake and insulin signaling are shown in Table 1.

Acute continuous endurance exercise with 45–60 min of training at 65–75% of maximum oxygen consumption () leads to higher rates of tyrosine phosphorylation of insulin receptor and IRS-1/2 and to increased activity of PI3-K in muscle of untrained healthy as well as insulin-resistant individuals [1215]. In contrast, short and light resistance with 5 sets of 8 repetitions of isokinetic leg extension shows no effect in endurance trained athletes [16] (Table 2). Furthermore, acute muscle contraction activates molecules of the distal insulin signaling which are known to be involved in GLUT4 translocation such as Rac1, AS160, and TBC1D1 [16, 47, 48] which will be described in more detail below. Recent animal studies have shown that only very intense muscle contraction in situ via sciatic nerve stimulation of multiple muscle types with 2–5 V as well as one bout of intense swimming for 120 min or 60 min of running with a speed of 22 m/min and incline of 10% led to an acute increase in phosphorylation and activity of key molecules like the different AKT isoforms (AKT-1, AKT-2, and AKT-3) and AS160 [4951] (Table 3).

In contrast to these studies, some human as well as animal studies reported no effect of acute exercise on proximal insulin signaling like changes in insulin receptor amount, IRS-1 phosphorylation, or PI3-K activity [1621]. In the study of Wojaszewski et al. [21], one-legged cycling exercise for 60 min at intensity of 18–23% of was not sufficient to induce changes in proximal insulin signaling in young trained individuals. Furthermore, 60 min of cycling at 75%   did not lead to changes in proximal signaling in untrained and obese individuals [19, 20]. In line with this, some animal studies found that a running speed of 18 m/min for 45 min as well as electrical stimulation with 1–3 V were also not sufficient to induce insulin signaling in skeletal muscle [17, 18].

The reason for these discrepant results in human and animal studies might lie in the differences in the intensity of training conditions in acute exercise. Moderate endurance exercise seems to acutely increase proximal signaling in untrained individuals [12, 13, 15], whereas short and light resistance and endurance training in trained individuals shows no effect [16, 21] (Tables 2 and 3). In addition, the time point after exercise when the effect of exercise is studied appears to be highly important. A recent review from Frøsig and Richter identified a critical time point of 3 to 4 h after exercise for exercise-induced increase in glucose uptake indicating a time-dependent course in the activation of exercise induced molecular signaling [22], which may be the reason for the unaltered signaling in measurements 16 and 24 h after exercise termination [19, 20]. Though training intensity and the time point of investigation appear to be important for exercise-induced activation of insulin signaling, there is still a lack of knowledge about the underlying mechanisms of acute exercise and effects of different training factors, such as modality and intensity, on insulin signaling.

Chronic exercise can also lead to higher rates of tyrosine phosphorylation of key molecules in the insulin signaling cascade in muscle of healthy as well as insulin-resistant individuals [52, 95, 96]. A recent exercise study observed enhanced whole-body insulin action and increased Akt and AS160 phosphorylation after 10 weeks of chronic resistance training with exercises for upper and lower body and running endurance training in untrained individuals [52] indicating an independence of exercise modality. Compared to untrained controls, trained humans show increased insulin-stimulated PI3-kinase activation. The positive association between PI3-kinase activation and endurance capacity () indicates that regular exercise leads to greater insulin-stimulated IRS-1-associated PI3-kinase activation in human skeletal muscle [14]. This is in line with recent animal studies showing that intense chronic endurance training in mice with a running speed of 20–32 m/min on a treadmill increases total AS160 phosphorylation [53].

3.2. AMPK Signaling Pathway

AMPK is a metabolic master switch regulating several intracellular systems and consists of two catalytic alpha-isoforms: α2- and α1-AMPK. AMPK is activated by phosphorylation by kinases such as liver kinase B1 (LKB1) [117] and is regulated by cellular energy demand. Increasing adenosine monophosphate/adenosine triphosphate (AMP/ATP) and creatine/phosphocreatine (Cr/PCr) ratios, reflecting for instance the glucose deprivation state [118], are important stimuli for AMPK activity. In line with this, activation of AMPK is positively associated with an increased skeletal muscle glucose uptake [23].

In obese diabetic and nondiabetic humans, exercise-induced stimulation of the AMPK activity is attenuated but can be fully activated by exercise with higher intensities of training as compared to healthy lean controls [24, 25]. Acute cycling endurance exercise at a moderate intensity of 50–70% of increased AMPK activity and resulted in a 2.7-fold increase in mRNA expression of AMPKα1 and AMPKα2 [24, 25].

Activation of AMPK by acute cycling exercise led to an enhanced glucose uptake in human skeletal muscle [26]. AMPK phosphorylation and activity showed an intensity-dependent response pattern. More intense (80% of ) acute cycling endurance exercise with the same amount of energy expenditure (400 kcal) resulted in a higher activation of signal transduction compared to less intense (40%  ) endurance exercise [27]. High-intensity interval training consisting of repeated sessions of intense work like all-out sprints for 30 sec (SIT) induces, with a minimum of effort (<80 kJ total), an increased phosphorylation of AMPK. Though this kind of training appears to mimic resistance exercise because of the intense, short-term muscle work, phosphorylation and activity of downstream targets linked to hypertrophy like p70 ribosomal S6 kinase and 4E binding protein 1 were unchanged [28] (Table 2).

While some acute exercise studies in animals showed that AMPK-deficient mice and LKB-deficient mice had a normal contraction-induced glucose uptake, which was independent of the knockout of the catalytic alpha-isoforms of AMPK [97, 98], other studies found that pharmacological inhibition of AMPK and LKB activity blunted contraction-induced glucose disposal in animal models by electrical stimulation [99, 100]. LKB1 knock-out in muscle provoked a reduced activity of the AMPKα2 isoform, and transgenic mice expressing a kinase-dead, dominant negative form of the AMPKα2 showed also a reduced AMPK activity and blunted glucose uptake. The authors assumed that either the maximal force production was reduced in this muscle, raising the possibility that the defect in glucose transport was due to a secondary decrease in force production and not impaired AMPKα2 activity, or the kinase-dead, dominant negative form of the AMPKα2 had a negative influence on glucose uptake [99, 100].

Chronic endurance as well as resistance exercise also induces AMPK activation and leads, furthermore, to changes in gene expression favoring GLUT4 translocation. AMPK phosphorylation is more strongly increased after 10 weeks of cycling at 65%–90% of maximum performance () exercise than after 10 weeks of leg-focused resistance training with an intensity of a 4-5-repetition maximum (RM) [8, 29]. In animal studies, chronic treadmill running as well as resistance training in the form of ladder climbing with weights activated AMPK phosphorylation and up-regulated expression of AMPK in rat pancreatic islets and skeletal muscle [30, 31] indicating that AMPK upregulation is independent of exercise modality in different tissues (Tables 2 and 3).

In light of the animal studies showing that AMPK-deficient mice have a normal contraction-induced glucose uptake [97, 98] other molecular pathways, comprising the Ca2+/calmodulin signaling pathway, appear to modulate exercise-induced glucose uptake and will be described in the following subsections.

3.3. Ca2+/Calmodulin Signaling Pathway

Changes of the calcium concentration in skeletal muscle cells lead to activation of signaling cascades that influence cellular metabolism including glucose uptake [119]. In diabetes, the calcium- (Ca2+-) dependent signaling pathway and subsequently glucose uptake are impaired [120]. Genome-wide studies for DNA methylation have shown that first-degree relatives of patients with diabetes have already altered DNA methylation of genes encoding proteins involved in calcium-dependent signaling compared to healthy individuals without positive family history. However, DNA methylation decreased after 6 months of cycling and aerobic exercise [33].

As result of skeletal muscle contraction, cytosolic Ca2+ concentration and consequently the number of Ca2+/calmodulin complexes increase. Further important key players in the Ca2+/calmodulin signaling pathway are the Ca2+/calmodulin-dependent protein kinases (CaMKs). These components are critical for exercise-induced glucose uptake [32]. Downstream components of the Ca2+/calmodulin signaling pathway are members of the histone deacetylase (HDAC) family and proteins of the myocyte enhancer factor 2 (MEF2) family leading to an enhanced expression rate of GLUT4 [8].

Ca2+ release and phosphorylation of CaMKII after acute endurance cycling exercise depend on training intensity. A matched amount of work with different intensities of 40% and 80% of led to an increase in CaMKII phosphorylation by 84% immediately after high-intensity but not low-intensity cycling endurance exercise indicating that greater force outputs result in enhanced Ca2+/calmodulin signaling [27]. Furthermore, also the duration of endurance exercise affects the Ca2+/calmodulin signaling pathway activity, with higher activity after longer duration. A 90-min acute cycling endurance exercise resulted in a progressive increase of CaMKII activity during exercise peaking at 90 min of training [34]. In line with this, a recent study comparing acute HIT cycling with traditional continuous cycling exercise showed a marked increase of CaMKII activity by HIT despite the same amount of total work after 30 min of 70%   [35] (Table 2).

In accordance with the acute exercise studies, a recent animal study showed that chronic endurance training on a treadmill increased the phosphorylation of CAMKII in pancreatic islets of rats in a dose-response manner [31].

In experimental mouse studies, incubation with the Ca2+/calmodulin inhibitor KN-93 decreased skeletal muscle glucose transport [121] and inhibited electrical contraction-induced CaMKII phosphorylation [102]. In addition to the decrease of contraction-induced glucose uptake via electrical stimulation, inhibition of CaMKII resulted in an increase of AMPK activity in a recent mice study, pointing to overlapping mechanisms between these two key signaling pathways: the Ca2+/calmodulin signaling pathway and the AMPK-signaling pathway [103]. Another key player in the context of glucose uptake-related signaling is the protein kinase mammalian target of rapamycin (mTOR) that will be addressed in the following section.

3.4. Mammalian Target of Rapamycin/Serine Kinase 6 (mTOR/p70SK6) Pathway

MTOR is a serine/threonine protein kinase that integrates diverse environmental cues by translating them into appropriate cellular responses. Disrupting the mTOR signaling pathway causes a decrease in glucose uptake in multiple cell types such as brain, muscle, and adipose tissue [122124] and can lead to insulin resistance [125].

High-force stimuli like resistance training lead to muscle adaptation preparing skeletal muscle for more intensive stress. This muscle adaptation which appears to be dysregulated in an insulin-resistant and diabetic state is initiated by the activation of the mTOR/ pathway [36, 126, 127]. This protein complex activates signaling cascades including binding proteins (elF4E), initiation factors (4E-BP1), and elongation factors (eEF2) leading to protein synthesis and subsequently to cellular hypertrophy [128]. MTOR also stimulates focal adhesion kinases (FAK) and increases FAK-phosphotransferase activity in order to activate muscle protein synthesis [129]. This adaptation is related to the intensity of the muscle contraction, increasing with higher training load. Acute cycling exercise of 70% of as well as leg-specific strength exercises of 70% of 1-RM increased mTOR phosphorylation. In particular, resistance training leads to higher activation of mTOR signaling compared to traditional endurance exercise despite a huge difference in workload (660 versus 130 kcal) [29, 3739].

Protein synthesis is regulated, in particular, by contraction-induced activation of the multiprotein complex mTORC1. This protein complex functions as a sensor or control unit which regulates the translation of proteins by assessing the cellular environment for optimal conditions and initiating translation of mRNA. Besides physical activity, potent stimulators of the mTOR/S6K pathway are insulin, insulin-like growth factor (IGF-1), cytokines like IL-6, sufficient amino acid levels in skeletal muscle, and full-energy depots [130].

During acute endurance as well as resistance exercise, mTOR signaling is inhibited via AMPK phosphorylation and signaling to suppress high-energy demanding procedures such as protein synthesis [4042]. However, after exercise, muscle protein synthesis increases in parallel to the activation of Akt/PKB (protein kinase B), mTOR, S6K, and eEF2.

One bout of intense treadmill walking at 70% of for 45 min in untrained old men as well as 70% of of one leg exercise for 60 min in untrained healthy young men led to significant activation of the insulin signaling as well as of the mTOR/SK6 pathway [43, 44]. In line with this, recent exercise studies showed that acute cycling-based HIT or intense leg-specific strength training [40] activates the mTOR signaling pathway in human muscle [39, 45]. Exercise-induced activation of mTOR signaling in leg-specific endurance and resistance training appears to be time-dependent with a continuous increase after termination of physical activity [40, 43]. In line with the human studies, mTOR signaling was upregulated in acute exercise studies in animals comprising treadmill running and electrical stimulation, with a time-dependent answer after exercise termination [46] (Tables 2 and 3).

Chronic exercise studies also demonstrate that long-term leg-specific resistance training with 4-5-RM in sedentary individuals and high intensity cycling with 70–85% of in untrained controls can activate the mTOR signaling pathway in human muscle [29, 38]. These results underline that the activation of mTOR signaling may be independent of exercise type as well as training history. Besides mTOR, there are other important downstream targets modulating glucose uptake that will be addressed in the following section.

3.5. Ras-Related C3 Botulinum Toxin Substrate 1 (Rac1), TBC1 Domain Family Members 1 and 2 (TBC1D1/2), and Akt Substrate of 160 kDa (AS160)

The proteins AS160, TBC1D1/2, and Rac1 are involved in insulin- as well as contraction-induced glucose uptake [131, 132] and are, therefore, points of convergence of these two pathways. These downstream targets are altered in an insulin-resistant or diabetic state showing a reduced signaling activity [101, 133136].

Acute endurance exercise studies in untrained and trained humans showed an increase in phosphorylation of TDC1D1/4 and AS160 in skeletal muscle in the first 4 hours after cycling and specific one-leg endurance exercise, especially under long-term training conditions with a training duration of at least 60 min at 65%   [16, 5456]. In line with these human studies, animal studies found that contraction-induced glucose uptake by electrical stimulation was also modulated by an increase in phosphorylation of AS160 and TBC1D1 proteins [57] (Tables 2 and 3).

Rac1, a key downstream target in the regulation of glucose uptake, was shown to modulate exercise- and insulin-stimulated GLUT4 translocation in human muscle, with an intensity-dependent response pattern, as shown in murine muscle [58, 59]. Animals were exercised at their 50% and 70% maximum running speed over 30 min on a treadmill, and the higher intensity program resulted in an larger increase of Rac1 activation. Given that the total amount of work differed between both measurements, the results are hard to interpret. The larger improvement may result from the higher intensity or from the greater amount of exercise. A future study comprising an alternative training protocol with identical energy expenditure but different intensities would help to clarify the role of exercise intensity in this context. Furthermore, in RAC1-deficient mice, GLUT4 translocation as well as glucose uptake decreased after acute electrical stimulated muscle contraction and insulin infusion as a sign of an inhibited signaling capacity [59, 60].

Glucose uptake and insulin signaling are influenced by inflammatory processes and specific cytokines [2]. The following section aims at shedding some light on the impact of inflammatory signaling on exercise-stimulated glucose uptake and insulin signaling.

4. Inflammation-Associated Signaling Pathways and Key Players

4.1. IκB Kinase/Nuclear Factor Kappa B Pathway (IKK/NF-κB)

Different environmental influences, for example, certain pathogens, can activate molecular signaling cascades leading to an inflammatory response mediated by the IKK/NF-κB pathway. Recognizing receptors are, in particular, Toll-like receptors (TLRs). TLR4 plays a key role in the activation of the pro-inflammatory NF-κB pathway. TLRs interact with pathogen-associated molecules, resulting in an activation of downstream signaling proteins, for example, MyD88 [137], and subsequently an immune reaction via cytokine release, for example, of IL-6 and TNF-α from adipose tissue. The adapter protein MyD88 also activates other inflammation-associated signaling pathways like MAPK signaling as described below in more detail [138]. TLRs are expressed on macrophages, which can be subdivided into pro-inflammatory M1 and anti-inflammatory M2 macrophages. Exercise studies have shown that physical activity modulates TLR-dependent pathways [2]. As a result, acute as well as chronic exercise can lead to reduced TLR expression [61] and phenotypic switching from M1 to M2 macrophages in adipose tissue of obese mice [62].

Cytokines like IL-6 or agents comprising microbial components trigger signaling cascades that converge in the activation of IκB kinase (IKK) enzyme complex and subsequently in a translocation of the protein complex NF-κB into the nucleus. This results in transcription of target genes for inflammatory immune reaction including cytokines like IL-6, TNF-α, and IL-15 [139]. Chronic activation of the NF-κB pathway contributes to insulin resistance and muscle wasting. Especially in type 2 diabetes, human muscle is characterized by an increased activity of this pathway [63].

Human and animal exercise studies have shown that acute as well as chronic exercise can reduce the activation of the IKK/NF-κB pathway. This attenuation of the inflammatory signaling was independent of the exercise modality, age, and training status [6369] (Tables 4 and 5).

During acute physical activity with a sufficient load, muscle contraction induces a marked increase of IL-6 expression in skeletal muscle but also suppresses IL-6 production in adipose tissue [70]. Increasing energy demands due to prolonged or intense acute training like marathon running or cycling at 88% of [7173] as well as shrinking depots of muscle glycogen [104] accelerate the increase of IL-6 plasma levels. Interestingly, a recent work from Castellani et al. showed that exercise induces also a specific increase of IL-6 in adipose tissue which occurred more rapidly in adipose tissue from trained mice in comparison to untrained mice when exercised at the same relative running speed on a treadmill. The authors speculated that the increase of IL-6 would be needed for the provision of lipids to the muscle and liver [74]. In line with this, Macpherson et al. showed an increasing IL-6 and decreasing M1 macrophages content in inguinal adipose tissue and an improved insulin action after an acute bout of treadmill running exercise in obese mice [75]. In line with the results of the acute exercises studies, chronic exercise also led to decreased activity of the IKK/NF-κB pathway after 8 weeks of cycling exercise at 70% of and intense whole-body strength exercise with 50–80% of 1-RM [63, 66] (Tables 4 and 5). Accordingly, a decreased plasma IL-6 concentration at rest as well as in response to chronic exercise appears to characterize a normal training adaptation [71].

The transient rise in IL-6 also appears to be responsible for the production of anti-inflammatory mediators like IL-10 or IL-1 receptor antagonist (IL-1RA). In particular IL-1RA prevents inflammatory processes by blocking signal transduction of the proinflammatory IL-1 and creates also an anti-inflammatory balance to the proinflammatory cytokine IL-1β [76, 77, 140]. Furthermore, elevated levels of IL-6 from skeletal muscle stimulate an anti-inflammatory signaling cascade that inhibits the secretion of proinflammatory cytokines like TNF-α or IL-1β, suppress the secretion of the acute-phase reactant C-reactive protein (CRP) from the liver, a general and unspecific marker for systemic inflammation [76, 77], downregulate monocyte TLR expression at both mRNA and cell surface protein levels, and finally inhibit the IKK/NF-κB pathway [6466]. Besides the TLR family, there are other receptor proteins like NOD-like receptors initiating inflammatory processes and subsequently modulating glucose uptake-related signaling which will be discussed in the following section.

4.2. Inflammasome Pathway

The NOD-like receptor (NLR) family is of key importance in the innate immune system. NLRs are responsible for recognizing pathogen and danger-associated molecular patterns. In response to stress signals, NLRs activate the inflammasome pathway which forms a multi-protein complex [2]. Participating components of inflammasome complexes are NLRs, neutrophilic alkaline phosphatases (NALPs), apoptosis-associated speck-like protein (ASC) and caspase-1. After its formation, this oligomer converts proinflammatory cytokines into active forms such as IL-1β. Increasing IL-1-β levels have been hypothesized to play a role in the progression of type 2 diabetes and its complications because its activity stimulates inflammatory processes leading to cell damage and apoptosis, in particular in pancreatic β-cells. Furthermore, IL-1β inhibits proximal and distal insulin signaling and mediates interorgan cross talk between adipocytes and the liver, contributing to systemic inflammation [2, 141143].

A recent review reported that chronic endurance and resistance training in mice decrease NLR family pyrin domain containing 3 (NLRP3) mRNA levels accompanied by reduced IL-18 levels, reflecting diminished activity of the NLR/inflammasome pathway [2]. IL-18 expression decreases under chronic intense endurance exercise conditions with sports like rowing, running, or cycling with an intensity which is at 70% of in humans [78, 79]. Only chronic training conditions, but not acute exercise, appear to reduce IL-18 mRNA expression [79]. In line with this, a recently published animal study with chronic treadmill running as endurance exercise and isometric strength training as resistance training showed a decrease of IL-18 expression in adipose tissue and plasma levels [80] (Table 5).

So far, there are no human exercise studies which measured acute or chronic effects of physical activity on the upstream elements of the inflammasome pathway. Further mechanistic studies are, therefore, needed to better understand the role of the inflammasome in the anti-inflammatory response to exercise. In contrast, the role of the C-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK) pathway in the modulation of exercise-dependent effects on glucose uptake and inflammatory response has been investigated by several animal as well as human studies.

4.3. C-Jun N-Terminal Kinase (JNK)/Mitogen-Activated Protein Kinase (MAPK) Pathway

Lipid accumulation in adipocytes and endoplasmic reticulum (ER) stress as well as a NF-κB dependent cytokine releases activate the JNK/MAPK pathway [139, 144]. This activation results in the serine phosphorylation of IRS-1 and the phosphorylation of the c-Jun component of activator protein-1 (AP-1). The phosphorylation of serine residues in insulin receptor substrate-1 leads to an impairment in the ability of IRS-1 to activate downstream phosphatidylinositol 3-kinase-dependent pathways which may cause insulin resistance [145147]. AP-1 is a transcription factor that mediates the gene expression of many cytokines. Subsequently, the JNK pathway leads to an inflammatory reaction, especially to TNF-α and IL-6 release [139]. JNKs are divided into 3 isoforms and belong to the MAPK family. The MAPK family comprises extracellular regulated kinases (ERKs), JNKs and p38, and mediates cell growth, differentiation, hypertrophy, apoptosis, and inflammation [144]. Furthermore, oxidative stress following reactive oxygen species (ROS) production induces JNKs and p38 MAPK activation reflecting an important immune defense mechanism [148]. JNK activation by skeletal muscle contraction is also associated with an increase in muscle IL-6 mRNA expression in mice acutely after endurance exercise in form of treadmill running [81].

Exercise studies in human and animal models showed that the JNK/MAPK pathway is activated in a dose-response pattern. In particular very intense acute exercise like marathon running or cycling at 70% of and intense dynamic pull exercise as resistance training with an one-repetition maximum (1-RM) of 85% stimulate JNK signaling in skeletal muscle [8284], independently of training modality. JNK activation results, as a physiological mechanism, in DNA repair and muscle regeneration [149]. In contrast, a recent animal study has shown that acute long-term exercise by swimming for 180 min reduces JNK phosphorylation and improves insulin signaling and sensitivity in adipose tissue from obese rat [69]. In particular, chronic endurance exercise in form of swimming and treadmill running contributes to a reduction in JNK phosphorylation and improves insulin signaling and sensitivity in adipose and hepatic tissue from obese rats [6769, 85].

Inflammatory signaling pathways are associated with insulin resistance and impaired glucose uptake, whereas adiponectin is an important, though controversially discussed, counterpart being positively associated with insulin sensitivity. This adipokine will be discussed in the following section.

4.4. Adiponectin

Adiponectin, an adipokine which is primarily released by white adipose tissue (WAT), appears to be a key player in glucose metabolism at least in rodents, whereas its relevance in humans is somewhat less clear [6]. The secreted adiponectin binds to its receptors AdipoR1 and AdipoR2 and activates AMPK, p38 MAPK, and peroxisome proliferator-activated receptor α (PPAR-α) following adaptor protein 1 (APPL1) release in skeletal muscle and liver [150]. As a result, adiponectin positively affects metabolism by increasing fatty acid oxidation and glucose uptake in muscle. Furthermore, it plays a critical role in the cross talk between different insulin-sensitive tissues [151, 152]. Adiponectin levels are decreased in patients with diabetes and low adiponectin levels are associated with insulin resistance and obesity [153, 154]. Recent mouse studies showed that pharmacological adiponectin agonists improve insulin sensitivity and other health-related parameters [155].

Only a limited number of acute exercise intervention studies focused on changes of adiponectin levels. In one study, circulating adiponectin levels increased 30 min after endurance exercise in the recovery phase [5]. The currently available data indicate that adiponectin levels change in dependence of exercise intensity, showing an increasing level by enhanced training intensity of 76%   in trained rowing athletes [86], whereas moderate and long-lasting cycling at 50% of for 120 min did not acutely increase adiponectin levels in trained individuals immediately after exercise [87] (Table 4).

Conflicting results were also observed under chronic exercise conditions. More intense endurance exercise in form of cycling and brisk walking at 70% of resulted in increases of adiponectin levels [88, 89]. Overweight and age seem to reduce the response of adiponectin to exercise [90]. In line with this, Simpson and Singh reported in their review that adiponectin expression levels are increased under high-intensity exercise conditions [91], regardless of training modality in untrained young lean or obese individuals, after chronic whole-body strength training or jogging [92, 93]. In line with this, Cho et al. showed that 40 minutes of HIT exercise on treadmill prevent the downregulation of AdipoR1 which was caused by a high fat diet in sedentary control animals [94] indicating the importance of intense training for the potential role of adiponectin.

In contrast, untrained and trained adiponectin knockout mice (AdKO) significantly increased glucose tolerance and insulin sensitivity after 8 weeks of treadmill running suggesting the presence of an unknown compensatory mechanism [53].

A recent meta-analysis found that chronic exercise did not significantly increase adiponectin levels. However, in subgroup analyses, all modalities tended to increase adiponectin. The lack of statistical power due to small group sizes may have contributed to the overall null-finding [3]. In contrast, lifestyle interventions with unstructured exercise alone or in combination with weight-reducing diet can positively influence adiponectin plasma levels [156]. Weight loss is an important factor contributing to increases in plasma levels of adiponectin [157159]. In conclusion, the impact of exercise on adiponectin levels needs further clarification. With respect to chronic effects it is important to investigate to what extent exercise effects on adiponectin may be mediated by weight loss.

4.5. Exercise, Inflammation, and Insulin Signaling

Circulating serum or plasma levels of cytokines are strongly linked with the onset of type 2 diabetes [160162]. The stimulation of inflammatory signaling cascades can lead to interference with the insulin signaling pathway [2]. During exercise, acute effects on cytokine regulation comprise an upregulation of both (i) proinflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6) and (ii) anti-inflammatory cytokines (IL-1RA, IL-10) [106].

Long-term effects of physical exercise are known to reduce markers of inflammation by decreasing adipocytokine production and cytokine release from skeletal muscle [163165]. The relationship between glucose uptake and adiponectin, IL-6, and TNF-α is shown in Figure 1.

The mechanistic impact of inflammation on insulin signaling has been studied for several cytokines. Currently available data suggest that TNF-α plays a direct role in the development of insulin resistance by decreasing glucose uptake into adipocytes via suppression of insulin receptor activity, AMPK activation, and downregulation of GLUT4 expression [165168]. Acute exercise did not change the expression pattern of TNF-α [169], whereas the increase of TNF-α during high intense physical activity like marathon running appears to be a response to muscle damage [104, 107, 108, 170]. Large cohort studies show that physical activity or chronic endurance exercise in form of walking reduces systemic subclinical inflammation [92] and the impact of exercise rises in a dose-response pattern regulated by frequency and intensity, but inflammation remains unchanged when exercise intensity was only moderate [66, 109, 171, 172]. A moderate community-based walking program with 3000 steps more per day did not change TNF-α plasma levels [109] and a chronic resistance training with only 2 units per week of only 3 sets of 3 exercises had also no impact on TNF-α protein content. In line with this, TNF-α plasma levels were reduced by high-intensity chronic resistance training, even though fat mass has not changed [173]. Also animal studies show that chronic exercise training, in particular endurance training like treadmill running, can reduce TNF-α levels [62].

IL-6 is another important protein in this context and is expressed by several tissues. As a myokine, muscle-derived IL-6 is acutely upregulated during exercise exposure [106] and mediates a physiological cross talk with WAT and liver in order to regulate glucose metabolism [160]. However, long-term effects of regular exercise show marked decreases of IL-6 levels [77]. The role of IL-6 is complex, as also evident by its diverse effects on molecular signaling. In adipose tissue, IL-6 mediates inflammatory processes and causes insulin resistance by downregulating GLUT4 and IRS-1 expression [139]. Furthermore, increasing IL-6 levels block PI3-K, another key player in insulin signaling, and induce TLR4 gene expression leading to enhanced inflammatory processes [174, 175]. In addition, IL-6 induces the downstream NF-κB signaling pathway which impairs insulin signaling and subsequently induces insulin resistance in insulin-dependent tissues of obese humans and animals [2]. In particular, IL-6 and liver interact in the context of exercise. A human exercise study with long-term cycling has shown that contraction-induced IL-6 release increased endogenous glucose production (EGP), thus underlining the importance of IL-6 for glucose homeostasis [105].

Experimental studies using mouse models yielded controversial findings. IL-6-deficient mice can develop a glucose-intolerant and insulin-resistant state indicating that balanced IL-6 levels have a positive effect on glucose uptake. Furthermore, mouse studies showed that circulating IL-6 levels increase glucose uptake and improve insulin sensitivity in skeletal muscle via AMPK activation [176].

Besides, the inflammasome pathway downregulates insulin signaling. The inflammasome pathway which is part of the innate immune system converts proinflammatory cytokines into active forms such as IL-1β or IL-18 which are decreased in their levels after chronic exercise [2]. Important proinflammatory chemokines which are influenced by exercise are interleukin 8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1). Both cytokines slightly increase after acute exercise; however, their circulating levels decrease after chronic exercise in human as well as animal model exhibiting an improved inflammation status [75, 77, 139, 160], as shown in Table 1.

5. Summary

Exercise is an important cornerstone in the prevention and treatment of metabolic disorders. Acute and chronic exercise activates different molecular signaling pathways that can counteract defects in signaling and associated metabolic processes (Table 1). Exercise interventions have shown that physical activity can increase GLUT4 protein expression and translation by activation of different molecular signaling pathways irrespective of the exercise modality. AMPK and Ca2+/calmodulin signaling pathways show a dose-response pattern and increase their activity with increasing intensity despite equal work rate in kcal when compared to less intense exercise.

The key players mTOR, AS160, TBC1D1/4, and Rac1 can be activated by exercise. Human exercise studies have demonstrated that acute and chronic physical activity, regardless of training modality, leads to increases in their activity and finally to improved glucose uptake. The change in activity reflects a dose-response pattern. MTOR and AS160 also exhibit a continuous time-dependent increase.

Metabolic disorders are accompanied by activated inflammation-related signaling pathways which result in elevated cytokine release. Proinflammatory immune mediators, like IL-1β, IL-6, or TNF-α, are important factors in the development of insulin resistance. Their expression is modulated by physical activity. In particular, chronic endurance and resistance training and high training intensity improve glucose uptake which is associated in the long term with decreased secretion of proinflammatory cytokines and increased release of anti-inflammatory proteins such as adiponectin.

In summary, the current literature points to a higher efficiency of more intense exercise because of a dose-response relationship regulating metabolic improvements. However, more high-quality exercise interventions as well as mechanistic studies have to be performed to fully understand the molecular mechanisms contributing to metabolic improvements.

6. Open Questions

Despite the high number of studies on exercise interventions and underlying mechanisms that have been conducted, we are far from understanding the details mediating the effects of exercise on glucose uptake. Single key players in this field were identified over time and confirmed with mechanistic human and animal studies. So far, there is still a lack of knowledge about the underlying mechanisms of exercise-induced glucose uptake in regard to training factors, such as point of termination or intensity, especially in proximal insulin signaling. When interpreting the responses to training, it is important to know, in particular when dealing with the issue of glucose uptake and related signaling pathways, when relative to the last bout, and preferably the last two bouts, the samples were collected to distinguish between acute and chronic training effects. Furthermore, exercise exposure can be considered the combined responses to intensity, bout duration, and bout frequency, where the product is usually considered to be total amount like total energy expenditure, but only a small number of intervention studies controlled for total work.

In regard to the key players of molecular signaling, the interplay of interacting pathways, such as the Ca2+/calmodulin signaling pathway and the AMPK pathway, is still elusive. The inflammatory signaling pathways involving IKK/NF-κB and the inflammasomes have not been sufficiently characterized in the context of the influence of acute as well as chronic exercise. The controversial results of the adiponectin exercise studies highlight potential species differences between men and mice and merit more mechanistic studies.

Furthermore, there is an intense need to detect to what extent the effects of physical exercise are independent of or explained by weight loss or change in body composition. Some of these questions require larger sample sizes and higher statistical power to quantify effects but also standardized methods for molecular measurements and high-quality study plans considering potential confounders.

Conflict of Interests

The authors declare that they have no conflict of interests.

References

  1. A. V. Ardisson Korat, W. C. Willett, and F. B. Hu, “Diet, lifestyle, and genetic risk factors for type 2 diabetes: a review from the Nurses' Health Study, Nurses' Health Study 2, and Health Professionals' Follow-up study,” Current Nutrition Reports, vol. 3, no. 4, pp. 345–354, 2014. View at: Publisher Site | Google Scholar
  2. R. Ringseis, K. Eder, F. C. Mooren, and K. Krüger, “Metabolic signals and innate immune activation in obesity and exercise,” Exercise Immunology Review, vol. 21, pp. 58–68, 2015. View at: Google Scholar
  3. Y. Hayashino, J. L. Jackson, T. Hirata et al., “Effects of exercise on C-reactive protein, inflammatory cytokine and adipokine in patients with type 2 diabetes: a meta-analysis of randomized controlled trials,” Metabolism, vol. 63, no. 3, pp. 431–440, 2014. View at: Publisher Site | Google Scholar
  4. E. J. Henriksen, “Invited review: effects of acute exercise and exercise training on insulin resistance,” Journal of Applied Physiology, vol. 93, no. 2, pp. 788–796, 2002. View at: Publisher Site | Google Scholar
  5. I. K. Martin, A. Katz, and J. Wahren, “Splanchnic and muscle metabolism during exercise in NIDDM patients,” The American Journal of Physiology, vol. 269, no. 3, pp. E583–E590, 1995. View at: Google Scholar
  6. M. C. F. Passos and M. C. Gonçalves, “Regulation of insulin sensitivity by adiponectin and its receptors in response to physical exercise,” Hormone and Metabolic Research, vol. 46, no. 9, pp. 603–608, 2014. View at: Publisher Site | Google Scholar
  7. J.-A. Simoneau, J. H. Veerkamp, L. P. Turcotte, and D. E. Kelley, “Markers of capacity to utilize fatty acids in human skeletal muscle: relation to insulin resistance and obesity and effects of weight loss,” The FASEB Journal, vol. 13, no. 14, pp. 2051–2060, 1999. View at: Google Scholar
  8. B. Egan and J. R. Zierath, “Exercise metabolism and the molecular regulation of skeletal muscle adaptation,” Cell Metabolism, vol. 17, no. 2, pp. 162–184, 2013. View at: Publisher Site | Google Scholar
  9. L. E. Gosselin, K. F. Kozlowski, L. Devinney-Boymel, and C. Hambridge, “Metabolic response of different high-intensity aerobic interval exercise protocols,” Journal of Strength and Conditioning Research, vol. 26, no. 10, pp. 2866–2871, 2012. View at: Publisher Site | Google Scholar
  10. J. R. Silva, G. P. Nassis, and A. Rebelo, “Strength training in soccer with a specific focus on highly trained players,” Sports Medicine—Open, vol. 1, article 17, 2015. View at: Publisher Site | Google Scholar
  11. P. D. Thompson, S. F. Crouse, B. Goodpaster, D. Kelley, N. Moyna, and L. Pescatello, “The acute versus the chronic response to exercise,” Medicine and Science in Sports and Exercise, vol. 33, no. 6, pp. S438–S445, 2001. View at: Publisher Site | Google Scholar
  12. K. Cusi, K. Maezono, A. Osman et al., “Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle,” The Journal of Clinical Investigation, vol. 105, no. 3, pp. 311–320, 2000. View at: Publisher Site | Google Scholar
  13. G. Perseghin, T. B. Price, K. F. Petersen et al., “Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects,” The New England Journal of Medicine, vol. 335, no. 18, pp. 1357–1362, 1996. View at: Publisher Site | Google Scholar
  14. J. P. Kirwan, L. F. del Aguila, J. M. Hernandez et al., “Regular exercise enhances insulin activation of IRS-1-associated PI3-kinase in human skeletal muscle,” Journal of Applied Physiology, vol. 88, no. 2, pp. 797–803, 2000. View at: Google Scholar
  15. K. F. Howlett, K. Sakamoto, H. Yu, L. J. Goodyear, and M. Hargreaves, “Insulin-stimulated insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity is enhanced in human skeletal muscle after exercise,” Metabolism: Clinical and Experimental, vol. 55, no. 8, pp. 1046–1052, 2006. View at: Publisher Site | Google Scholar
  16. A. Deshmukh, V. G. Coffey, Z. Zhong, A. V. Chibalin, J. A. Hawley, and J. R. Zierath, “Exercise-induced phosphorylation of the novel Akt substrates AS160 and filamin A in human skeletal muscle,” Diabetes, vol. 55, no. 6, pp. 1776–1782, 2006. View at: Publisher Site | Google Scholar
  17. J. L. Treadway, D. E. James, E. Burcel, and N. B. Ruderman, “Effect of exercise on insulin receptor binding and kinase activity in skeletal muscle,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 256, no. 1, pp. E138–E144, 1989. View at: Google Scholar
  18. L. J. Goodyear, F. Giorgino, T. W. Balon, G. Condorelli, and R. J. Smith, “Effects of contractile activity on tyrosine phosphoproteins and PI 3-kinase activity in rat skeletal muscle,” American Journal of Physiology—Endocrinology and Metabolism, vol. 268, no. 5, pp. 987–995, 1995. View at: Google Scholar
  19. D. J. O'Gorman, H. K. R. Karlsson, S. McQuaid et al., “Exercise training increases insulin-stimulated glucose disposal and GLUT4 (SLC2A4) protein content in patients with type 2 diabetes,” Diabetologia, vol. 49, no. 12, pp. 2983–2992, 2006. View at: Publisher Site | Google Scholar
  20. G. D. Wadley, N. Konstantopoulos, L. Macaulay et al., “Increased insulin-stimulated Akt pSer473 and cytosolic SHP2 protein abundance in human skeletal muscle following acute exercise and short-term training,” Journal of Applied Physiology, vol. 102, no. 4, pp. 1624–1631, 2007. View at: Publisher Site | Google Scholar
  21. J. F. P. Wojtaszewski, B. F. Hansen, J. Gade et al., “Insulin signaling and insulin sensitivity after exercise in human skeletal muscle,” Diabetes, vol. 49, no. 3, pp. 325–331, 2000. View at: Publisher Site | Google Scholar
  22. C. Frøsig and E. A. Richter, “Improved insulin sensitivity after exercise: focus on insulin signaling,” Obesity, vol. 17, no. 3, pp. S15–S20, 2009. View at: Publisher Site | Google Scholar
  23. B. E. Kemp, K. I. Mitchelhill, D. Stapleton, B. J. Michell, Z.-P. Chen, and L. A. Witters, “Dealing with energy demand: the AMP-activated protein kinase,” Trends in Biochemical Sciences, vol. 24, no. 1, pp. 22–25, 1999. View at: Publisher Site | Google Scholar
  24. N. Musi, N. Fujii, M. F. Hirshman et al., “AMP-activated protein kinase (AMPK) is activated in muscle of subjects with type 2 diabetes during exercise,” Diabetes, vol. 50, no. 5, pp. 921–927, 2001. View at: Publisher Site | Google Scholar
  25. A. Sriwijitkamol, D. K. Coletta, E. Wajcberg et al., “Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes: a time-course and dose-response study,” Diabetes, vol. 56, no. 3, pp. 836–848, 2007. View at: Publisher Site | Google Scholar
  26. B. Benziane, T. J. Burton, B. Scanlan et al., “Divergent cell signaling after short-term intensified endurance training in human skeletal muscle,” American Journal of Physiology—Endocrinology and Metabolism, vol. 295, no. 6, pp. E1427–E1438, 2008. View at: Publisher Site | Google Scholar
  27. B. Egan, B. P. Carson, P. M. Garcia-Roves et al., “Exercise intensity-dependent regulation of peroxisome proliferator-activated receptor γ coactivator-1α mRNA abundance is associated with differential activation of upstream signalling kinases in human skeletal muscle,” The Journal of Physiology, vol. 588, no. 10, pp. 1779–1790, 2010. View at: Publisher Site | Google Scholar
  28. M. J. Gibala, S. L. McGee, A. P. Garnham, K. F. Howlett, R. J. Snow, and M. Hargreaves, “Brief intense interval exercise activates AMPK and p38 MAPK signaling and increases the expression of PGC-1α in human skeletal muscle,” Journal of Applied Physiology, vol. 106, no. 3, pp. 929–934, 2009. View at: Publisher Site | Google Scholar
  29. K. Vissing, S. L. McGee, J. Farup, T. Kjølhede, M. H. Vendelbo, and N. Jessen, “Differentiated mTOR but not AMPK signaling after strength vs endurance exercise in training-accustomed individuals,” Scandinavian Journal of Medicine and Science in Sports, vol. 23, no. 3, pp. 355–366, 2013. View at: Publisher Site | Google Scholar
  30. L. Luo, A.-M. Lu, Y. Wang et al., “Chronic resistance training activates autophagy and reduces apoptosis of muscle cells by modulating IGF-1 and its receptors, Akt/mTOR and Akt/FOXO3a signaling in aged rats,” Experimental Gerontology, vol. 48, no. 4, pp. 427–436, 2013. View at: Publisher Site | Google Scholar
  31. V. C. Calegari, C. C. Zoppi, L. F. Rezende, L. R. Silveira, E. M. Carneiro, and A. C. Boschero, “Endurance training activates AMP-activated protein kinase, increases expression of uncoupling protein 2 and reduces insulin secretion from rat pancreatic islets,” Journal of Endocrinology, vol. 208, no. 3, pp. 257–264, 2011. View at: Publisher Site | Google Scholar
  32. K. I. Stanford and L. J. Goodyear, “Exercise and type 2 diabetes: molecular mechanisms regulating glucose uptake in skeletal muscle,” Advances in Physiology Education, vol. 38, no. 4, pp. 308–314, 2014. View at: Publisher Site | Google Scholar
  33. M. D. Nitert, T. Dayeh, P. Volkov et al., “Impact of an exercise intervention on DNA methylation in skeletal muscle from first-degree relatives of patients with type 2 diabetes,” Diabetes, vol. 61, no. 12, pp. 3322–3332, 2012. View at: Publisher Site | Google Scholar
  34. A. J. Rose, B. Kiens, and E. A. Richter, “Ca2+-calmodulin-dependent protein kinase expression and signalling in skeletal muscle during exercise,” Journal of Physiology, vol. 574, no. 3, pp. 889–903, 2006. View at: Publisher Site | Google Scholar
  35. A. Combes, J. Dekerle, N. Webborn, P. Watt, V. Bougault, and F. N. Daussin, “Exerciseinduced metabolic fluctuations influence AMPK, p38MAPK and CaMKII phosphorylation in human skeletal muscle,” Physiological Reports, vol. 3, Article ID e12462, 2015. View at: Publisher Site | Google Scholar
  36. A. Katta, S. Kakarla, M. Wu et al., “Altered regulation of contraction-induced Akt/mTOR/p70S6k pathway signaling in skeletal muscle of the obese Zucker rat,” Experimental Diabetes Research, vol. 2009, Article ID 384683, 9 pages, 2009. View at: Publisher Site | Google Scholar
  37. A. Philp, D. L. Hamilton, and K. Baar, “Signals mediating skeletal muscle remodeling by resistance exercise: PI3-kinase independent activation of mTORC1,” Journal of Applied Physiology, vol. 110, no. 2, pp. 561–568, 1985. View at: Publisher Site | Google Scholar
  38. C. A. Stuart, M. E. A. Howell, J. D. Baker et al., “Cycle training increased glut4 and activation of mammalian target of rapamycin in fast twitch muscle fibers,” Medicine and Science in Sports and Exercise, vol. 42, no. 1, pp. 96–106, 2010. View at: Publisher Site | Google Scholar
  39. D. M. Camera, J. Edge, M. J. Short, J. A. Hawley, and V. G. Coffey, “Early time course of akt phosphorylation after endurance and resistance exercise,” Medicine and Science in Sports and Exercise, vol. 42, no. 10, pp. 1843–1852, 2010. View at: Publisher Site | Google Scholar
  40. H. C. Dreyer, S. Fujita, J. G. Cadenas, D. L. Chinkes, E. Volpi, and B. B. Rasmussen, “Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle,” Journal of Physiology, vol. 576, no. 2, pp. 613–624, 2006. View at: Publisher Site | Google Scholar
  41. D. M. Thomson, C. A. Fick, and S. E. Gordon, “AMPK activation attenuates S6K1, 4E-BP1, and eEF2 signaling responses to high-frequency electrically stimulated skeletal muscle contractions,” Journal of Applied Physiology, vol. 104, no. 3, pp. 625–632, 2008. View at: Publisher Site | Google Scholar
  42. K. Inoki, H. Ouyang, T. Zhu et al., “TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth,” Cell, vol. 126, no. 5, pp. 955–968, 2006. View at: Publisher Site | Google Scholar
  43. H. Mascher, B. Ekblom, O. Rooyackers, and E. Blomstrand, “Enhanced rates of muscle protein synthesis and elevated mTOR signalling following endurance exercise in human subjects,” Acta Physiologica, vol. 202, no. 2, pp. 175–184, 2011. View at: Publisher Site | Google Scholar
  44. S. Fujita, B. B. Rasmussen, J. G. Cadenas et al., “Aerobic exercise overcomes the age-related insulin resistance of muscle protein metabolism by improving endothelial function and Akt/mammalian target of rapamycin signaling,” Diabetes, vol. 56, no. 6, pp. 1615–1622, 2007. View at: Publisher Site | Google Scholar
  45. J. K. Pugh, S. H. Faulkner, A. P. Jackson, J. A. King, and M. A. Nimmo, “Acute molecular responses to concurrent resistance and high-intensity interval exercise in untrained skeletal muscle,” Physiological Reports, vol. 3, no. 4, Article ID e12364, 2015. View at: Publisher Site | Google Scholar
  46. B. A. Edgett, M. L. Fortner, A. Bonen, and B. J. Gurd, “Mammalian target of rapamycin pathway is up-regulated by both acute endurance exercise and chronic muscle contraction in rat skeletal muscle,” Applied Physiology, Nutrition and Metabolism, vol. 38, no. 8, pp. 862–869, 2013. View at: Publisher Site | Google Scholar
  47. S. J. Maarbjerg, L. Sylow, and E. A. Richter, “Current understanding of increased insulin sensitivity after exercise—emerging candidates,” Acta Physiologica, vol. 202, no. 3, pp. 323–335, 2011. View at: Publisher Site | Google Scholar
  48. L. Sylow, M. Kleinert, C. Pehmøller et al., “Akt and Rac1 signaling are jointly required for insulin-stimulated glucose uptake in skeletal muscle and downregulated in insulin resistance,” Cellular Signalling, vol. 26, no. 2, pp. 323–331, 2014. View at: Publisher Site | Google Scholar
  49. C. M. Castorena, E. B. Arias, N. Sharma, and G. D. Cartee, “Postexercise improvement in insulin-stimulated glucose uptake occurs concomitant with greater AS160 phosphorylation in muscle from normal and insulin-resistant rats,” Diabetes, vol. 63, no. 7, pp. 2297–2308, 2014. View at: Publisher Site | Google Scholar
  50. K. Sakamoto, M. F. Hirshman, W. G. Aschenbach, and L. J. Goodyear, “Contraction regulation of Akt in rat skeletal muscle,” The Journal of Biological Chemistry, vol. 277, no. 14, pp. 11910–11917, 2002. View at: Publisher Site | Google Scholar
  51. J. F. P. Wojtaszewski, Y. Higaki, M. F. Hirshman et al., “Exercise modulates postreceptor insulin signaling and glucose transport in muscle-specific insulin receptor knockout mice,” Journal of Clinical Investigation, vol. 104, no. 9, pp. 1257–1264, 1999. View at: Publisher Site | Google Scholar
  52. L. A. Consitt, J. Van Meter, C. A. Newton et al., “Impairments in site-specific AS160 phosphorylation and effects of exercise training,” Diabetes, vol. 62, no. 10, pp. 3437–3447, 2013. View at: Publisher Site | Google Scholar
  53. I. R. Ritchie, D. C. Wright, and D. J. Dyck, “Adiponectin is not required for exercise training-induced improvements in glucose and insulin tolerance in mice,” Physiological Reports, vol. 2, no. 9, Article ID e12146, 2014. View at: Publisher Site | Google Scholar
  54. M. H. Vendelbo, A. B. Møller, J. T. Treebak et al., “Sustained AS160 and TBC1D1 phosphorylations in human skeletal muscle 30 min after a single bout of exercise,” Journal of Applied Physiology, vol. 117, no. 3, pp. 289–296, 2014. View at: Publisher Site | Google Scholar
  55. J. T. Treebak, J. B. Birk, A. J. Rose, B. Kiens, E. A. Richter, and J. F. P. Wojtaszewski, “AS160 phosphorylation is associated with activation of α 2β2γ1- but not α 2β2γ3-AMPK trimeric complex in skeletal muscle during exercise in humans,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 292, no. 3, pp. E715–E722, 2007. View at: Publisher Site | Google Scholar
  56. J. T. Treebak, C. Frøsig, C. Pehmøller et al., “Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle,” Diabetologia, vol. 52, no. 5, pp. 891–900, 2009. View at: Publisher Site | Google Scholar
  57. M. D. Bruss, E. B. Arias, G. E. Lienhard, and G. D. Cartee, “Increased phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle in response to insulin or contractile activity,” Diabetes, vol. 54, no. 1, pp. 41–50, 2005. View at: Publisher Site | Google Scholar
  58. L. Sylow, L. L. Møller, M. Kleinert, E. A. Richter, and T. E. Jensen, “Rac1—a novel regulator of contraction-stimulated glucose uptake in skeletal muscle,” Experimental Physiology, vol. 99, no. 12, pp. 1574–1580, 2014. View at: Publisher Site | Google Scholar
  59. L. Sylow, T. E. Jensen, M. Kleinert et al., “Rac1 is a novel regulator of contraction-stimulated glucose uptake in skeletal muscle,” Diabetes, vol. 62, no. 4, pp. 1139–1151, 2013. View at: Publisher Site | Google Scholar
  60. L. Sylow, L. L. V. Møller, M. Kleinert, E. A. Richter, and T. E. Jensen, “Stretch-stimulated glucose transport in skeletal muscle is regulated by Rac1,” Journal of Physiology, vol. 593, no. 3, pp. 645–656, 2015. View at: Publisher Site | Google Scholar
  61. N. Kawanishi, H. Yano, Y. Yokogawa, and K. Suzuki, “Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet-induced obese mice,” Exercise Immunology Review, vol. 16, pp. 105–118, 2010. View at: Google Scholar
  62. N. Kawanishi, T. Mizokami, H. Yano, and K. Suzuki, “Exercise attenuates M1 macrophages and CD8+ T cells in the adipose tissue of obese mice,” Medicine and Science in Sports and Exercise, vol. 45, no. 9, pp. 1684–1693, 2013. View at: Publisher Site | Google Scholar
  63. A. Sriwijitkamol, C. Christ-Roberts, R. Berria et al., “Reduced skeletal muscle inhibitor of κBβ content is associated with insulin resistance in subjects with type 2 diabetes: reversal by exercise training,” Diabetes, vol. 55, no. 3, pp. 760–767, 2006. View at: Publisher Site | Google Scholar
  64. G. I. Lancaster, Q. Khan, P. Drysdale et al., “The physiological regulation of toll-like receptor expression and function in humans,” The Journal of Physiology, vol. 563, no. 3, pp. 945–955, 2005. View at: Publisher Site | Google Scholar
  65. M. Oliveira and M. Gleeson, “The influence of prolonged cycling on monocyte Toll-like receptor 2 and 4 expression in healthy men,” European Journal of Applied Physiology, vol. 109, no. 2, pp. 251–257, 2010. View at: Publisher Site | Google Scholar
  66. P. Rodriguez-Miguelez, R. Fernandez-Gonzalo, M. Almar et al., “Role of Toll-like receptor 2 and 4 signaling pathways on the inflammatory response to resistance training in elderly subjects,” Age, vol. 36, article 9734, 2014. View at: Publisher Site | Google Scholar
  67. G. da Luz, M. J. S. Frederico, S. da Silva et al., “Endurance exercise training ameliorates insulin resistance and reticulum stress in adipose and hepatic tissue in obese rats,” European Journal of Applied Physiology, vol. 111, no. 9, pp. 2015–2023, 2011. View at: Publisher Site | Google Scholar
  68. C. Medeiros, M. J. Frederico, G. da Luz et al., “Exercise training reduces insulin resistance and upregulates the mTOR/p70S6k pathway in cardiac muscle of diet-induced obesity rats,” Journal of Cellular Physiology, vol. 226, no. 3, pp. 666–674, 2011. View at: Publisher Site | Google Scholar
  69. A. G. Oliveira, B. M. Carvalho, N. Tobar et al., “Physical exercise reduces circulating lipopolysaccharide and TLR4 activation and improves insulin signaling in tissues of DIO rats,” Diabetes, vol. 60, no. 3, pp. 784–796, 2011. View at: Publisher Site | Google Scholar
  70. D. Lyngsø, L. Simonsen, and J. Bülow, “Interleukin-6 production in human subcutaneous abdominal adipose tissue: the effect of exercise,” Journal of Physiology, vol. 543, no. 1, pp. 373–378, 2002. View at: Publisher Site | Google Scholar
  71. C. P. Fischer, “Interleukin-6 in acute exercise and training: what is the biological relevance?” Exercise Immunology Review, vol. 12, pp. 6–33, 2006. View at: Google Scholar
  72. K. Ostrowski, T. Rohde, M. Zacho, S. Asp, and B. K. Pedersen, “Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running,” The Journal of Physiology, vol. 508, no. 3, pp. 949–953, 1998. View at: Publisher Site | Google Scholar
  73. M. Leggate, M. A. Nowell, S. A. Jones, and M. A. Nimmo, “The response of interleukin-6 and soluble interleukin-6 receptor isoforms following intermittent high intensity and continuous moderate intensity cycling,” Cell Stress and Chaperones, vol. 15, no. 6, pp. 827–833, 2010. View at: Publisher Site | Google Scholar
  74. L. Castellani, C. G. Perry, R. E. MacPherson et al., “Exercise-mediated IL-6 signaling occurs independent of inflammation and is amplified by training in mouse adipose tissue,” Journal of Applied Physiology, vol. 119, pp. 1347–1354, 2015. View at: Publisher Site | Google Scholar
  75. R. E. Macpherson, J. S. Huber, S. Frendo-Cumbo, J. A. Simpson, and D. C. Wright, “Adipose tissue insulin action and IL-6 signaling after exercise in obese mice,” Medicine & Science in Sports & Exercise, vol. 47, no. 10, pp. 2034–2042, 2015. View at: Google Scholar
  76. A. M. W. Petersen and B. K. Pedersen, “The anti-inflammatory effect of exercise,” Journal of Applied Physiology, vol. 98, no. 4, pp. 1154–1162, 2005. View at: Publisher Site | Google Scholar
  77. E. Hopps, B. Canino, and G. Caimi, “Effects of exercise on inflammation markers in type 2 diabetic subjects,” Acta Diabetologica, vol. 48, no. 3, pp. 183–189, 2011. View at: Publisher Site | Google Scholar
  78. N. P. Kadoglou, D. Perrea, F. Iliadis, N. Angelopoulou, C. Liapis, and M. Alevizos, “Exercise reduces resistin and inflammatory cytokines in patients with type 2 diabetes,” Diabetes Care, vol. 30, no. 3, pp. 719–721, 2007. View at: Publisher Site | Google Scholar
  79. L. Leick, B. Lindegaard, D. Stensvold, P. Plomgaard, B. Saltin, and H. Pilegaard, “Adipose tissue interleukin-18 mRNA and plasma interleukin-18: effect of obesity and exercise,” Obesity, vol. 15, no. 2, pp. 356–363, 2007. View at: Publisher Site | Google Scholar
  80. C. Mardare, K. Krüger, G. Liebisch et al., “Endurance and resistance training affect high fat diet-induced increase of ceramides, inflammasome expression, and systemic inflammation in mice,” Journal of Diabetes Research, vol. 2016, Article ID 4536470, 13 pages, 2016. View at: Publisher Site | Google Scholar
  81. M. Whitham, M. H. S. Chan, M. Pal et al., “Contraction-induced interleukin-6 gene transcription in skeletal muscle is regulated by c-Jun terminal kinase/activator protein-1,” Journal of Biological Chemistry, vol. 287, no. 14, pp. 10771–10779, 2012. View at: Publisher Site | Google Scholar
  82. D. Aronson, M. D. Boppart, S. D. Dufresne, R. A. Fielding, and L. J. Goodyear, “Exercise stimulates c-Jun NH2 kinase activity and c-Jun transcriptional activity in human skeletal muscle,” Biochemical and Biophysical Research Communications, vol. 251, no. 1, pp. 106–110, 1998. View at: Publisher Site | Google Scholar
  83. M. D. Boppart, S. Asp, J. F. P. Wojtaszewski, R. A. Fielding, T. Mohr, and L. J. Goodyear, “Marathon running transiently increases c-Jun NH2-terminal kinase and p38γ activities in human skeletal muscle,” The Journal of Physiology, vol. 526, no. 3, pp. 663–669, 2000. View at: Publisher Site | Google Scholar
  84. A. J. Galpin, A. C. Fry, L. Z. F. Chiu, D. B. Thomason, and B. K. Schilling, “High-power resistance exercise induces MAPK phosphorylation in weightlifting trained men,” Applied Physiology, Nutrition and Metabolism, vol. 37, no. 1, pp. 80–87, 2012. View at: Publisher Site | Google Scholar
  85. E. Passos, C. D. Pereira, I. O. Gonçalves et al., “Role of physical exercise on hepatic insulin, glucocorticoid and inflammatory signaling pathways in an animal model of non-alcoholic steatohepatitis,” Life Sciences, vol. 123, pp. 51–60, 2015. View at: Publisher Site | Google Scholar
  86. J. Jürimäe, P. Hofmann, T. Jürimäe et al., “Plasma adiponectin response to sculling exercise at individual anaerobic threshold in college level male rowers,” International Journal of Sports Medicine, vol. 27, no. 4, pp. 272–277, 2006. View at: Publisher Site | Google Scholar
  87. C. Punyadeera, A. H. G. Zorenc, R. Koopman et al., “The effects of exercise and adipose tissue lipolysis on plasma adiponectin concentration and adiponectin receptor expression in human skeletal muscle,” European Journal of Endocrinology, vol. 152, no. 3, pp. 427–436, 2005. View at: Publisher Site | Google Scholar
  88. A. D. Kriketos, S. K. Gan, A. M. Poynten, S. M. Furler, D. J. Chisholm, and L. V. Campbell, “Exercise increases adiponectin levels and insulin sensitivity in humans,” Diabetes Care, vol. 27, no. 2, pp. 629–630, 2004. View at: Publisher Site | Google Scholar
  89. S. Lim, H. C. Sung, I.-K. Jeong et al., “Insulin-sensitizing effects of exercise on adiponectin and retinol-binding protein-4 concentrations in young and middle-aged women,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 6, pp. 2263–2268, 2008. View at: Publisher Site | Google Scholar
  90. V. B. O'Leary, C. M. Marchetti, R. K. Krishnan, B. P. Stetzer, F. Gonzalez, and J. P. Kirwan, “Exercise-induced reversal of insulin resistance in obese elderly is associated with reduced visceral fat,” Journal of Applied Physiology, vol. 100, no. 5, pp. 1584–1589, 2006. View at: Publisher Site | Google Scholar
  91. K. A. Simpson and M. A. F. Singh, “Effects of exercise on adiponectin: a systematic review,” Obesity, vol. 16, no. 2, pp. 241–256, 2008. View at: Publisher Site | Google Scholar
  92. T. Kondo, I. Kobayashi, and M. Murakami, “Effect of exercise on circulating adipokine levels in obese young women,” Endocrine Journal, vol. 53, no. 2, pp. 189–195, 2006. View at: Publisher Site | Google Scholar
  93. I. G. Fatouros, S. Tournis, D. Leontsini et al., “Leptin and adiponectin responses in overweight inactive elderly following resistance training and detraining are intensity related,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 11, pp. 5970–5977, 2005. View at: Publisher Site | Google Scholar
  94. J. K. Cho, S. Kim, H. R. Hong, J. H. Yoon, and H. Kang, “Exercise training improves whole body insulin resistance via adiponectin receptor 1,” International Journal of Sports Medicine, 2016. View at: Publisher Site | Google Scholar
  95. C. Frøsig, A. J. Rose, J. T. Treebak, B. Kiens, E. A. Richter, and J. F. P. Wojtaszewski, “Effects of endurance exercise training on insulin signaling in human skeletal muscle: Interactions at the level of phosphatidylinositol 3-kinase, Akt, and AS160,” Diabetes, vol. 56, no. 8, pp. 2093–2102, 2007. View at: Publisher Site | Google Scholar
  96. M. K. Holten, M. Zacho, M. Gaster, C. Juel, J. F. P. Wojtaszewski, and F. Dela, “Strength training increases insulin-mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 diabetes,” Diabetes, vol. 53, no. 2, pp. 294–305, 2004. View at: Publisher Site | Google Scholar
  97. N. Fujii, M. F. Hirshman, E. M. Kane et al., “AMP-activated protein kinase α2 activity is not essential for contraction- and hyperosmolarity-induced glucose transport in skeletal muscle,” Journal of Biological Chemistry, vol. 280, no. 47, pp. 39033–39041, 2005. View at: Publisher Site | Google Scholar
  98. J. Jeppesen, S. J. Maarbjerg, A. B. Jordy et al., “LKB1 regulates lipid oxidation during exercise independently of AMPK,” Diabetes, vol. 62, no. 5, pp. 1490–1499, 2013. View at: Publisher Site | Google Scholar
  99. N. Lefort, E. St-Amand, S. Morasse, C. H. Côté, and A. Marette, “The α-subunit of AMPK is essential for submaximal contraction-mediated glucose transport in skeletal muscle in vitro,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 295, no. 6, pp. E1447–E1454, 2008. View at: Publisher Site | Google Scholar
  100. K. Sakamoto, A. McCarthy, D. Smith et al., “Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction,” The EMBO Journal, vol. 24, no. 10, pp. 1810–1820, 2005. View at: Publisher Site | Google Scholar
  101. L. Sylow, T. E. Jensen, M. Kleinert et al., “Rac1 signaling is required for insulin-stimulated glucose uptake and is dysregulated in insulin-resistant murine and human skeletal muscle,” Diabetes, vol. 62, no. 6, pp. 1865–1875, 2013. View at: Publisher Site | Google Scholar
  102. C. A. Witczak, N. Fujii, M. F. Hirshman, and L. J. Goodyear, “Ca2+/calmodulin-dependent protein kinase kinase-α regulates skeletal muscle glucose uptake independent of AMP-activated protein kinase and Akt activation,” Diabetes, vol. 56, no. 5, pp. 1403–1409, 2007. View at: Publisher Site | Google Scholar
  103. C. A. Witczak, N. Jessen, D. M. Warro et al., “CaMKII regulates contraction- but not insulin-induced glucose uptake in mouse skeletal muscle,” American Journal of Physiology—Endocrinology and Metabolism, vol. 298, no. 6, pp. E1150–E1160, 2010. View at: Publisher Site | Google Scholar
  104. C. Keller, A. Steensberg, H. Pilegaard et al., “Transcriptional activation of the IL-6 gene in human contracting skeletal muscle: influence of muscle glycogen content,” The FASEB Journal, vol. 15, no. 14, pp. 2748–2750, 2001. View at: Google Scholar
  105. M. A. Febbraio, N. Hiscock, M. Sacchetti, C. P. Fischer, and B. K. Pedersen, “Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction,” Diabetes, vol. 53, no. 7, pp. 1643–1648, 2004. View at: Publisher Site | Google Scholar
  106. K. Ostrowski, T. Rohde, S. Asp, P. Schjerling, and B. K. Pedersen, “Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans,” The Journal of Physiology, vol. 515, no. 1, pp. 287–291, 1999. View at: Publisher Site | Google Scholar
  107. R. L. Starkie, J. Rolland, D. J. Angus, M. J. Anderson, and M. A. Febbraio, “Circulating monocytes are not the source of elevations in plasma IL-6 and TNF-α levels after prolonged running,” American Journal of Physiology—Cell Physiology, vol. 280, no. 4, pp. C769–C774, 2001. View at: Google Scholar
  108. K. Suzuki, M. Yamada, S. Kurakake et al., “Circulating cytokines and hormones with immunosuppressive but neutrophil-priming potentials rise after endurance exercise in humans,” European Journal of Applied Physiology, vol. 81, no. 4, pp. 281–287, 2000. View at: Publisher Site | Google Scholar
  109. S. R. Gray, G. Baker, A. Wright, C. F. Fitzsimons, N. Mutrie, and M. A. Nimmo, “The effect of a 12 week walking intervention on markers of insulin resistance and systemic inflammation,” Preventive Medicine, vol. 48, no. 1, pp. 39–44, 2009. View at: Publisher Site | Google Scholar
  110. M. Roden, “Exercise in type 2 diabetes: to resist or to endure?” Diabetologia, vol. 55, no. 5, pp. 1235–1239, 2012. View at: Publisher Site | Google Scholar
  111. K. S. C. Röckl, C. A. Witczak, and L. J. Goodyear, “Signaling mechanisms in skeletal muscle: acute responses and chronic adaptations to exercise,” IUBMB Life, vol. 60, no. 3, pp. 145–153, 2008. View at: Publisher Site | Google Scholar
  112. J. R. Zierath, A. Krook, and H. Wallberg-Henriksson, “Insulin action and insulin resistance in human skeletal muscle,” Diabetologia, vol. 43, no. 7, pp. 821–835, 2000. View at: Publisher Site | Google Scholar
  113. M. Björnholm, Y. Kawano, M. Lehtihet, and J. R. Zierath, “Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation,” Diabetes, vol. 46, no. 3, pp. 524–527, 1997. View at: Publisher Site | Google Scholar
  114. A. Krook, R. A. Roth, X. J. Jiang, J. R. Zierath, and H. Wallberg-Henriksson, “Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects,” Diabetes, vol. 47, no. 8, pp. 1281–1286, 1998. View at: Publisher Site | Google Scholar
  115. J. W. Ryder, J. Yang, D. Galuska et al., “Use of a novel impermeable biotinylated photolabeling reagent to assess insulin- and hypoxia-stimulated cell surface GLUT4 content in skeletal muscle from type 2 diabetic patients,” Diabetes, vol. 49, no. 4, pp. 647–654, 2000. View at: Publisher Site | Google Scholar
  116. J. R. Zierath, L. He, A. Gumà, E. Odegaard Wahlström, A. Klip, and H. Wallberg-Henriksson, “Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM,” Diabetologia, vol. 39, no. 10, pp. 1180–1189, 1996. View at: Publisher Site | Google Scholar
  117. V. A. Lira, C. R. Benton, Z. Yan, and A. Bonen, “PGC-1α regulation by exercise training and its influences on muscle function and insulin sensitivity,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 299, no. 2, pp. E145–E161, 2010. View at: Publisher Site | Google Scholar
  118. B. B. Kahn, T. Alquier, D. Carling, and D. G. Hardie, “AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism,” Cell Metabolism, vol. 1, no. 1, pp. 15–25, 2005. View at: Publisher Site | Google Scholar
  119. D. R. Park, K. H. Park, B. J. Kim, C. S. Yoon, and U. H. Kim, “Exercise ameliorates insulin resistance via Ca2+ signals distinct from those of insulin for GLUT4 translocation in skeletal muscles,” Diabetes, vol. 64, no. 4, pp. 1224–1234, 2015. View at: Publisher Site | Google Scholar
  120. J. T. Lanner, J. D. Bruton, A. Katz, and H. Westerblad, “Ca2+ and insulin-mediated glucose uptake,” Current Opinion in Pharmacology, vol. 8, no. 3, pp. 339–345, 2008. View at: Publisher Site | Google Scholar
  121. D. C. Wright, K. A. Hucker, J. O. Holloszy, and D. H. Han, “Ca2+ and AMPK both mediate stimulation of glucose transport by muscle contractions,” Diabetes, vol. 53, no. 2, pp. 330–335, 2004. View at: Publisher Site | Google Scholar
  122. R. Rashmi, C. DeSelm, C. Helms et al., “AKT inhibitors promote cell death in cervical cancer through disruption of mTOR signaling and glucose uptake,” PLoS ONE, vol. 9, no. 4, Article ID e92948, 2014. View at: Publisher Site | Google Scholar
  123. C. L. Buller, R. D. Loberg, M.-H. Fan et al., “A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1 glucose transporter expression,” The American Journal of Physiology—Cell Physiology, vol. 295, no. 3, pp. C836–C843, 2008. View at: Publisher Site | Google Scholar
  124. M. J. Pereira, J. Palming, M. Rizell et al., “mTOR inhibition with rapamycin causes impaired insulin signalling and glucose uptake in human subcutaneous and omental adipocytes,” Molecular and Cellular Endocrinology, vol. 355, no. 1, pp. 96–105, 2012. View at: Publisher Site | Google Scholar
  125. M. Kleinert, L. Sylow, D. J. Fazakerley et al., “Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo,” Molecular Metabolism, vol. 3, no. 6, pp. 630–641, 2014. View at: Publisher Site | Google Scholar
  126. M. Fraenkel, M. Ketzinel-Gilad, Y. Ariav et al., “mTOR inhibition by rapamycin prevents β-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes,” Diabetes, vol. 57, no. 4, pp. 945–957, 2008. View at: Publisher Site | Google Scholar
  127. S. C. Bodine, T. N. Stitt, M. Gonzalez et al., “Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo,” Nature Cell Biology, vol. 3, no. 11, pp. 1014–1019, 2001. View at: Publisher Site | Google Scholar
  128. M. Sandri, “Signaling in muscle atrophy and hypertrophy,” Physiology, vol. 23, no. 3, pp. 160–170, 2008. View at: Publisher Site | Google Scholar
  129. S. Klossner, A.-C. Durieux, D. Freyssenet, and M. Flueck, “Mechano-transduction to muscle protein synthesis is modulated by FAK,” European Journal of Applied Physiology, vol. 106, no. 3, pp. 389–398, 2009. View at: Publisher Site | Google Scholar
  130. K. Huang and D. C. Fingar, “Growing knowledge of the mTOR signaling network,” Seminars in Cell and Developmental Biology, vol. 36, pp. 79–90, 2014. View at: Publisher Site | Google Scholar
  131. H. F. Kramer, C. A. Witczak, E. B. Taylor, N. Fujii, M. F. Hirshman, and L. J. Goodyear, “AS160 regulates insulin- and contraction-stimulated glucose uptake in mouse skeletal muscle,” The Journal of Biological Chemistry, vol. 281, no. 42, pp. 31478–31485, 2006. View at: Publisher Site | Google Scholar
  132. K. Vichaiwong, S. Purohit, D. An et al., “Contraction regulates site-specific phosphorylation of TBC1D1 in skeletal muscle,” Biochemical Journal, vol. 431, no. 2, pp. 311–320, 2010. View at: Publisher Site | Google Scholar
  133. C. Y. Christ-Roberts, T. Pratipanawatr, W. Pratipanawatr, R. Berria, R. Belfort, and L. J. Mandarino, “Increased insulin receptor signaling and glycogen synthase activity contribute to the synergistic effect of exercise on insulin action,” Journal of Applied Physiology, vol. 95, no. 6, pp. 2519–2529, 2003. View at: Publisher Site | Google Scholar
  134. L. JeBailey, O. Wanono, W. Niu, J. Roessler, A. Rudich, and A. Klip, “Ceramide- and oxidant-induced insulin resistance involve loss of insulin-dependent Rac-activation and actin remodeling in muscle cells,” Diabetes, vol. 56, no. 2, pp. 394–403, 2007. View at: Publisher Site | Google Scholar
  135. H. Cho, J. Mu, J. K. Kim et al., “Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ),” Science, vol. 292, no. 5522, pp. 1728–1731, 2001. View at: Publisher Site | Google Scholar
  136. P. H. Albers, A. J. T. Pedersen, J. B. Birk et al., “Human muscle fiber type-specific insulin signaling: impact of obesity and type 2 diabetes,” Diabetes, vol. 64, no. 2, pp. 485–497, 2015. View at: Publisher Site | Google Scholar
  137. O. S. Kwon, R. E. Tanner, K. M. Barrows et al., “MyD88 regulates physical inactivity-induced skeletal muscle inflammation, ceramide biosynthesis signaling, and glucose intolerance,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 309, no. 1, pp. E11–E21, 2015. View at: Publisher Site | Google Scholar
  138. S. Akira and S. Sato, “Toll-like receptors and their signaling mechanisms,” Scandinavian Journal of Infectious Diseases, vol. 35, no. 9, pp. 555–562, 2003. View at: Publisher Site | Google Scholar
  139. L. Chen, R. Chen, H. Wang, and F. Liang, “Mechanisms linking inflammation to insulin resistance,” International Journal of Endocrinology, vol. 2015, Article ID 508409, 9 pages, 2015. View at: Publisher Site | Google Scholar
  140. A. Steensberg, C. P. Fischer, C. Keller, K. Møller, and B. K. Pedersen, “IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 285, no. 2, pp. E433–E437, 2003. View at: Publisher Site | Google Scholar
  141. H. Wen, E. A. Miao, and J. P.-Y. Ting, “Mechanisms of NOD-like receptor-associated inflammasome activation,” Immunity, vol. 39, no. 3, pp. 432–441, 2013. View at: Publisher Site | Google Scholar
  142. J. Jager, T. Grémeaux, M. Cormont, Y. Le Marchand-Brustel, and J.-F. Tanti, “Interleukin-1β-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression,” Endocrinology, vol. 148, no. 1, pp. 241–251, 2007. View at: Publisher Site | Google Scholar
  143. C. Herder, E. Dalmas, M. Böni-Schnetzler, and M. Y. Donath, “The IL-1 pathway in type 2 diabetes and cardiovascular complications,” Trends in Endocrinology & Metabolism, vol. 26, no. 10, pp. 551–563, 2015. View at: Publisher Site | Google Scholar
  144. H. F. Kramer and L. J. Goodyear, “Exercise, MAPK, and NF-κB signaling in skeletal muscle,” Journal of Applied Physiology, vol. 103, no. 1, pp. 388–395, 2007. View at: Publisher Site | Google Scholar
  145. Z. Gao, D. Hwang, F. Bataille et al., “Serine phosphorylation of insulin receptor substrate 1 by inhibitor κB kinase complex,” The Journal of Biological Chemistry, vol. 277, no. 50, pp. 48115–48121, 2002. View at: Publisher Site | Google Scholar
  146. K. Müssig, H. Staiger, H. Fiedler et al., “Shp2 is required for protein kinase C-dependent phosphorylation of serine 307 in insulin receptor substrate-1,” Journal of Biological Chemistry, vol. 280, no. 38, pp. 32693–32699, 2005. View at: Publisher Site | Google Scholar
  147. K. Müssig, H. Fiedler, H. Staiger et al., “Insulin-induced stimulation of JNK and the PI 3-kinase/mTOR pathway leads to phosphorylation of serine 318 of IRS-1 in C2C12 myotubes,” Biochemical and Biophysical Research Communications, vol. 335, no. 3, pp. 819–825, 2005. View at: Publisher Site | Google Scholar
  148. E. Kefaloyianni, C. Gaitanaki, and I. Beis, “ERK1/2 and p38-MAPK signalling pathways, through MSK1, are involved in NF-κB transactivation during oxidative stress in skeletal myoblasts,” Cellular Signalling, vol. 18, no. 12, pp. 2238–2251, 2006. View at: Publisher Site | Google Scholar
  149. M. Karin and E. Gallagher, “From JNK to pay dirt: jun kinases, their biochemistry, physiology and clinical importance,” IUBMB Life, vol. 57, no. 4-5, pp. 283–295, 2005. View at: Publisher Site | Google Scholar
  150. T. Kadowaki, K. Hara, T. Yamauchi, Y. Terauchi, K. Tobe, and R. Nagai, “Molecular mechanism of insulin resistance and obesity,” Experimental Biology and Medicine, vol. 228, no. 10, pp. 1111–1117, 2003. View at: Google Scholar
  151. M. J. Yoon, G. Y. Lee, J. J. Chung, Y. H. Ahn, S. H. Hong, and J. B. Kim, “Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha,” Diabetes, vol. 55, no. 9, pp. 2562–2570, 2006. View at: Publisher Site | Google Scholar
  152. X. Mao, C. K. Kikani, R. A. Riojas et al., “APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function,” Nature Cell Biology, vol. 8, no. 5, pp. 516–523, 2006. View at: Publisher Site | Google Scholar
  153. C. Herder, M. Carstensen, and D. M. Ouwens, “Anti-inflammatory cytokines and risk of type 2 diabetes,” Diabetes, Obesity and Metabolism, vol. 15, no. 3, pp. 39–50, 2013. View at: Publisher Site | Google Scholar
  154. K. Ohashi, R. Shibata, T. Murohara, and N. Ouchi, “Role of anti-inflammatory adipokines in obesity-related diseases,” Trends in Endocrinology and Metabolism, vol. 25, no. 7, pp. 348–355, 2014. View at: Publisher Site | Google Scholar
  155. M. Okada-Iwabu, T. Yamauchi, M. Iwabu et al., “A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity,” Nature, vol. 503, no. 7477, pp. 493–499, 2013. View at: Publisher Site | Google Scholar
  156. L. M. Belalcazar, W. Lang, S. M. Haffner et al., “Improving adiponectin levels in individuals with diabetes and obesity: insights from Look AHEAD,” Diabetes Care, vol. 38, no. 8, pp. 1544–1550, 2015. View at: Publisher Site | Google Scholar
  157. L. M. Belalcazar, W. Lang, S. M. Haffner et al., “Adiponectin and the mediation of HDL-cholesterol change with improved lifestyle: the look AHEAD study,” Journal of Lipid Research, vol. 53, no. 12, pp. 2726–2733, 2012. View at: Publisher Site | Google Scholar
  158. Y. Deng and P. E. Scherer, “Adipokines as novel biomarkers and regulators of the metabolic syndrome,” Annals of the New York Academy of Sciences, vol. 1212, pp. E1–E19, 2010. View at: Google Scholar
  159. C. Herder, M. Peltonen, P.-A. Svensson et al., “Adiponectin and bariatric surgery: associations with diabetes and cardiovascular disease in the Swedish Obese Subjects Study,” Diabetes Care, vol. 37, no. 5, pp. 1401–1409, 2014. View at: Publisher Site | Google Scholar
  160. B. K. Pedersen and H. Bruunsgaard, “Possible beneficial role of exercise in modulating low-grade inflammation in the elderly,” Scandinavian Journal of Medicine and Science in Sports, vol. 13, no. 1, pp. 56–62, 2003. View at: Publisher Site | Google Scholar
  161. C. Herder, J. Baumert, A. Zierer et al., “Immunological and cardiometabolic risk factors in the prediction of type 2 diabetes and coronary events: MONICA/KORA Augsburg case-cohort study,” PLoS ONE, vol. 6, no. 6, Article ID e19852, 2011. View at: Publisher Site | Google Scholar
  162. C. Herder, J. Baumert, B. Thorand et al., “Chemokines as risk factors for type 2 diabetes: results from the MONICA/KORA Augsburg study, 1984–2002,” Diabetologia, vol. 49, no. 5, pp. 921–929, 2006. View at: Publisher Site | Google Scholar
  163. C. Herder, M. Peltonen, W. Koenig et al., “Anti-inflammatory effect of lifestyle changes in the Finnish Diabetes Prevention Study,” Diabetologia, vol. 52, no. 3, pp. 433–442, 2009. View at: Publisher Site | Google Scholar
  164. F. Ribeiro, A. J. Alves, J. A. Duarte, and J. Oliveira, “Is exercise training an effective therapy targeting endothelial dysfunction and vascular wall inflammation?” International Journal of Cardiology, vol. 141, no. 3, pp. 214–221, 2010. View at: Publisher Site | Google Scholar
  165. P. L. Gordon, E. Vannier, K. Hamada et al., “Resistance training alters cytokine gene expression in skeletal muscle of adults with type 2 diabetes,” International Journal of Immunopathology and Pharmacology, vol. 19, no. 4, pp. 739–749, 2006. View at: Google Scholar
  166. G. S. Hotamisligil, “The role of TNFα and TNF receptors in obesity and insulin resistance,” Journal of Internal Medicine, vol. 245, no. 6, pp. 621–625, 1999. View at: Publisher Site | Google Scholar
  167. R. Halse, S. L. Pearson, J. G. McCormack, S. J. Yeaman, and R. Taylor, “Effects of tumor necrosis factor-α on insulin action in cultured human muscle cells,” Diabetes, vol. 50, no. 5, pp. 1102–1109, 2001. View at: Publisher Site | Google Scholar
  168. J. M. Youd, S. Rattigan, and M. G. Clark, “Acute impairment of insulin-mediated capillary recruitment and glucose uptake rat skeletal muscle vivo by TNF-α,” Diabetes, vol. 49, no. 11, pp. 1904–1909, 2000. View at: Publisher Site | Google Scholar
  169. M. A. Nimmo, M. Leggate, J. L. Viana, and J. A. King, “The effect of physical activity on mediators of inflammation,” Diabetes, Obesity and Metabolism, vol. 15, no. 3, pp. 51–60, 2013. View at: Publisher Site | Google Scholar
  170. B. K. Pedersen and M. A. Febbraio, “Point: interleukin-6 does have a beneficial role in insulin sensitivity and glucose homeostasis,” Journal of Applied Physiology, vol. 102, no. 2, pp. 814–816, 1985. View at: Google Scholar
  171. F.-C. Hsu, S. B. Kritchevsky, Y. Liu et al., “Association between inflammatory components and physical function in the health, aging, and body composition study: a principal component analysis approach,” Journals of Gerontology—Series A: Biological Sciences and Medical Sciences, vol. 64, no. 5, pp. 581–589, 2009. View at: Publisher Site | Google Scholar
  172. M. Hawkins, L. M. Belalcazar, K. B. Schelbert, C. Richardson, C. M. Ballantyne, and A. Kriska, “The effect of various intensities of physical activity and chronic inflammation in men and women by diabetes status in a national sample,” Diabetes Research and Clinical Practice, vol. 97, no. 1, pp. e6–e8, 2012. View at: Google Scholar
  173. K. D. Flack, K. P. Davy, M. W. Hulver, R. A. Winett, M. I. Frisard, and B. M. Davy, “Aging, resistance training, and diabetes prevention,” Journal of Aging Research, vol. 2011, Article ID 127315, 12 pages, 2011. View at: Publisher Site | Google Scholar
  174. J. Yin, Z. Hao, Y. Ma et al., “Concomitant activation of the PI3K/Akt and ERK1/2 signalling is involved in cyclic compressive force-induced IL-6 secretion in MLO-Y4 cells,” Cell Biology International, vol. 38, no. 5, pp. 591–598, 2014. View at: Publisher Site | Google Scholar
  175. T. H. Kim, S. E. Choi, E. S. Ha et al., “IL-6 induction of TLR-4 gene expression via STAT3 has an effect on insulin resistance in human skeletal muscle,” Acta Diabetologica, vol. 50, no. 2, pp. 189–200, 2013. View at: Publisher Site | Google Scholar
  176. M. A. Febbraio, “Role of interleukins in obesity: implications for metabolic disease,” Trends in Endocrinology and Metabolism, vol. 25, no. 6, pp. 312–319, 2014. View at: Publisher Site | Google Scholar

Copyright © 2016 Martin Röhling et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder
Views5076
Downloads1773
Citations

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.