Adaptations to exercise training within skeletal muscle in adults with type 2 diabetes or impaired glucose tolerance: a systematic review

Authors

  • Yi Wang,

    1. Exercise, Health and Performance Faculty Research Group, Faculty of Health Sciences, University of Sydney, Sydney, NSW, Australia
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  • David Simar,

    1. School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia
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  • Maria A. Fiatarone Singh

    Corresponding author
    1. Exercise, Health and Performance Faculty Research Group, Faculty of Health Sciences, University of Sydney, Sydney, NSW, Australia
    2. Faculty of Medicine, University of Sydney, Sydney, Australia
    3. Hebrew SeniorLife and Jean Mayer USDA Human Nutrition Center on Aging at Tufts University, Boston, MA, USA
    • University of Sydney, K221, Cumberland Campus, 75 East Street, Lidcombe, 2141, NSW, Australia.
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Abstract

The aim of this investigation was to review morphological and metabolic adaptations within skeletal muscle to exercise training in adults with type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT). A comprehensive, systematic database search for manuscripts was performed from 1966 to March 2008 using computerized databases, including Medline, Premedline, CINAHL, AMED, EMBASE and SportDiscus. Three reviewers independently assessed studies for potential inclusion (exposure to exercise training, T2DM or IGT, muscle biopsy performed). A total of 18 exercise training studies were reviewed. All morphological and metabolic outcomes from muscle biopsies were collected. The metabolic outcomes were divided into six domains: glycogen, glucose facilitated transporter 4 (GLUT4) and insulin signalling, enzymes, markers of inflammation, lipids metabolism and so on. Beneficial adaptations to exercise were seen primarily in muscle fiber area and capillary density, glycogen, glycogen synthase and GLUT4 protein expressions. Few randomized controlled trials including muscle biopsy data existed, with a small number of subjects involved. More trials, especially robustly designed exercise training studies, are needed in this field. Future research should focus on the insulin signalling pathway to better understand the mechanism of the improvements in insulin sensitivity and glucose homeostasis in response to various modalities and doses of exercise in this cohort. Copyright © 2009 John Wiley & Sons, Ltd.

Introduction

Diabetes mellitus is a worldwide epidemic. It is reported by the International Diabetes Federation that at least 177 million people in the world have diabetes and World Health Organization figures estimate that this will rise to 300 million by 2025 1. Approximately 90–95% of people who are diagnosed with diabetes have type 2 diabetes, which results from insulin resistance combined with relative insulin deficiency 2. The beneficial effect of exercise on insulin sensitivity has been well established 3. Exercise alone, in the absence of body weight change, is able to enhance glucose homeostasis 4. Because skeletal muscle is the largest reservoir for glucose disposal 5, muscle wasting from aging, sarcopenia and/or inactivity exacerbates problems of peripheral glucose uptake due to insulin deficiency or insensitivity. Muscle weakness, decreased muscle mass and decreases in skeletal muscle fiber numbers and size are related to, and may precede, insulin resistance, glucose intolerance, and type 2 diabetes 6, 7. Although it has been shown that exercise can enhance insulin sensitivity and glycemic control 4, 8, the mechanisms underlying such benefits are not fully understood. Indeed there are recent reviews of the metabolic benefits of physical activity 9–12, but there is no systematic review of the effects of exercise on specific skeletal muscle adaptations in people with impaired glucose tolerance (IGT) or type 2 diabetes to our knowledge.

Therefore, the purpose of this investigation was to systemically review morphological and metabolic adaptations within skeletal muscle to exercise training in people with type 2 diabetes mellitus or IGT, for the purpose of identifying underlying mechanisms that may be targeted in future pharmacologic or lifestyle interventions to combat this global epidemic.

Methods

A systematic review of all published literature, regardless of study design, investigating adaptations within skeletal muscle to exercise training exposure in individuals with type 2 diabetes mellitus or IGT was conducted. One of the (YW) authors conducted the search; the other two authors (DS and MFS) reviewed all retrieved articles for eligibility, and accuracy of data extraction onto pre-designed forms. Disagreements were resolved by consensus. A quantitative meta-analysis was not undertaken due to the wide variety of interventions used and outcomes assessed, but individual effect sizes (ESs) were calculated within each trial whenever possible using published data.

Literature search

A literature review was conducted from the year 1966 to 2008 using computerized databases including Medline (1967–2008), Premedline (most recently published), CINAHL (1982–2008), AMED (1985–2008), EMBASE (1966–2008) and SportDiscus (1967–2008), with the last search being conducted in March 2008. Firstly, three categorical searches were conducted using the following keywords: (1) ‘exercise’, ‘physical activity’, ‘training’, ‘aerobic’, ‘resistance’, ‘weight lifting’ or ‘strength’; (2) ‘diabet’, ‘insulin’ or ‘glucose’; and (3) ‘biopsy’ or ‘muscle’. Secondly, searches 1–3 were combined using ‘AND’ and duplicate results were removed. All titles were manually searched for potential inclusion. Reference lists of retrieved papers, authors' names, and review articles were hand-searched for additional relevant citations. Unpublished theses were not included in the literature search.

Inclusion criteria

Articles were selected from the initial search on the basis of the following criteria: the study design was a randomized controlled trial, non-randomized controlled trial, or uncontrolled trial with the intervention of an aerobic or resistance or combined training; human subjects with type 2 diabetes or IGT were used; a muscle biopsy was conducted; the full-length article was published in a peer-reviewed journal. Aerobic exercise involves exercise performed for extended periods with large muscle activity involving hundreds of consecutive repetitions that challenge the delivery of oxygen to the active muscles. Resistance training involves weight training or the use of high-resistance machines with exercise that is limited to a few repetitions (generally less than 20) before exhaustion 13. Dietary co-interventions were allowed, only if the exercise effect could be isolated from the dietary effect.

Exclusion criteria

Studies were excluded for the following reasons: only animal subjects were studied; subjects without diabetes or IGT were included; only subjects with type 1 diabetes were included; an acute exposure only to an exercise bout of any kind (<3 sessions); an exercise intervention meeting the above definitions was not included in the study design; no biopsy results were presented; they were non-English language papers or unpublished; the articles were reviews or abstracts.

Quality assessment

Study quality was assessed based on a modification of Delphi List 14 for assessing the quality of randomized control trials and was extended to non-randomized controlled trials. Additional quality variables considered were supervision of exercise training, compliance, and dropout rate; all considered important in exercise studies.

Statistical analysis

Data were extracted for the description of methodology and outcomes of each trial. From this data, values reported as standard error (SE) of the mean were converted to standard deviation (SD). Study characteristics were summarized as mean (SD) or median (range) as appropriate for normal or non-normally distributed data, respectively. Relative ES (mean changeTreatment − mean changeControl) ÷ SDPooledbaseline was calculated for controlled trials if it was applicable 15. ES for each of the controlled trials was interpreted according to the method of Cohen 16.

Results

Search results

The study screening process at each step is presented in Figure 1. The 26 papers 17–42 were retrieved from 18 studies including 3 randomized controlled trials reported in 9 publications 17–25 (2 trials reported in 8 publications with resistance training 17–24 and 1 with aerobic training 25), 2 non-randomized controlled trials 26, 27 (with aerobic training 26, 27) and 13 uncontrolled trials reported in 15 publications 28–42 (11 trials reported in 13 publications with aerobic training 28, 30–41, 1 with resistance training 42 and 1 with combined training 29).

Figure 1.

Flow chart of study search results

Study quality assessment

An assessment of the study quality according to a modified Delphi list is presented in Table 1. The study quality was performed for three randomized controlled trials reported in nine publications 17–25 and two non-randomized controlled trials 26, 27. In general, the study quality was moderate, and none of the studies met all of the Delphi list quality criteria. No randomized controlled trials reported allocation concealment. All studies specified their inclusion criteria, and reported groups or subjects were similar at baseline regarding important prognostic valuables. Four studies published in ten papers reported dropouts with rates ranging from 0–9.1% 17–24, 26, 27. One study published in four papers reported exercise compliance 17–20. Only one study published in four papers reported blinding of outcome assessors 17–20. The participants from four studies reported in ten publications performed their training intervention under complete supervision 17–26; in the other studies, instructions were given on how to increase the physical activities and the exercise sessions were recorded 27. One study published in four papers employed an intention-to-treat (ITT) analysis with imputation of missing data 17–20 (60 out of 62 subjects completed the study, method of imputation not reported); one study published in four papers 21–24 planned an intention-to-treat analysis but had no dropouts.

Table 1. Study quality
CitationRandomization performed?Treatment allocation concealed?Groups/subjects similar at baseline regarding important prognostic values?Eligibility criteria specified?Blinded outcome assessors?Compliance reported?Supervision of exercise sessions?Dropouts reported?Did the analysis include an intention-to-treat analysis?Were point estimates and measures of variability presented for the primary outcome measures?
  1. NR, not reported; N/A, not applicable.

Hughes et al.26NoN/AYesYesNRNoYesNoNoYes
Castaneda et al.17YesNRYesYesYesYesYesYesYesYes
Dela et al.21YesNRYesYesNRNoYesYesYesYes
Fritz et al.27NoN/AYesYesNRNoNoYesNoYes
Hays et al.25YesNRYesYesNRNoYesYesNoYes

Cohort characteristics

A summary description of each of the study cohorts is shown in Table 2.

Table 2a. Study cohort and intervention characteristics (randomized controlled trials)
TrialCitationStudy populationStudy groupsExercise interventionTime interval between EX and biopsy (h)
AgeHealth statusGendernExerciseControlModalityIntensityVolumeFrequency (times/week)Duration (week)
  1. PRT, progressive resistance training; T2DM, type 2 diabetes mellitus; HC, healthy control; IGT, impaired glucose tolerance; VO2max, maximal oxygen uptake; 1RM, one-repetition maximum testing; M/F, male/female.

  2. High, Mod, Low definitions based on American College of Sports Medicine (ACSM) criteria.

1Castaneda et al.17 Castaneda et al.18 Gordon et al.19 Brooks et al.20PRT (66 ± 2) Control (66 ± 1) PRT (66 ± 8) Control ( 60 ±4 ) PRT (67±2) control (67±2) PRT (66 ±2 ) Control ( 66±1 )T2DMM/FPRT (n = 26) Control (n = 24) PRT (n = 13)Control (n=5) PRT (n= 15 )Control (n=15) PRT (n =24) control (n =18 )PRTUsual carePneumatic resistance training machines (chest and leg press, upper back, knee extension and flexion)High week 1–8: 60–80% baseline 1RM; week 10–14: 70–80% mid-study 1RMThree sets of eight repetitions on each of the five machines31672 (two biopsies: one before and one after the training or usual care)
2Dela et al.21 Juel et al.22 Holten et al.23 Wojtaszewski et al.24T2DM (60 ± 2) HC (61 ± 2) T2DM (62 ± 2) HC (61 ±2) T2DM (62±2) HC (61±2) T2DM (61±2) HC (62±2)T2DMM/FT2DM (n = 10)HC (n = 7)One-leg strength trainingUsual careOne-leg strength training (leg press, knee extension and hamstring curl)High week 1–2: 50% 1RM; week 3–6: 70–80% 1RMthree sets of ten repetitions3616–18 (one biopsy: after training from both the trained and untrained legs)
3Hays et al.25Diet + exercise (64.8 ± 2.0) Diet (67.5 ± 2.2)IGTM/FDiet + exercise (n = 11) Diet (n = 9)Aerobic training + dietDietCycle ergometry High-carbohydrate dietHigh 80% VO2max 150% of predicted energy requirements45 min/session41272 (two biopsies: one before and one after the training + diet or diet)
Table 2b. Study cohort and intervention characteristics (non-randomized controlled trials)
TrialCitationStudy populationStudy groupsExercise interventionTime interval between EX and biopsy (h)
AgeHealth statusGendernExerciseControlModalityIntensityVolumeFrequency (times/week)Duration (week)
  1. T2DM, type 2 diabetes mellitus; IGT, impaired glucose tolerance NR, not reported M/F, male/female. High, Mod, Low definitions based on ACSM criteria.

  2. Exercise responders: subjects who showed a decrease in both systolic and diastolic blood pressure (an indicator of response to exercise).

1Hughes et al.2653–78IGTM/FDiet + exercise (n = 10)Aerobic training + dietDietCycle ergometry High-carbohydrate dietHigh 75% maximal heart rate reserve Maintaining body weight45 min/ session41296 (two biopsies: one before and one after the training + diet or diet)
     Diet (n = 10)        
2Fritz et al.27Exercise responders (62 ± 2.9)T2DMM/FExercise responders (n = 5)Aerobic trainingUsual careBrisk walkingLow45 min/ session316NR (two biopsies: one before and one after the training or usual care)
  Exercise non-responders (52 ± 3.2)  Exercise non-responders (n = 4)        
  Control (60 ± 1.7)  Control (n = 6)        
Table 2c. Study cohort and intervention characteristics (uncontrolled trials)
TrialCitationStudy populationExercise paradigmExercise interventionTime interval between EX and biopsy (h)
AgeHealth statusGendernModalityIntensityVolumeFrequency (times/week)Duration (week)
  1. T2DM, type 2 diabetes mellitus IGT, impaired glucose tolerance NGT, normal glucose tolerance HC, healthy control T1DM, type 1 diabetes mellitus HI, high intensity LI, low intensity VO2max, maximal oxygen uptake 1RM, one-repetition maximum testing NR, not reported M/F, male/female.

  2. High, Mod, Low definitions based on ACSM criteria.

1Krotkiewski et al.28T2DM (49.8 ± 2.1) HC (46.2 ± 3.3)T2DMM/FT2DM (n = 33) HC (n = 13)Aerobic trainingCycle ergometryHigh 80–90% VO2maxTotal 50 min (alternating heavy and light periods, heavy: 4 min cycle ergometry; light: walking, jogging and calisthenics)312NR (two biopsies: one before and one after the training)
2Lithell et al.29T2DM (54) Obese (39) T1DM (43)T2DM/ Obese/ T1DMM/FT2DM (n = 10) Obese (n = 10) T1DM (n = 11)Aerobic training + muscle power trainingCycle ergometry + muscle power training (static and dynamic training of muscle power in arms, abdomen, back and legs)High aerobic 80–90% VO2max; light muscle power trainingTotal 50 min (3 4-min bouts of cycle ergometry + 3 bouts of muscle power training between the intervals)2–31096 (48 for T1DM) (two biopsies: one before and one after the training)
3Hughes et al.30HI (60.9 ± 2.4) LI (67.9 ± 1.9)IGTM/FHI (n = 9) LI (n = 9)Aerobic trainingCycle ergometryMod: 50% maximal heart rate reserve High: 75% maximal heart rate reserve55 min/session41296 (two biopsies: one before and one after the training)
4Dela et al.31T2DM (59 ± 1) HC (58 ± 2)T2DMMT2DM (n = 7) HC (n = 8)One-leg aerobic trainingOne-legged cycle ergometryMod 70% one-legged cycle VO2max30 min/session6916 (two biopsies: one before training from untrained leg, one after training from trained leg)
 Dela et al.32T2DM (59 ± 1) HC (58 ± 3)          
5Williamson et al.33Exercisers (M: 64 ± 3; F: 65 ± 4)NGT/ IGT/ T2DMM/FNGT (n = 60) IGT (n = 20) T2DM (n = 10)Aerobic trainingTreadmill walking and jogging; or cycling and/or rowing ergometryHigh at time of biopsy week 1–24: 65–70% maximal heart rate Week 25–36: 75–85% maximal heart rateWeek 1–24: 30 min/session Week 25–36: 50 min/session3–536NR (two biopsies: one before and one after the training)
6Bruce et al.34T2DM (48 ± 2) HC (46 ± 3)T2DM/HCMT2DM (n = 7) HC (n = 6)Aerobic trainingCycle ergometryMod 70% VO2max60 min/session3836–48 (four biopsies: two before and two after training (one before and one after insulin clamp))
7Christ-Roberts et al.35T2DM (45 ± 4) HC (36 ± 2)T2DM/HCM/FT2DM (n = 6) HC (n = 16)Aerobic trainingCycle ergometryMod 60% VO2max progressively increased to 70% VO2max20 min/session progressively increased to 45 min/session3 progressively increased to 4824–26.5 (four biopsies: two before and two after training (one before and one after insulin clamp))
 Sriwijitkamol et al.36T2DM (45 ± 3) HC (36 ± 3)  T2DM (n = 6) HC (n = 8)       
8Kim et al.3760.5 ± 5.5IGTMn = 10Aerobic trainingTreadmillMod 60–70% heart rate reserve60 min/session31248 (two biopsies: one before and one after the training)
9Scheede- Bergdahl et al.38T2DM (58.7 ± 2.4) HC (56.8 ± 1.9)T2DM/HCMT2DM (n = 8) HC (n = 5)Aerobic trainingRowing ergometryMod 65% maximal heart rate30 min/session3–48NR (two biopsies: one before and one after the training)
10Bradley et al., 39T2DM + IGT (50 ± 11.3) HC (49 ± 5.7)T2DM + IGT/HCM/FT2DM + IGT (n = 7) HC (n = 7)Aerobic trainingCycle ergometryMod 60% VO2max50 min/session54NR (three biopsies: one before exercise, one after 7-day training and 1 after 28-day training)
11Mensink et al.40NRT2DMNRn = 8Aerobic trainingBicyclingHigh 85% maximal heart rate150 min/week2–352NR (two biopsies: one before and one after the training)
12O'Leary et al.41Exercise + diet (67.4 ± 4.5) Exercise (65.0 ± 4.6)IGTM/FExercise + diet (n = 11) Exercise (n = 10)Aerobic trainingNRHigh 85% maximal heart rate60 min/session512NR (two biopsies: one before and one after the training)
13Praet et al.4259.1 ± 7.5T2DMMn = 11Progressive resistance trainingFour resistance-type exercise machines targeting the upper body and leg press and leg extensionHigh week 1–5: 50% 1RM; week 6–10: 50–60% 1RMTwo sets of ten repetitions310NR (two biopsies: one before and one after the training)

Sample size

In total, the 18 studies consisted of 291 subjects, ranging in size from 6 to 50, with median 10 and interquartile range 44.

Gender

In the randomized controlled trials and non-randomized controlled trials, all studies consisted of mixed gender cohorts 17–27; in the uncontrolled trials, five studies published in six papers were in male cohorts 31, 32, 34, 37, 38, 42, seven studies published in eight papers were in mixed cohorts 28–30, 33, 35, 36, 39, 41 and one study did not report gender 40.

Age

Most subjects were middle-aged or older, with few subjects above 65. Across all cohorts, the age ranged from 36 to 66, with median 59 and interquartile range 30.

BMI

Body mass index (BMI) was reported in all but four uncontrolled studies 28, 29, 31, 40. Almost all subjects were overweight or obese with mean BMI 29.6 ± 3.1 kg/m2, except for one uncontrolled study 37 with lean subjects (BMI = 23.6 ± 2.5 kg/m2).

Health status

Most [61% (11/18)] trials 17–24,27–29,31,32,34–36,38,40,42 included only type 2 diabetes; 28% (5/18) of trials 25, 26, 30, 37, 41 included only IGT; 11% (2/18) of trials 33, 39 included both type 2 diabetes and IGT. Overall, 66% of the subjects studied had type 2 diabetes and 34% of the subjects had IGT.

Except for one uncontrolled trial 33, all other studies of type 2 diabetes 17–24,27–29,31,32,34–36,38–40,42 reported the subjects' diabetic medications. Among these studies, two trials reported in five papers included some or all subjects with insulin treatment 17–20, 42; subjects in the other 10 studies reported in 15 publications 21–24, 27–29, 31, 32, 34–36, 38–40 were treated only with oral agents or did not take diabetic medications. In studies including type 2 diabetes, 18% of subjects took insulin, 81% took oral agents, and 16% did not take diabetic medications. Duration of diabetes was reported in all but four studies published in five papers 29, 33, 35, 36, 39 and ranged from 2.5 to 12.1 years with median 6.0 years and interquartile range 9.6 years across these nine trials.

Only two studies published in five papers 17–20, 27 reported medications other than diabetic medications, and only one study published in four papers 17–20 reported chronic diseases other than type 2 diabetes, which included hypertension, cardiovascular disease, or exercise limitations.

Nine trials published in ten papers 25,26,29,30,33,, 35–38,42 reported habitual physical activity level as “sedentary”, although precise definitions were not given.

Intervention characteristics

Table 2 provides an overview of the training interventions.

Exercise modality

In the exercise training studies, the most common form of training prescribed (78% of studies) was aerobic training. Two randomized controlled trials reported in eight papers 17–24 and one uncontrolled trial 42 used resistance training, and one uncontrolled trial 29 used combined aerobic and resistance training.

Intensity

Except for one study 27 of low intensity aerobic training, all exercise prescriptions consisted of either moderate or high intensity aerobic and/or resistance training. In the three resistance training studies reported in 9 publications, the intensity increased progressively from 50 to 80% of the one-repetition maximum (1RM) 17–24, 42, thus concluding training with high intensity progressive resistance training at the time of biopsy. In the aerobic training studies, the intensity was low in one study, moderate in six studies, and high in six studies. One study used moderate intensity in one group and high in the other 30. The combined training study utilized high intensity aerobic training (80–90% VO2max) plus light muscle power training 29.

Volume

In the three resistance training studies reported in nine publications, the volume was three sets of eight repetitions 17–20, three sets of ten repetitions 21–24, and two sets of ten repetitions 42. In the aerobic training and combined training studies, the volume varied from 30 31, 32, 38 to 60 34, 37, 41 min per session of continuous exercise, mean 48 ± 9 min.

Frequency

Three sessions per week was the most common training prescription 17–24, 27, 28, 34, 37, 42, but it ranged from two 29, 40 to six sessions per week 31, 32.

Duration

Trial duration ranged from 4 to 52 weeks, median 12 weeks; the majority of studies were between 4 and 16 weeks 17–32, 34–39, 41, 42 and two studies were between 36 and 52 weeks 36, 40.

Time of biopsy

Ten trials published in 17 papers 17–26, 29–32, 34–36 reported time interval between the last exercise session and biopsy. It ranged from 16 to 96 h, with median 60 and interquartile range 80.

Outcome measures

Morphological outcomes

In general, morphological outcomes were improved after exercise training with moderate to large ESs, and were specific to the type of training (Tables 3 and 4). Muscle fiber size (muscle fiber diameter or cross-sectional area) of both Type I and Type II fibers significantly increased in three studies published in four papers 19, 20, 23, 29, but not in the fourth 42, which included resistance training. Of the three positive studies, two studies published in three papers 19, 20, 23 included only resistance training and one included combined training 29. In contrast, muscle fiber size did not increase in any of the three trials that included only aerobic training 30, 33, 37. However, capillary density increased after aerobic training 29, 37, but not after resistance training 23.

Table 3. Morphological outcomes (randomized controlled trials and non-randomized controlled trials)
TrialStudy designCitationOutcomeResultsCalculationStatistics
VariableMethodGroupPre-exercise (Mean ± SD)Post-exercise (Mean ± SD)Changes (%)Effect sizep value (TRA vs. CON)
  1. RCT, randomized controlled trial; CON, control; EXE, exercise; NS, not significant.

1RCTHolten et al.23Muscle fiber types (fraction of type I to type II)HistologyCON 0.56 ± 0.166− 8.9 NS
     EXE 0.51 ± 0.133   
   Muscle fiber diameter (µm): type IHistologyCON 59.3 ± 5.64+ 4.0 NS
     EXE 61.7 ± 3.65   
   type IIHistologyCONNR62.5 ± 5.97+ 5.9Unable to be calculatedp < 0.05
     EXE 66.2 ± 3.98   
   Average diameter of muscle fibers (µ m)HistologyCON 60.9 ± 5.31+ 5.4 ± 5.64 p < 0.05
     EXE 64.1 ± 3.98   
   Capillary density (number of capillaries per millimeter squared of muscle)HistologyCON EXE 228 ± 89.55 225 ± 96.18-1.3 NS
2RCTGordon et al.19Cross-sectional area (µ m2): type I fibersHistologyCON EXE4850 ± 964 4303 ± 15004637 ± 1400 5405 ± 1960-4.4 + 25.61.043p < 0.05
   type II fibersHistologyCON EXE4550 ± 1476 4102 ± 16484175 ± 1524 5103 ± 1472-8.2 + 24.40.880p < 0.05
  Brooks et al.20Cross-sectional area (µ m2): type I fibersHistologyCON EXE4546 ± 1176.9 4068 ± 12804381 ± 1325.1 4928 ± 1860-3.6 + 21.10.828p = 0.04
   type II fibersHistologyCON EXE4330 ± 1508.2 3885 ± 13904201 ± 1464.6 4605 ± 1415-3.0 + 18.50.589p = 0.04
Table 4. Morphological outcomes (uncontrolled trials)
TrialCitationOutcomeResultsStatistics
VariableMethodGroupPre-exercise (Mean ± SD)Post-exercise (Mean ± SD)Changes (%)p value (Pre vs. Post)
  1. IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus; EXE, exercise; NR, not reported; NS, not significant.

1Lithell et al.29Muscle fiber area (µ m2 × 103): type IIaHistologyEXE4.59 ± 0.416.07 ± 0.91+ 32.2p < 0.05
  Capillaries/type IIa fiberHistologyEXE4.1 ± 0.24.8 ± 0.3+ 17.1p < 0.05
  Capillaries (mm2)HistologyEXE289 ± 65286 ± 59-1.0%NS
2Hughes et al.30Fraction of type I muscle fiber (%)HistologyEXE43 ± 13.2743 ± 9.950NS
3Williamson et al.33Capillary basement membrane widthElectron microscopyIGT T2DMNR NRNR NRDecrease Decreasep < 0.05 p < 0.05
4KimMean occurrence (%): type IHistologyEXE50.7 ± 4.652.5 ± 8.5+ 3.6NS
 et al.37type IIaHistologyEXE30.4 ± 5.929.8 ± 8.9-2.0NS
  type IIxHistologyEXE18.7 ± 3.217.5 ± 2.9-6.4NS
  Cross-sectional area (µ m2): type IHistologyEXE3699 ± 3963910 ± 392+ 5.7NS
  type IIaHistologyEXE3452 ± 5563720 ± 474+ 7.8NS
  type IIxHistologyEXE3066 ± 2693089 ± 286+ 0.8NS
  Capillaries per fiber: type IHistologyEXE3.8 ± 0.14.2 ± 0.1+ 10.5p < 0.05
  type IIaHistologyEXE3.6 ± 0.23.9 ± 0.2+ 8.3NS
  type IIxHistologyEXE2.8 ± 0.22.9 ± 0.2+ 3.6NS
  Diffusional area (µ m2): type IHistologyEXE976 ± 121936 ± 90-4.1NS
  type IIaHistologyEXE968 ± 147937 ± 90-3.2NS
  type IIxHistologyEXE1100 ± 91960 ± 118-12.7NS
5Praet et al.Muscle fiber distribution (%):      
 42type IHistologyEXE47 ± 745 ± 10-4.3NS
  type IIaHistologyEXE41 ± 845 ± 9+ 9.8NS
  type IIxHistologyEXE16 ± 810 ± 3-37.5NS
  Cross-sectional area (µ m2): type IHistologyEXE7867 ± 34827831 ± 2667-0.5NS
  type IIaHistologyEXE7700 ± 22258400 ± 3293+ 9.1NS
  type IIxHistologyEXE5250 ± 18474704 ± 2040-10.4NS

One randomized controlled trial including resistance training 20 reported that the improved muscle fiber cross-sectional area was accompanied by reduced whole body insulin resistance. The other randomized controlled trial included one-leg resistance training 23 and reported that the increased leg glucose clearance was more than explained by increases in muscle mass. However, four uncontrolled trials 29, 30, 37, 42 did not report any relationships between the changes in the morphological outcomes and whole body insulin sensitivity.

Metabolic outcomes

Glycogen and glycogen synthase

Increased glycogen and glycogen synthase levels were the most consistent positive adaptations observed (Tables 5 and 6), and in general, the ESs were very large. Four trials reported in five publications 17, 18, 25, 26, 30 (one with resistance training and three with aerobic training) of six studies reported in seven publications for glycogen 17, 18, 23, 25, 26, 30, 42, reported significant improvements in glycogen content, and one 23 of those six studies reported a trend for increased glycogen content after resistance training. The other study [42] reported that glycogen content inside the muscle fibres didn't change significantly after exercise. Three (one with resistance training and two with aerobic training) 23, 32, 35 out of four studies for glycogen synthase 23, 25, 32, 35 reported significant increases in this enzyme activity after training durations ranging from 6 to 9 weeks. In one study 25, the combination of a high-carbohydrate diet and exercise resulted in a significant decrease in glycogen synthase compared to the high-carbohydrate diet only group. Thus, both resistance and aerobic training have been shown to improve glycogen and glycogen synthase, and no data are available on direct comparisons of the efficacy of different exercise modalities for these outcomes.

Table 5. Metabolic outcomes—glycogen (randomized controlled trials and non-randomized controlled trials)
TrialStudy designCitationOutcomeResultsCalculationStatistics
VariableMethodGroupPre-exercise (Mean ± SD)Post-exercise (Mean ± SD)Changes (%)Effect sizeP value (EXE vs. CON)
  1. RCT, randomized controlled trial; NRCT, non-randomized controlled trial; CON, control; EXE, exercise; NR, not reported; NS, not significant.

1RCTCastaneda et al.17Glycogen (mmol glucose/kg muscle)HTRAokinase enzymatic methodCON EXE61.4 ± 38.5 60.3 ± 20.2647.2 ± 33.5 79.1 ± 25.98-23 ± 30 + 31 ± 36.41.086p = 0.04
  Castaneda et al.18Glycogen (mmol glucose/kg muscle)HTRAokinase enzymatic methodCON EXE66.7 ± 25.47 60.2 ± 63.2357.7 ± 52.42 83.2 ± 81.57-13 + 38.20.664p = 0.04
2RCTHolten et al.23Glycogen (nmol mg-1 dry weight-1)Microtiter plate assayCON EXENR316 ± 63.02 366 ± 89.55+ 15.8Unable to be calculatedNS
   Glycogen synthase protein content CON EXE NR NR+ 13 ± 16.6 NS
   Glycogen synthase total activity CON EXE NR NR+ 21 ± 13.3 p < 0.05
3RCTHays et al.25Glycogen (µ mol.g wet weight-1.h-1) CON EXE371.3 ± 48.07 344.7 ± 73.79319.4 ± 62.93 616.7 ± 119.17-14.0 + 78.95.088p < 0.001
   Glycogen synthase activity (I/D) CON EXE0.18 ± 0.06 0.21 ± 0.070.23 ± 0.06 0.13 ± 0.03+ 27.8 -38.11.977p < 0.001
4NRCTHughes et al.26Glycogen (mmol/kg wet weight) CON EXE79.8 ± 13.60 78.5 ± 26.8683.1 ± 14.26 161.1 ± 52.07+ 4.1 + 105.23.725NR
Table 6. Metabolic outcomes—glycogen (uncontrolled trials)
TrialCitationOutcomeResultsStatistics
VariableMethodGroupPre-exercise (Mean ± SD)Post-exercise (Mean ± SD)Changes (%)P value (pre vs. post)
  1. EXE, exercise; NR, not reported; NS, not significant; PAS, periodic acid-Schiff stain activity indicating glycogen content inside the muscle fibers.

1Dela et al.32Glycogen synthase mRNA (arbitrary units/total RNA)Northern blotEXE22 ± 5.6633 ± 8.49+ 51 ± 62.2p < 0.05
2Hughes et al.30Glycogen (mmol glucose/kg muscle) EXE61.6 ± 23.5476.6 ± 23.97+ 24.4p < 0.05
3Christ-Roberts et al.35Glycogen synthase 0.1 EXE basal1.85 ± 1.672.59 ± 2.38+ 40p < 0.05 vs. pre
    EXE insulin2.49 ± 1.512.77 ± 1.85+ 11.2p < 0.05 vs. basal
  Glycogen synthase 10 EXE basal14.43 ± 6.6120.84 ± 6.59+ 44.4p < 0.01 vs. pre
    EXE insulin13.59 ± 4.7918.04 ± 6.46+ 32.7p < 0.01 vs. pre
  Glycogen synthase FV EXE basal0.11 ± 0.050.11 ± 0.080NS
    EXE insulin0.18 ± 0.080.14 ± 0.08-22.2NS
4Praet et al.42PAS (AU)Immunohisto- chemistryEXE28 ± 2NR− 3.6NS (p = 0.662)

GLUT 4 and insulin signalling

Five 23, 30, 31, 35, 37 out of seven 18,23,27,30,31,, 35,37 studies reported that glucose facilitated transporter 4 (GLUT4) mRNA and/or protein expression increased after either resistance or aerobic exercise training (Tables 7 and 8). However, one randomized controlled trial with resistance training reported that GLUT4 mRNA did not change, but human sodium dependent D-glucose co-transporter 3 (hSGLT3) mRNA significantly increased 18.

Table 7. Metabolic outcomes—GLUT4 and insulin signaling (randomized controlled trials and non-randomized controlled trials)
TrialStudy desighCitationOutcomeResultsCalculationStatistics
VariableMethodGroupPre-exercise (Mean ± SD)Post-exercise (Mean ± SD)Changes (%)Effect sizep value (EXE vs. CON)
  1. RCT, randomized controlled trial; NRCT, non-randomized controlled trial; CON, control; EXE, exercise; NR, not reported; NS, not significant; IR, insulin receptor; IRS-1, insulin receptor substrate-1; PI-3K, phosphatidylinositol 3-kinase; PI-3K p85, the p85 subunit of PI-3K; PKB, protein kinase B; GLUT4, glucose facilitated transporter 4; hSGLT3, human sodium dependent d-glucose co-transporter 3; AMPK, 5AMP-activated protein kinase; EX responders: subjects who showed a decrease in both systolic and diastolic blood pressure (an indicator of response to exercise).

21RCTHolten et al.23GLUT4 proteinWestern blotCONNRNR Unable to be calculated 
     EXE NR+ 40 p < 0.05
   IRWestern blotCON NR   
     EXE NR+ 21 ± 19.9 p < 0.05
   IRS-1Western blotCON NR   
     EXE NRNR NS
   PI-3K p85Western blotCON NR   
     EXE NRNR NS
   PKB-α/βWestern blotCON NR   
     EXE NR+ 12 ± 23.2 p < 0.05
  Wojtaszewski et al.24AMPKα1 mRNAReal-time Polymerase Chain Reaction (PCR)CONNR0.13 ± 0.17NRUnable to be calculatedNS
     EXE 0.11 ± 0.13   
   AMPKα2 mRNAReal-time PCRCON 0.17 ± 0.27   
     EXE 0.16 ± 0.36NR NS
   AMPKβ1 mRNAReal-time PCRCON 0.10 ± 0.10   
     EXE 0.12 ± 0.10NR NS
   AMPKβ2 mRNAReal-time PCRCON 0.14 ± 0.20   
     EXE 0.18 ± 0.23NR NS
   AMPKγ1 mRNAReal-time PCRCON 0.11 ± 0.10   
     EXE 0.09 ± 0.07NR NS
   AMPKγ2 mRNAReal-time PCRCON 0.28 ± 0.46   
     EXE 0.30 ± 0.33NR NS
   AMPKγ3 mRNAReal-time PCRCON 0.29 ± 0.23   
     EXE 0.15 ± 0.13− 42 ± 23.2 p = 0.008
   AMPKα1 proteinWestern blotCON NR   
     EXE NR+ 16 ± 0 p < 0.009
   AMPKα2 proteinWestern blotCON NR   
     EXE NR+ 5 ± 0 NS
   AMPKβ1 proteinWestern blotCON NR   
     EXE NR+ 2 ± 0 NS
   AMPKβ2 proteinWestern blotCON NR   
     EXE NR+ 14 ± 3.3 p < 0.01
   AMPKγ1 proteinWestern blotCON NR   
     EXE NR+ 29 ± 6.6 p < 0.01
   AMPKγ2a proteinWestern blotCON NR   
     EXE NR− 8 ± 3.3 NS
   AMPKγ2b proteinWestern blotCON NR   
     EXE NR+ 7 ± 3.3 NS
   AMPKγ3 proteinWestern blotCON NR   
     EXE NR− 48 ± 16.6 p < 0.008
   αAMPK-Thr172Western blotCON 11 ± 1   
   phosphorylation EXE 11 ± 1NR NS
2RCTCastaneda et al.18hSGLT3 mRNAReal-time PCRCONNRNRNRUnable to be calculated 
     EXENRNRNR p = 0.03
   hSGLT3 proteinHistology and WesternCONNRNRNR  
    blotEXENRNRNR NS
   GLUT4 mRNAReal-time PCRCONNRNRNR  
     EXENRNRNR NS
   GLUT4 proteinHistology and WesternCONNRNRNR  
    blotEXENRNRNR NS
3NRCTFritz et al.27GLUT4 mRNATaqMan-based Multi-Fluidic Card (MFC)CONNRNRNRUnable to be calculatedNS
     EX non-responderNRNRDecrease p < 0.01
     EX responderNRNRNR NS
Table 8. Metabolic outcomes—GLUT4 and insulin signaling (uncontrolled trials)
TrialCitationOutcomeResultsStatistics
VariableMethodGroupPre-exercise (Mean ± SD)Post-exercise (Mean ± SD)Changes (%)p value (pre vs. post)
  1. EXE, exercise; NR, not reported; NS, not significant; PI-3K, phosphatidylinositol 3-kinase; GLUT4, glucose facilitated transporter 4.

1Hughes et al.30GLUT4 protein (O.D. units)Western blotEXE6981 ± 1577.911 197 ± 4197.6+ 60.4p < 0.05
2Dela et al.31GLUT4 mRNANorthern blotEXENRNRNRp < 0.05 p < 0.05
  GLUT4 proteinWestern blotEXENRNR+ 30 
3Christ-Roberts et al.35GLUT4 proteinWestern blotEXENRNR+ 22 ± 19.9p < 0.05
  Phosphor-Akt (Ser473)Western blotEXENRNR+ 30 ± 19.9p < 0.001
  PI-3K EXE—basal –insulin0.55 ± 0.370.46 ± 0.32-16.4NS
     0.70 ± 0.400.56 ± 0.32-20NS
4Kim et al.37GLUT4 protein (%)Western blotEXE107.7 ± 15.3177.9 ± 20.7+ 65.2p < 0.01

As for other parameters in the insulin signalling pathway, one randomized controlled trial 23 showed that the protein content of insulin receptor (IR) increased. The serine/threonine kinase Akt, also known as protein kinase B (PKB), has recently come to the forefront as a potential downstream mediator of insulin signalling pathway 35. Notably, both aerobic training 35 and resistance training 23 have improved Akt/protein kinase B.

Overall, the improvements of GLUT4, insulin receptor and Akt/protein kinase B by both resistance and aerobic exercise could play a beneficial role in insulin sensitivity, if these preliminary findings are confirmed.

One randomized controlled trial of resistance training 18 reported that the change in hSGLT3 transcript levels was positively correlated with glucose uptake, as measured by the change in muscle glycogen stores (r = 0.53, p = 0.02). The other randomized controlled trial of one-leg resistance training 23 reported that the increased protein content of GLUT4, insulin receptor, protein kinase B are part of the mechanism behind the improvement in insulin action. Two uncontrolled trials 31, 37 did not report any relationships between the changes in the morphological outcomes and whole body insulin sensitivity. And, in another two uncontrolled trials, one 30 reported that the increase in GLUT4 was not significantly related to the changes in insulin-stimulated glucose disposal and the other 35 reported that the improvements in the phosphatidylinositol (PI) 3-kinase of insulin receptor signalling and GLUT4 expression were accompanied by improved insulin-stimulated glucose disposal and insulin-stimulated glucose storage.

Enzymes

Only few data were available (Tables 9 and 10). In the only resistance training trial reported in three publications 22–24 for hydroxyl-acyl-CoA dehydrogenase (HAD), which is involved in lipid oxidation, no significant changes were shown, whereas aerobic training 34, 37 significantly improved HAD. Citrate synthase, a measure of oxidative capacity, was also improved by this aerobic training intervention 34, but not by resistance training 22–24. One trial 34 reported that the enhanced insulin sensitivity observed after exercise was associated with a marked increase in citrate synthase and HAD. However, other studies did not report such relationships.

Table 9. Metabolic outcomes—enzymes (randomized controlled trials and non-randomized controlled trials)
TrialStudy designCitationOutcomeResultsCalculationStatistics
VariableMethodGroupPre-exercise (Mean ± SD)Post-exercise (Mean ± SD)Changes (%)Effect sizep value EXE vs. CON)
  1. RCT, randomized controlled trial; NRCT, non-randomized controlled trial; CON, control; EXE, exercise; NR, not reported; NS, not significant; HAD, hydroxyl-acyl-CoA dehydrogenase; LDH, lactate dehydrogenase.

1RCTJuel et al.22LDH activity (µ mol min-1 (g dry weight of muscle tissue)-1)Roche/ Hitachi 912 analyserCONNR966 ± 308.45 Unable to be calculated 
     EXE 1069 ± 613.58+ 10.7 NS
  Holten et al.23Citrate synthase (µ mol min-1 (g dry weight of muscle tissue)-1) CON EXENR70 ± 16.58 70 ± 16.580Unable to be calculatedNS
   HAD (µ mol min-1 (g dry weight of muscle tissue)-1) CON EXE 119 ± 19.90 120 ± 29.85+ 0.8 NS
   LDH (µ mol min-1 (g dry weight of muscle tissue)-1) CON EXE 966 ± 308.45 1069 ± 613.58+ 10.7 NS
  Wojtaszewski et al.24Citrate synthase (µ mol min-1 (g dry weight of muscle tissue)-1) CON EXENR70 ± 16.58 70 ± 16.580Unable to be calculatedNS
   HAD (µ mol min-1 (g dry weight of muscle tissue)-1) CON EXE 119 ± 19.90 120 ± 29.85+ 0.8 NS
   LDH (µ mol min-1 (g dry weight of muscle tissue)-1) CON EXE 966 ± 308.45 1069 ± 613.58+ 10.7 NS
2NRCTFritz et al.27Hexokinase (HK) 2 mRNAMFCCONNRNRNRUnable to be calculatedNS
     EX non-responderNRNRNR NS
     EX responderNRNRNR NS
Table 10. Metabolic outcomes—enzymes (uncontrolled trials)
TrialCitationOutcomeResultsStatistics
VariableMethodGroupPre-exercise (Mean ± SD)Post-exercise (Mean ± SD)Changes (%)p value (pre vs. post)
  1. EXE, exercise; NR, not reported; NS, not significant; β-HAD, β-hydroxyl-acyl-CoA dehydrogenase; SDH, succinate dehydrogenase.

1Bruce et al.34Citrate synthase (µmol/g−1 min−1) EXE4.4 ± 1.417.6 ± 2.26+ 72.7p < 0.001
  β-HAD (µmol/g−1 min−1) EXE5.3 ± 1.988.6 ± 2.55+ 62.3p < 0.001
2Kim et al.37Citrate Synthase (µmol/g−1 min−1) EXE9.89 ± 3.85 1.35 ± 1.0111.15 ± 4.81+ 12.7NS
  β-HAD (µmol/g−1 min−1) EXE 2.92 ± 1.42+ 116.3p < 0.05 NS
  β-HAD/Citrate synthase EXE0.16 ± 0.150.31 ± 0.34+ 93.8NS
3Praet et al.42SDH (AU)Histochemical stainingEXE54 ± 28NR− 9.3NS (p = 0.522)

Inflammatory factors

Two trials 19, 36 measured some inflammatory factors, but one 19 of them did not find any changes after exercise (Tables 11 and 12). The other trial of aerobic exercise 36 reported some beneficial changes, which included increases in inhibitor κB α (IκBα), inhibitor κB β (IκBβ), nuclear factor κB p50 (NFκB p50) and reduction in tumor necrosis factor α (TNFα) protein. It has been hypothesized that excessive activity of IκB/NFκB is the mechanism underlying skeletal muscle insulin resistance 43. This trial 36 also reported that subjects with type 2 diabetes had reduced IκB protein abundance in muscle compared to healthy subjects. It is noteworthy that abundance at the protein level of IκB is inversely correlated with the activity of the IκB/NFκB pathway (decreased IκB levels reflecting increased phosphorylation and proteolysis of the protein), thereby contributing to the activation of IκB/NFκB pathway and leading to insulin resistance. Therefore, in this study, the increases of inhibitor κB α, inhibitor κB β and NFκB p50 protein levels in response to training showed that this abnormality is potentially modifiable by exercise training 36. None of these studies presented any data investigating whether whole body insulin sensitivity was associated with changes in these inflammatory markers, however.

Table 11. Metabolic outcomes—inflammatory factors (randomized controlled trials and non-randomized controlled trials)
TrialStudy designCitationOutcomeResultsCalculationStatistics
VariableMethod Pre-exercise (Mean ± SD)Post-exercise (Mean ± SD)Changes (%)Effect sizep value (EXE vs. CON)
  1. fn RCT, randomized controlled trial; CON, control; EXE, exercise; NR, not reported; NS, not significant; TNFα, tumor necrosis factor α; IL1β, interleukin − 1β; TGF β1, transforming growth factor-β1; CD18,panleukocyte marker.

1RCTGordon et al.19IL − 1β mRNAReal-time PCRCONNRNRNRUnable to be calculated 
     EXENRNRNR p = 0.05
   TNFα mRNAReal-time PCRCONNRNRNR  
     EXENRNR+ 63% p = 0.30
   TGFβ1 mRNAReal-time PCRCONNRNRNR  
     EXENRNR+ 55% p = 0.15
   CD18 mRNAReal-time PCRCONNRNRNR  
     EXENRNRNR NS
Table 12. Metabolic outcomes—inflammatory factors (uncontrolled trials)
TrialCitationOutcomeResultsStatistics
VariableMethodGroupPre-exercise (Mean ± SD)Post-exercise (Mean ± SD)Changes (%)p value (pre vs. post)
  1. EXE, exercise; NR, not reported; NS, not significant; IκB, inhibitor of κB; NFκB p50, nuclear factor κB p50; NFκB p65, nuclear factor κB p65; IKK, IκB kinase; TNFα, tumor necrosis factor α.

1SriwijikamoIκBα proteinWestern blotEXENRNR+ 98%p < 0.05
 et al.36IκBβ proteinWestern blotEXENRNR+ 185%p < 0.05
  NFκB p50 proteinWestern blotEXENRNR+ 140%p < 0.05
  NFκB p65 proteinWestern blotEXENRNRNRNS
  IKKβ phosphorylationWestern blotEXENRNRNRNS
  IKKβ proteinWestern blotEXENRNRNRNS
  TNFα proteinWestern blotEXENRNRDecreasep < 0.05

Lipids

Some beneficial improvements were seen in lipid metabolism after exercise training (Tables 13 and 14). In the two aerobic training trials 34, 37 for intra-muscular triglyceride concentration (IMTG), it decreased significantly after exercise training. One of those two studies 34 also showed that the enhanced insulin sensitivity observed after exercise was associated with a marked decrease in intra-muscular triglyceride concentration. Two other aerobic training trials 27, 40 reported increases of uncoupling protein 3 (UCP3) after exercise training, which would theoretically protect mitochondria against lipid-induced mitochondrial damage 44. Increases in adiponectin receptor I and II were reported in one aerobic training trial 41, and these changes could play a part role in improved insulin sensitivity. However, no consistent pattern has been demonstrated for other lipid or adipokine outcomes.

Table 13. Metabolic outcomes—lipids (randomized controlled trials and non-randomized controlled trials)
TrialStudy designCitationOutcomeResultsCalculationStatistics
VariableMethodGroupPre-exercise (Mean ± SD)Post-exercise (Mean ± SD)Changes (%)Effect sizep value (pre vs. post)p value (EXE vs. CON)
  1. RCT, randomized controlled trial; NRCT, non-randomized controlled trial; NR, not reported; NS, not significant; UCP3, uncoupling protein 3; LPL, lipoprotein lipase; CD36, collagen type I receptor; DGKδ, diacylglycerol kinase δ; NRF-1, nuclear respiratory factor-1; ACCα, acetyl-CoA-carboxylase α; ACCβ, acetyl-CoA-carboxylase β; ACC, acetyl-CoA-carboxylase; PPARδ, peroxisome proliferators-activated receptor-δ; H3, histone 3; CAP, Cb1-associated protein; FAT4, fatty acid transporter 4; FOX O1A, forkhead box O1A; PPARγ, peroxisome proliferators-activated receptor γ; PGC − 1α, peroxisome proliferators-activated receptor gamma co-activator − 1α; PGC − 1β, peroxisome proliferators-activated receptor gamma co-activator − 1β; PRC, PGC-1 related Co-activator; SCD, stearoyl-CoA desaturase; SREBP1, sterol regulatory element binding transcription factor 1; EX responder, showing a decrease in both diastolic and SBP—an indicator of response to exercise; LCACoA, long-chain fatty acyl CoA; TGm, muscle triacylglycerol; IMTG, intra-muscular triglyceride concentration.

1RCTWojtaszewski et al.24ACCβ-Ser221 phosphorylation ACCβWestern blot Western blotCON EXE CON EXENR13 ± 6.63 16 ± 9.95 NR NRNR + 49 ± 13.2Unable to be calculated NS p < 0.01
2NRCTFritzDGKδ mRNAMFCCONNRNRNR NS 
  et al.27  EX non-responderNRNRNR NS 
     EX responderNRNRIncrease p = 0.16NR
   DGKδ proteinWestern blotCONNRNRNR NS 
     EX non-responderNRNRNR NS 
     EX responderNRNRNR NSNR
   UCP3 mRNAMFCCONNRNRNR NS 
     EX non-responderNRNRNR NS 
     EX responderNRNRIncrease p = 0.16NR
   UCP3 proteinWestern blotCONNRNRNR NS 
     EX non-responderNRNRNRUnable toNS 
     EX responderNRNRIncreasebep < 0.05NR
   NRF-1 mRNAMFCCONNRNRNRcalculatedNS 
     EX non-responderNRNRNR NS 
     EX responderNRNRIncrease p = 0.14NR
   ACCα mRNAMFCCONNRNRNR NS 
     EX non-responderNRNRDecrease p = 0.08 
     EX responderNRNRNR NSNR
   ACCβ mRNAMFCCONNRNRNR NS 
     EX non-responderNRNRDecrease p = 0.12 
     EX responderNRNRNR NSNR
   CD36 mRNAMFCCONNRNRNR NS 
     EX non-responderNRNRDecrease p = 0.02 
     EX responderNRNRNR NSNR
   ACC proteinWestern blotCONNRNRNR NS 
     EX non-responderNRNRNR NS 
     EX responderNRNRNR NSNR
   Peroxisome proliferator–activated receptor (PPAR)δ mRNAReal-time PCRCONNRNRNR NS 
     EX non-responderNRNRNR NS 
     EX responderNRNRIncrease p = 0.13NR
   PPARδ proteinWestern blotCONNRNRNR NS 
     EX non-responderNRNRNR NS 
     EX responderNRNRIncrease p < 0.05NR
   H3 proteinWestern blotCONNRNRNRUnable toNS 
     EX non-responderNRNRNRbeNS 
     EX responderNRNRNRcalculatedNSNR
   CAP mRNAMFCCONNRNRNR NS 
     EX non-responderNRNRNR NS 
     EX responderNRNRNR NSNR
   Fatty acidMFCCONNRNRNR NS 
   transporter (FAT) EX non-responderNRNRNR NS 
   4 mRNA EX responderNRNRNR NSNR
   Forkhead boxMFCCONNRNRNR NS 
   (FOX) O1A mRNA EX non-responderNRNRNR NS 
     EX responderNRNRNR NSNR
   Lipoprotein lipaseMFCCONNRNRNR NS 
   (LPL) mRNA EX non-responderNRNRNR NS 
     EX responderNRNRNR NSNR
   PPARγ mRNAMFCCONNRNRNR NS 
     EX non-responderNRNRNR NS 
     EX responderNRNRNR NSNR
   PPARγMFCCONNRNRNR NS 
   co-activator EX non-responderNRNRNR NS 
   mRNA EX responderNRNRNR NSNR
   PGC 1 − α mRNAMFCCONNRNRNR NS 
     EX non-responderNRNRNR NS 
     EX responderNRNRNR NSNR
   PGC 1 − β mRNAMFCCONNRNRNR NS 
     EX non-responderNRNRNR NS 
     EX responderNRNRNR NSNR
   PGC-1 relatedMFCCONNRNRNRUnable toNS 
   co-activator (PRC) EX non-responderNRNRNRbeNS 
   mRNA EX responderNRNRNRcalculatedNSNR
   Stearoyl-CoAMFCCONNRNRNR NS 
   desaturase (SCD) EX non-responderNRNRNR NS 
   mRNA EX responderNRNRNR NSNR
   SREBP 1 mRNAMFCCONNRNRNR NS 
     EX non-responderNRNRNR NS 
     EX responderNRNRNR NSNR
   AdiponectionMFCCONNRNRNR NS 
   receptor mRNA EX non-responderNRNRNR NS 
     EX responderNRNRNR NSNR
Table 14. Metabolic outcomes—lipids (uncontrolled trials)
TrialCitationOutcomeResultsStatistics
VariableMethodGroupPre-exercise (Mean ± SD)Post-exercise (Mean ± SD)Changes (%)p value (pre vs. post)
  1. EXE, exercise; NR, not reported; NS, not significant; UCP3, uncoupling protein 3; LPL, lipoprotein lipase; LCACoA, long-chain fatty acyl CoA; TGm, muscle triacylglycerol; IMTG, intra-muscular triglyceride concentration.

1Lithell et al.29Lipoprotein lipase (LPL) activity (mU/g) EXE31 ± 9.9533 ± 9.95+ 6.5NS
2Bruce et al.34LCACoA (nmol/g wet EXE—basal11.9 ± 5.3710.6 ± 4.24− 10.9NS
  weight) –insulin12.3 ± 1.4111.4 ± 2.83− 7.3NS
  TGm (mmol/kg dry weight) EXE89.0 ± 65.6247.5 ± 32.24− 47p < 0.05
3Kim et al.37IMTG (%)Oil red OEXE3.1 ± 1.12.8 ± 0.8− 9.7p < 0.05
  IMTG droplet size (µm2)Oil red OEXE0.7 ± 0.10.7 ± 0.20NS
5Mensink et al.40UCP3 protein (AU)Western blotEXE91.3 ± 44.9162.0 ± 58.4+ 77.4p < 0.05
6O'Leary et al. [41]Adiponectin receptor I mRNAReal-time PCREXENRNRIncreasep < 0.03
  Adiponectin receptor II mRNA EXENRNRIncreasep < 0.02
7Praet et al.42IMGL (AU)Oil red O and immunolabelled cellular constituentEXE12 ± 3NR+ 33.3NS
        (p = 0.327)

Others

Very limited data are available on other outcomes (Tables 15 and 16).

Table 15. Metabolic outcomes—others (randomized controlled trials and non-randomized controlled trials)
TrialStudy designCitationOutcomeResultsCalculationStatistics
VariableMethodGroupPre-exercise (Mean ± SD)Post-exercise (Mean ± SD)Changes (%)Effect sizep value (EXE vs. CON)
  1. RCT, randomized controlled trial; CON, control; EXE, exercise; NR, not reported; NS, not significant; MCT1, monocarboxylate transporter 1; MCT4, monocarboxylate transporter 4.

1RCTDela et al.21Na, K-pump isoform α1Western blotCONNRNR Unable to be 
     EXE NR+ 45calculatedp = 0.052
   Na, K-pump isoform α2Western blotCON NR  
     EXE NR+ 41 p < 0.05
   Na, K-pump isoform βWestern blotCON NR  
     EXE NR+ 47 p = 0.06
   Na+/H+ exchangerWestern blotCON NR  
   protein NHE1 EXE NRNR NS
  Juel et al.22MCT1 in total crudeWestern blotCONNRNR Unable to be 
   membranes EXE NR+ 75calculatedp < 0.05
   MCT4 in total crudeWestern blotCON NR  
   membranes EXE NR+ 6 NS
   Lactate concentration CON NR  
     EXE NRNR NS
Table 16. Metabolic outcomes—others (uncontrolled trials)
TrialCitationOutcomeResultsStatistics P value (pre vs. post)
VariableMethodGroupPre-exercise (Mean ± SD)Post-exercise (Mean ± SD)Changes (%)
  1. EXE, exercise; MT-I + II, metallothioneins I and II; nNOSµ, neuronal nitric oxide synthase µ.

1Scheede-BergdahlMT-I + II proteinHistologyEXENRNRNRNS
 et al.38MT-I + II mRNAReal-time PCREXE1.13 ± 0.31.19 ± 0.51+ 5.3NS
2Bradley et al.39nNOSµ proteinWestern blotEXENRNRNRNS

One randomized controlled trial reported increases of Na, K-pump content 21, which has been demonstrated to be low in patients with type 2 diabetes compared to healthy adults 45, 46 and has been reported to increase both with endurance and sprint training in healthy individuals 47–52. The intracellularly produced lactate leaves the cell via simple diffusion and two proteins: monocarboxylate transporter (MCT) 1 and MCT4 53. The density of MCT1 and/or MCT4 in human skeletal muscle is elevated after endurance training 54–56 and resting blood lactate concentrations may be elevated in patients with type 2 diabetes 57–59. One randomized controlled trial 22 reported a significant increase of MCT after resistance exercise. One uncontrolled trial reported increases of metallothioneins I and II (MTs-I + II), which have antioxidant, anti-inflammatory, and antiapoptotic functions 38.

Discussion

Quality and quantity of retrieved studies

A limited amount of data exists exploring the adaptation of skeletal muscle to exercise training in subjects with IGT or type 2 diabetes. Only 3 randomized controlled trials, 2 non-randomized controlled trials and 13 uncontrolled trials of exercise training adaptations were isolated after extensive searches of the published literature. The quality of the randomized controlled trials and non-randomized controlled trials was only moderate, and none of the studies met all of the Delphi list quality criteria. Most of these studies did not report exercise compliance and blinding of outcome assessors, and did not employ an intention-to-treat analysis. Most of the trials included small sample sizes (median 10), which could cause inaccuracy due to subjects' individual differences and type II error due to underpowering.

Morphological outcomes

Of the four studies reported in five papers 19,20,23,, 29,42, which included resistance 19, 20, 23, 42 or combined modality 29, muscle fiber size was significantly increased by an average of 19.0% in three studies reported in four publications 19, 20, 23, 29, but not in any of the three aerobic training trials 30, 33, 37. The 19% increase in fiber area in diabetes is somewhat lower than the 28% increase in healthy older (60- to 72-year-old) subjects reported 60, 61. In contrast, capillary density increased after aerobic training 29, 37, but not after resistance training 23. These findings were, respectively, consistent with the known effects of resistance training or aerobic training in healthy adults. In healthy untrained adults, the principal adaptation to resistance training is the significant increase in muscle fiber size 62, 63. Eventually, the increases in size for a large number of fibers will result in a noticeable increase in the cross-sectional size of the muscle 63. However, there is usually no increase in the numbers of capillaries observed after resistance training. The increases in size of muscle fibers result in the muscle capillaries being moved apart, a situation that has been described as capillary dilution 63. One systematic review reported conflicting evidence regarding the effects of resistance training on muscle capillarization in the elderly subjects 64. An increase in muscle fiber size was accompanied by significant increases in capillary contacts per fiber, capillary to fiber ratio and capillary to fiber perimeter exchange index, but the growth of capillaries was proportional to fiber growth, resulting in no change to sharing factor, capillary density or capillary contacts per fiber area 64–66.

On the other hand, the major adaptation to aerobic exercise is muscle tissue capillarization 63. Harris also reported that aerobic exercise can result in positive structural and functional changes with respect to skeletal muscle capillarization in elderly subjects 64. Similarly, an eight-week aerobic exercise intervention increased capillary contacts, capillary-to-fiber ratio, and capillary density in both healthy young and elderly subjects, but did not change any of the parameters regarding muscle fiber size 67.

Thus, resistance training may improve muscle fiber size but not capillarization in subjects with IGT or type 2 diabetes, whereas aerobic exercise may improve muscle capillarization but not muscle fiber size in these subjects. These adaptations appear qualitatively and quantitatively similar to the adaptations observed in healthy young and older adults. However, there are no studies directly comparing the magnitude of such benefits in cohorts with and without diabetes.

Glycogen and glycogen synthase

Glycogen content increased in all but one 42 of six studies reported in seven papers 17, 18, 23, 25, 26, 30, 42; significantly in five studies published in four papers 17, 18, 25, 26, 30, and with a similar trend (15.8%, p < 0.1) after resistance training in the last 23. It is likely that limitation in study design (one legged training, short (6 weeks) duration may have attenuated the response in this study 23 and that small sample size (10) may have resulted in a type II error. The other study 42, which reported no significant change in glycogen (p = 0.662) after resistance training, was the only study that included long-standing (diabetes duration 12.1 ± 7.0 years), insulin-treated (exogenous insulin treatment for 7.0 ± 8.0 years) subjects. This study included subjects with more severe type 2 diabetes than any other retrieved studies. The long diabetes duration requiring insulin treatment may have blunted the ability to store glycogen in these subjects in response to exercise, and measurement of glycogen synthase would have been helpful to determine why glycogen storage could not be increased in these subjects.

Glycogen synthase increased after both resistance and aerobic training 23, 32, 35, but not when aerobic exercise was combined with a high CHO diet compared to diet alone 25. This may be explained by the fact that participants in the diet plus exercise group had greater muscle glycogen content than did the diet only group, and this was associated with a lower proportion of active muscle glycogen synthase relative to inactive enzyme 25 due to down-regulation of the enzyme. A lower active to inactive glycogen synthase activity ratio limits glycogen storage 68 and thus the major site of insulin-stimulated glucose disposal during a euglycemic-hyperinsulinemic clamp 69. Thus, by chronic stimulation of glucose uptake in muscle, exercise plus a high-carbohydrate diet result in a greatly increased muscle glycogen content with a concomitant decrease in active glycogen synthase, limiting any further effect of exercise on glucose disposal during laboratory testing, as was seen in this study 25.

GLUT4

GLUT4 mRNA and/or protein expression increased in five 23, 30, 31, 35, 37 of seven trials 18, 23, 27, 30, 31, 35, 37 after exercise training. In one negative randomized controlled trial of resistance training 18, hSGLT3, an insulin-independent glucose transporter (but not GLUT4 mRNA), markedly increased in the exercise group 18. GLUT4 allows transport of glucose down its concentration gradient, while hSGLT3 transports glucose against its concentration gradient 70. In this trial 18, muscle glycogen storage significantly increased after training and there was a significant direct association between enhanced hSGLT3 transcript levels and increased muscle glycogen stores. Taken together, the data suggest that insulin-independent hSGLT3 but not insulin-dependent GLUT4 may have been involved in the observed, exercise-stimulated muscle glucose storage 18. However, this trial was the only one that reported that the subjects had ‘uncontrolled type 2 diabetes (characterized by poor glycemic control and sustained hyperglycemia)’ and was the only one reported that some of the subjects were treated with insulin 18 out of the seven studies for GLUT4 18, 23, 27, 30, 31, 35, 37. Five of the other six studies 23, 30, 31, 35, 37 for GLUT4 expression showed significant increases. Among these, two trials 30, 37 included patients with IGT; one trial included patients with type 2 diabetes in good health without insulin treatment 35 and the other two trials 23, 31 did not report that their patients had uncontrolled type 2 diabetes or took insulin. It is possible that the state of glucose control in these subjects could be better than that in Castaneda's study 18, and that this may explain the observed GLUT4 adaptation.

Unlike hSGLT3, GLUT4 is insulin-dependent, and it translocates from the intracellular vesicle storage to the sarcolemma in response to exercise and/or insulin action 71. It has been proposed that insulin resistant individuals have a defect in GLUT4 trafficking and targeting leading to reduced GLUT4 in the cell membrane in skeletal muscle 72–74. Thus, the more severe insulin resistance in Castaneda's study 18 may have caused the inability of exercise to stimulate GLUT4 function, and different degrees of insulin resistance may be associated with different pathways of exercise-enhanced glucose uptake. However, as there is only one trial 18 investigating hSGLT3 and exercise, further investigation is required to confirm these findings and assess the relevance to enhanced glucose uptake after exercise.

Enzymes/inflammatory factors/lipids and miscellaneous adaptations

Five studies reported in seven publications 22–24,27,34,, 37,42 investigated enzymes, and three of them 22–24, 27, 42 did not find any significant changes. Citrate synthase and HAD were markedly improved by aerobic training 34, 37 but not by resistance training 22–24. The changes in amount of citrate synthase and HAD (73% and 62%, respectively) after exercise training in subjects of type 2 diabetes mellitus were similar to those in a healthy control group (85% and 48%, respectively) 34. Other than exercise modality, there is no obvious explanation for this lack of adaptation in resistance training studies.

Of the three studies 19, 27, 36 measured inflammatory factors, two 19, 27 did not find any significant changes and one 36 reported some beneficial changes: increases in inhibitor κB α/inhibitor κB β/NFκB and reduction in tumor necrosis factor α. Adiponectin receptor I and II increases were reported in one aerobic training trial 41.

Eight studies 24, 27, 29, 34, 37, 40–42 tested some parameters of lipid metabolism. Some beneficial improvements were seen in this domain after exercise training. Two aerobic training trials 34, 37 reported decreases in intra-muscular triglyceride concentration. Two other aerobic training trials 27, 40 reported increases of uncoupling protein 3. However, no consistent pattern has been demonstrated for other lipid outcomes.

Notably, all positive adaptations above (enzymes/ inflammatory factors/lipids) are from uncontrolled trials 34, 36, 37, 40, 41, except one nonrandomized controlled trial, which reported the increases of uncoupling protein (UCP)3 27. These results can therefore only be considered a weak form of evidence at present, and they require confirmation in randomized controlled trials.

Biopsy time

Time intervals between the last exercise session and biopsy are provided in Table 2. However, no correlation could be found between biopsy time and metabolic outcomes.

Limitations of this investigation and future directions for research

The biggest limitation of existing data is the small quantity (only three randomized controlled trials) and moderate quality of available literature. Since there were only five controlled trials, data available for ES calculations were quite limited, and therefore the magnitude and consistency of changes observed in many domains require confirmation in future trials. For all outcomes, inadequate reporting of mean and SD precluded calculation of ES in many studies.

Only 3 trials included resistance training, and the other 14 trials included aerobic or combined exercise training. As it has been shown in this investigation that resistance training did improve muscle fibre size as well as insulin signalling and glycogen storage (a capacity for glucose uptake and storage) in patients with type 2 diabetes or IGT, more studies focused on resistance training are required, as it may represent an important alternative approach to effectively manage diabetes and attenuate its long-term complications. In particular, direct comparisons of the relative benefits of aerobic versus resistance training for exercise-induced skeletal muscle adaptation are needed.

Unfortunately, most studies in this review included moderate- to high-intensity exercise (only one study included low intensity exercise), 30–60 min each session, 2–6 times/week, and 4–16 weeks in duration (only two studies included training more than 16 weeks). Therefore, limited data were available with which to examine dose–response effects across varying exercise characteristics. Thus, no obvious conclusions could be drawn from the extracted results that we had analyzed.

Exercise clearly improves insulin sensitivity and glucose homeostasis 9. The purpose of this review was to examine changes at the level of skeletal muscle, which may explain the overall benefits to metabolic control in this rapidly expanding cohort. The most consistent adaptations were in the areas of improved muscle fiber size and glucose transport, with inconsistent evidence for beneficial adaptations in the areas of enzymes, inflammatory factors, and lipid metabolism. Some of those studies 18, 20, 23, 30, 34, 35, 41 reported positive correlations between improved whole body insulin sensitivity and adaptations to exercise in the area of muscle fiber size, glucose transport, enzymes and lipid metabolism. However, preliminary results reviewed here still need to be confirmed in additional controlled, large trials in this cohort.

Future studies should investigate the insulin signalling pathway to better understand the mechanism of the improvements in insulin sensitivity and glucose homeostasis in response to exercise in this cohort. In addition, whole and regional body composition rising criterion methods, whole body insulin sensitivity and long-term glucose control measurements and their relationships to skeletal muscle morphological and biochemical changes should be included to advance understanding in this field. Elucidation of this pathway and its adaptation may allow the development of improved pharmacological, dietary, and physical activity interventions to address the most important mediators of glucose regulation. Ultimately, this understanding may lead to earlier diagnosis, greater prevention, and reduced clinical sequelae and morbidity associated with insulin resistance and type 2 diabetes.

Acknowledgements

Yi Wang was supported by University of Sydney International Postgraduate Research Scholarship.

Conflict of interest

None declared.

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