Resistance training to improve type 2 diabetes: working toward a prescription for the future

R E V I E W Open Access
Resistance training to improve type 2
diabetes: working toward a prescription for
the future
Dominik H. Pesta 1,2,3,4* , Renata L. S. Goncalves5 , Anila K. Madiraju 6
, Barbara Strasser 7† and Lauren M. Sparks 8,9*†
Abstract
The prevalence of type 2 diabetes (T2D) is rapidly increasing, and effective strategies to manage and prevent this
disease are urgently needed. Resistance training (RT) promotes health benefits through increased skeletal muscle
mass and qualitative adaptations, such as enhanced glucose transport and mitochondrial oxidative capacity. In
particular, mitochondrial adaptations triggered by RT provide evidence for this type of exercise as a feasible lifestyle
recommendation to combat T2D, a disease typically characterized by altered muscle mitochondrial function.
Recently, the synergistic and antagonistic effects of combined training and Metformin use have come into question
and warrant more in-depth prospective investigations. In the future, clinical intervention studies should elucidate
the mechanisms driving RT-mitigated mitochondrial adaptations in muscle and their link to improvements in
glycemic control, cholesterol metabolism and other cardiovascular disease risk factors in individuals with T2D.
Keywords: Resistance training, Type 2 diabetes, Skeletal muscle, Mitochondrial function
Background
The significance of resistance training for individuals with
type 2 diabetes: moving beyond what we already know
The prevalence of type 2 diabetes (T2D) continues to in-
crease. Within the next 20 years, the number of people
affected by this disease is expected to reach almost 600
million worldwide [1]. T2D is accompanied by a host of
risk factors including dyslipidemia, hypertension and
cardiovascular disease [2], thus putting a severe burden
on our global health care systems. Apart from medica-
tion, chronic exercise (i.e. systematic training performed
repeatedly) is a proven prevention and treatment strat-
egy for individuals with pre-diabetes and T2D [3–5]. Re-
cent reviews and meta-analyses, including the 2016 joint
position statement on physical activity and T2D from
the American Diabetes Association [6], have highlighted
the beneficial effects of chronic endurance training (ET),
resistance training (RT) and/or combined (ET + RT) inter-
ventions for ameliorating insulin sensitivity and glycemic
control in individuals with T2D [7, 8]. Chronic ET alone
has a well-established role in enhancing insulin sensitivity
via glucose uptake and disposal (reviewed in [9]) and in
increasing muscle mitochondrial density and oxidative
capacity [10]. A limited number of studies have demon-
strated that chronic RT alone enhances glycemic control
[11, 12] and muscle substrate metabolism in individuals
with T2D [13], yet the underlying mechanisms inducing
these health benefits, particularly those related to muscle
mitochondrial function, remain to be elucidated.
The present review focuses on the effects of chronic
RT on glycemic control, substrate metabolism and the
molecular mechanisms that may influence these adapta-
tions in individuals with T2D. We place a special em-
phasis on skeletal muscle, the interaction between anti-
diabetic medication use and training stimulus, and in-
corporate adipose tissue as another significant target
organ for RT-mediated metabolic adaptations in T2D.
Since little is known about the independent effects of
chronic RT on mitochondrial adaptations in skeletal
muscle and adipose tissue of individuals with T2D, we
identify gaps in the current literature and raise
* Correspondence: [e-mail];
[e-mail]
†Equal contributors
1
Department of Sport Science, Medical Section, University of Innsbruck,
Fürstenweg 185, Innsbruck, Austria
8
Translational Research Institute for Metabolism and Diabetes, Florida
Hospital, 301 E. Princeton Street, Orlando, FL 32804, USA
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Pesta et al. Nutrition & Metabolism (2017) 14:24
DOI 10.1186/s12986-017-0173-7

important questions that future RT-focused trials in in-
dividuals with T2D will hopefully address. Improving
our understanding of the mechanisms underpinning
chronic RT-mitigated metabolic adaptions in T2D will
move the scientific community (researchers and clini-
cians alike) beyond what we already know and toward
future investigations focused on molecular determinants
of the individual training responses in T2D.
Chronic resistance training effects on muscle
mass, fiber type and glycemic control
Resistance training-induced gains in muscle mass are not
solely responsible for improved muscle substrate metab-
olism in type 2 diabetes
Skeletal muscle is responsible for ~80% of insulin-
mediated glucose uptake in the postprandial state [14],
and uptake is markedly blunted in individuals with T2D
[15]. In fact, when compared with lean healthy individ-
uals, skeletal muscle of individuals with T2D exhibits a
decreased capacity to oxidize both glucose and fat [16].
Chronic RT increases muscle mass and strength, largely
due to induction of muscle hypertrophy and neuromus-
cular remodeling [17] through the phosphatidylinositol 3
kinase (PI3K)- Akt - mammalian target of rapamycin
(mTOR) pathway [18] (Fig. 1). These gains are typically
associated with and often surmised to underlie improve-
ments in muscle substrate (glucose and fat) metabolism
even in the absence of direct evidence. Recent reports
have shown that in addition to increasing strength [12],
9 months of RT enhanced oxidation of both fatty acid-
and glycolytic-derived substrates in skeletal muscle of in-
dividuals with T2D [13]. The 1.4 kg increase in muscle
mass observed was interpreted to be the root cause of
these metabolic adaptations, yet many other factors such
as improvements in insulin signaling could be respon-
sible for the RT-induced improvements in substrate me-
tabolism and glycemic control [19]. At the molecular
level, calmodulin-dependent protein kinase (CaMK) II, a
critical sensor for intracellular calcium signaling and
muscle remodeling, is activated in an exercise intensity-
dependent manner. CaMK II phosphorylates transcrip-
tion factors such as histone deacetylases (HDACs) [20],
which upon phosphorylation are exported from the nu-
cleus leading to activation of transcription factors such
as myocyte enhancing factor (MEF) 2 and its target
genes [e.g., peroxisome proliferator-activated receptor-
gamma coactivator 1 alpha (PGC-1α), glucose trans-
porter protein 4 (GLUT4), thereby improving glycemic
control [21] (Fig. 1). Of note, a recent review assessing
the different characteristics of ET, RT and combined
training interventions and their associations with gly-
cemic control among individuals with T2D concluded
that increasing the number of exercise sessions (by vol-
ume and frequency) showed greater benefits than either
mode or intensity of the training itself [22]. Unfortu-
nately, data regarding the effects of varied intensities
and durations of RT on muscle mass are limited. To this
point, when expressed per kilogram of body weight, glu-
cose disposal rates are ~40–45% higher in weightlifter-
s—individuals characterized by large amounts of muscle
mass—compared to untrained individuals [23]; however,
when normalized to muscle mass, glucose disposal rates
no longer differ between weightlifters and untrained
controls. These results underline the importance of un-
derstanding that chronic RT can have separate but
equally important impacts on skeletal muscle in terms of
strength and substrate utilization, and that while in-
creased muscle mass can contribute to enhanced whole-
body glucose-disposal rates, it does not necessarily sug-
gest that the exercise regimen altered the inherent cap-
acity of muscle to more effectively metabolize substrate.
Metabolic adaptations within skeletal muscle in response
to resistance training: how much does fiber type matter?
Type IIx fibers are described as having a glycolytic pheno-
type, relying on glucose more than fat as a fuel, and facili-
tating short-duration anaerobic activities. It has been
shown that Type IIx fibers are present in a higher propor-
tion in individuals with T2D [4]. Hyperinsulinemia—a
hallmark feature of insulin resistance and T2D—can shift
muscle fiber type toward a glycolytic phenotype by in-
creasing Type IIx myosin heavy chain gene expression [5].
Physical inactivity and immobilization have similar effects
on fiber type shift [21]. Interestingly, first-degree relatives
of individuals with T2D have a ~30% higher proportion of
Type IIx fibers than individuals without a family history of
T2D. Type IIx fiber content was also negatively associated
with glucose disposal rates in these same individuals [6].
Paradoxically, elite strength and speed athletes have a high
proportion of Type IIx fibers and are metabolically
healthy, yet the high proportion of Type IIx fibers ob-
served in individuals with T2D is concomitant with overall
blunted substrate oxidation and appears to be less advan-
tageous for these individuals. It is tempting to speculate
that the high number of Type IIx fibers in individuals with
T2D could be “trained” to utilize fuel more effectively as
observed in strength-based athletes. Four to six weeks of
moderate intensity RT (at 40–50% of the one-repetition
maximum, 1RM) markedly increased skeletal muscle glu-
cose uptake in non-obese individuals with T2D [24],
which was largely attributed to a shift in fiber type toward
Type IIa fibers. Single fiber analysis revealed that Type IIa
fibers were the ones with the highest glucose uptake and
GLUT4 content among the Type II fiber population [25,
26]. Type IIa fibers also had a higher capillary density and
showed a greater insulin response than Type IIx fibers
[27]. Although Type IIa fibers exhibited more marked
glycogen depletion during an exercise bout and faster
Pesta et al. Nutrition & Metabolism (2017) 14:24 Page 2 of 10

glycogen re-synthesis following the exercise bout [28], it
remains to be determined whether altering fiber type dis-
tribution benefits individuals with T2D in this respect. It is
entirely possible that fiber type composition is irrelevant if
the cellular metabolic machinery (e.g., glucose transport,
mitochondria, etc.) is dysfunctional. In other words, quan-
tity does not necessarily equal quality. Challenging the
idea that switching fiber type confers a metabolic advan-
tage, two independent studies demonstrated that chronic
RT-driven improvements in insulin responsiveness and
high-density lipoprotein (HDL) levels in individuals with
T2D occurred without any changes in fiber type compos-
ition [29, 30], a phenomenon routinely observed in
healthy individuals [31]. Metabolic adaptations within
muscle can therefore occur independently of a change in
muscle fiber type composition. It is important to note that
direct comparisons of the effects of different durations
and intensities of RT on fiber type composition are virtu-
ally absent from the literature.
Chronic resistance training and mitochondrial
fitness
Resistance training effects on muscle mitochondrial
function in individuals with type 2 diabetes: how much
do we really know?
Perturbations in mitochondrial oxidative capacity play a
major role in the development and progression of insu-
lin resistance and T2D [32]. As few as 3 days of high-fat
feeding are sufficient to induce insulin resistance and re-
duce muscle mitochondrial oxidative phosphorylation at
Fig. 1 Summarizes the physiological stimuli, triggered by resistance training and the specific molecular signaling events leading to a number of
beneficial adaptive responses. These multifactorial benefits induced by resistance training can either be mediated independently of an increase in
muscle mass (e.g., increased key insulin signaling proteins resulting in improved insulin action, enhanced post-exercise oxygen consumption
resulting in a decrease of adipose tissue mass, increased mitochondrial content positively affecting fatty acid oxidation capacity and improved
glucose homeostasis due to augmented rates of glycogen synthesis). The benefits can also be associated with an increase in muscle mass (e.g.,
improved glycemic control via increased glucose transporter 4 protein expression, increased resting energy expenditure and metabolic demand
via increased muscle protein turnover). Increased substrate oxidation during exercise can alter redox state and energy charge, signaling for activa-
tion of SIRT family members and AMPK. Downstream activation of PGC-1α and FOXO1 can promote fatty acid oxidation, mitochondrial biogenesis
and increased antioxidant effects. ROS signaling during exercise can also promote mitochondrial function and bolster antioxidant defense via
SOD, GPX and PRDX. Mechanical stress (e.g., contraction) during exercise triggers calcium signaling that promotes glucose uptake via GLUT4,
muscle growth and differentiation via MEF2 and Akt-mTOR, and has a negative effect on the activity of FOXO family members (FOXO1, FOXO3a),
minimizing autophagy and muscle atrophy. Please see text for more information. Adapted from [92]. Abbreviations: AMP: Adenosine monophosphate;
AMPK: Adenosine monophosphate activated kinase; ATF: activating transcription factor; CaMK: Ca2+
/calmodulin-dependent protein kinase; CREB: cAMP
response element-binding protein; ERK: extracellular signal–regulated kinase; FOXO: Forkhead box protein O; GLUT4: glucose transporter 4; HDAC: Histone
deacetylases; IL-6: interleukin 6; JNK: c-Jun N-terminal kinases; mTOR: mammalian target of rapamycin; MEF: myocyte enhancing factor; NAD/H+: Nicotinea-
mide adenine dinucleotide; NRF1/2: nuclear respiratory factor 1/2; p70 S6K: ribosomal protein S6 kinase beta-1; PGC1-α: peroxisome proliferator-activated
receptor gamma co-activator 1-alpha; PI3K: phosphatidylinositol-3-kinases; ROS: reactive oxygen species; SIRT: silent mating type information regulation
homolog; TFAM: mitochondrial transcription factor A;
Pesta et al. Nutrition & Metabolism (2017) 14:24 Page 3 of 10