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Journal of Nutrition and Metabolism
Volume 2012, Article ID 268197, 13 pages
doi:10.1155/2012/268197
Review Article
Resistance Training in Type II Diabetes Mellitus:
Impact on Areas of Metabolic Dysfunction in
Skeletal Muscle and Potential Impact on Bone
Richard J. Wood and Elizabeth C. O’Neill
Department of Exercise Science & Sport Studies, Springfield College, 263 Alde n St. Athletic Training/Exercise Science Complex,
Springfield, MA 01109, USA
Correspondence should be addressed to Richard J. Wood, rwood@spfldcol.edu
Received 8 August 2011; Revised 24 October 2011; Accepted 24 November 2011
Academic Editor: Tai C. Chen
Copyright © 2012 R. J. Wood and E. C. O’Neill. 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.
The prevalence of Type II Diabetes mellitus (T2DM) is increasing rapidly and will continue to be a major healthcare expenditure
burden. As such, identification of effective lifestyle treatments is paramount. Skeletal muscle and bone display metabolic and
functional disruption in T2DM. Skeletal muscle in T2DM is characterized by insulin resistance, impaired glycogen synthesis,
impairments in mitochondria, and lipid accumulation. Bone quality in T2DM is decreased, potentially due to the effects of
advanced glycation endproducts on collagen, impaired osteoblast activity, and lipid accumulation. Although exercise is widely
recognized as an important component of treatment for T2DM, the focus has largely been on aerobic exercise. Emerging research
suggests that resistance training (strength training) may imposepotent and unique benefits in T2DM. The purpose of this review is
to examine the role of resistance training in treating the dysfunction in skeletal muscleand the potential role for resistance training
in treating the associated dysfunction in bone.
1. Introduction
The rapid increase in incidence of Type 2 Diabetes Mellitus
(T2DM) underscores the importance of identifying effective
treatment strategies. Between 2000 and 2030, the number of
people with T2DM worldwide is expected to rise from 171
million to 366 million, and this increase is expected even if
current levels of obesity remain constant [1].
In adults, T2DM accounts for 90–95% of all diagnosed
cases of diabetes. Insulin resistance is usually an early char-
acteristic of T2DM. The chronic need for elevated insulin
secretion can lead an inability for pancreatic production to
meet needs and ultimately to β-cell failure.
Several comorbidities to T2DM exist including cardio-
vascular disease, retinopathy, nephropathy, hypertension,
and amputation. According to the National Diabetes Fact
Sheet, published by the Centers for Disease Control, the total
direct cost for diagnosed cases of diabetes in the United States
in 2007 was $174 billion, which is startling giventhat the total
number of people with diabetes increases by 37% when in-
cluding undiagnosed cases [2].
Though the etiology of T2DM is unclear and likely mul-
tifactorial, a considerable body of evidence has identified
dysfunction in both skeletal muscle and bone in T2DM. Peo-
ple with T2DM display insulin resistance in skeletal muscle
[3], characterized by buildup of intramuscular triglyceride
[4,5], and impaired mitochondrial function [6], and this
dysfunction has been implicated in the etiology of T2DM.
Bone also appears to be affected by T2DM. Fracture rates are
29% higher for diabetic populations as compared to those
without diabetes. When examined according to specific frac-
ture sites, risk of fracture in people with T2DM can be twice
as high as compared to people without T2DM [7]. Although
conflicting data exist, some studies suggest that bone mineral
density is actually higher in people with T2DM; yet the
quality of the bone is reduced, potentially as a consequence
of reduced osteoblast cell growth [8,9] or excessive lipid
accumulation within bone [8].
2Journal of Nutrition and Metabolism
Over the coming decades, the identification of effective
treatment strategies will be key to minimizing the incredible
burden of T2DM on healthcare costs. Though often a critical
part of the treatment algorithm, drug therapy is expensive
and can be accompanied by serious side effects [10]. The
identification of effective lifestyle modification strategies
is critically important for practitioners and researchers.
The inclusion of exercise in lifestyle management provides
benefits beyond dietary modification alone, making exercise
an important part of lifestyle therapy. Though an abundance
of research involving exercise in the treatment of T2DM has
focused on aerobic training, a growing body of evidence
supports the importance of resistance training as a part of
lifestyle therapy. Further, in people with T2DM, resistance
training has been shown to positively impact glycemic
control [11], adiposity [12], and lipids [13], in many cases to
a similar degree to aerobic training [14,15]. The purpose of
this review is to (1) examine the impact of resistance training
on the dysfunction in skeletal muscle and (2) hypothesize
about the potential role of resistance training on bone in
people with T2DM.
2. Musculoskeletal Dysfunction in T2DM
2.1. Dysfunction in Skeletal Muscle in T2DM (This Section
Highlights the Effects of Diabetes on Skeletal Muscle)
2.1.1. Insulin Resistance. Insulin resistance is the reduced re-
sponse of a target tissue (including skeletal muscle, adipose
tissue, etc.) to insulin as compared to a healthy control. In
essence, insulin is ineffective despite elevated concentrations.
Skeletal muscle is the primary site for insulin-mediated glu-
cose uptake in the postprandial state. Insulin binds the recep-
tor in skeletal muscle, which causes the phosphorylation
of tyrosine molecules on the insulin receptor. This causes
the insulin receptor substrate-1 (IRS-1) to move to the cell
membrane and become phosphorylated on adjacent tyrosine
molecules. Next, phosphatidylinositol-3 kinase (PI-3 kinase)
is activated, causing the downstream activation of Akt
(also called protein kinase B) and the phosphorylation
of Akt substrate 160 (AS160), which ultimately facilitates
the translocation of GLUT4 to the sarcolemma. GLUT4 is
responsible for the transport of glucose into skeletal muscle
cells (TANIGUCHI CM 2006 7). Skeletal muscle in people
with T2DM typically displays some degree of insulin re-
sistance, characterized by a disruption in the signaling
cascade described previously, specifically defective tyrosine
phosphorylation of IRS-1 and defects in PI-3 kinase and Akt
activation (KROOK A 2000 49; CUSI K 2000 105). DeFronzo
et al. [16] found that insulin-stimulated leg glucose uptake is
reduced by 50% in people with T2DM.
Insulin resistance in skeletal muscle is considered by
some to be the primary defect in T2DM [3]giventhatit
occurs decades before β-cell failure [17]. Using a cross-sec-
tional design, Perseghin et al. [18] found that lean, normo-
glycemic, sedentary offspring of patients with T2DM had
significantly lower (∼27%) skeletal muscle insulin sensitiv-
ity as compared to healthy control subjects. The offspring
of patients with T2DM also displayed significantly higher
(∼31%) fasting insulin. Jallut et al. [19] found that the pro-
gression from normal glucose tolerance to impaired glucose
tolerance is characterized by a substantial reduction in insu-
lin sensitivity, but serum glucose response to an oral glucose
tolerance test was only modestly impacted. Together, these
studies and many others [20–22]indicatethatskeletalmuscle
insulin resistance is an early defect in T2DM.
Though cause and effect has not been clearly elucidated,
a number of areas of dysfunction within skeletal muscle are
related to the disruptions caused to the insulin signaling
cascade and ultimately to the degree of insulin resistance.
These include impairments in glycogen synthesis, impaired
mitochondrial function, and lipid accumulation around and
within muscle.
2.1.2. Impaired Glycogen Synthesis. After consumption of
carbohydrate, consequent blood glucose elevations cause the
secretion of insulin, which stimulates glucose uptake by the
liver and skeletal muscle. Under euglycemic hyperinsuline-
mic conditions, approximately 80% of glucose uptake occurs
in skeletal muscle [23]. Once taken up by the cell, glucose can
either be oxidized to carbon dioxide and water or converted
to glycogen [23], the latter being regulated by glycogen
synthase. The impairment of glycogen synthase activity is
thought to be one of the earliest defects in skeletal muscle
seen in T2DM [24]. Using nuclear magnetic resonance,
Perseghin et al. [18] studied glycogen synthesis in the off-
spring of two parents with T2DM with normal glucose toler-
ance and found that reductions in glycogen synthesis could
almost entirely account for reductions in insulin-stimulated
glucose uptake in skeletal muscle. Using similar techniques,
Shulman et al. [25] found that glycogen synthesis rates were
approximately 57% lower in patients with T2DM as com-
pared to healthy controls. However, using muscle biopsy and
subsequent quantitative histology, He and Kelley [26]found
that muscle glycogen content was similar between lean non-
diabetic, obese non-diabetic, and obese diabetic patients.
Furthermore, when expressed relative to oxidative enzyme
content, obese-diabetic patients tended to have higher mus-
cle glycogen content, although differences were not statisti-
cally significant. Together these studies indicate that glycogen
synthesis may be impaired early in the onset of skeletal
muscle insulin resistance, and that the capacity of skeletal
muscle to utilize fuel may be an important consideration.
2.1.3. Mitochondrial Dysfunction. The disruption of normal
mitochondrial biology can occur with insulin resistance long
before the development of T2DM. Morino et al. [27]found
that insulin-resistant offspring of patients with T2DM dis-
played a 60% lower insulin-mediated skeletal muscle glucose
uptake and a 38% lower muscle mitochondrial density than
healthy controls. Others have also reported differences in
mitochondrial ultra-structure and size in T2DM [28,29].
The oxidative capacity of skeletal muscle mitochondria
may also be impaired in T2DM. Kelley et al. [28]found
significantly reduced mitochondrial electron transport in the
skeletal muscle taken from the vastus lateralis of participants
Journal of Nutrition and Metabolism 3
with T2DM as compared to lean, healthy controls. Interest-
ingly, Larsen et al. [30] found attenuated mitochondrial re-
spiration in vastus lateralis muscle samples but not in mito-
chondria from the deltoid muscle from people with T2DM.
Furthermore, using muscle biopsy samples, Ritov et al. [31]
found that participants with T2DM (as compared to lean,
healthy controls) had similar or higher production of reduc-
ing equivalents (NADH) from the Krebs Cycle and β-oxida-
tion. Taken together, these studies indicate an impaired oxi-
dative capacity of skeletal muscle in T2DM.
The delivery of normal or excessive amounts of reducing
equivalents to a poorly functioning electron transport chain
(described above) describes an environment that would favor
a “backlog” in energy metabolism. This backlog in meta-
bolism is associated with the accumulation of specific inter-
mediates of lipid metabolism including fatty acyl-CoA, cer-
amides, and diacylglycerols. All of these intermediates cor-
relate with insulin resistance and directly alter the insulin
signaling cascade described previously [32].
2.1.4. Accumulation of Lipid. Excessive accumulation of lipid
within muscle has been shown to contribute to insulin resis-
tance in both human and animal models [4,5]. The accumu-
lation is potentially due to the combination of the impaired
ability of mitochondrial function (whether due to diabetic
etiology, sedentary behavior, or both) and increased uptake
of lipid into skeletal muscle under postprandial conditions.
Kelley and Simoneau [33] found that in the postprandial
state, fatty acid uptake was higher in patients with T2DM,
where fat oxidation was reduced (supporting the progressive
increase in muscle-lipid storage).
Lipid accumulation can occur both around muscle cells
(extramyocellular lipids are stored within adipocytes within
muscle tissue) and within muscle fibers (intramuscular tri-
glycerides). According to Szcepaniak et al., intramuscular tri-
glycerides are increased in obesity, and store quantity is posi-
tively related to severity of insulin resistance. Furthermore,
increased intramuscular triglycerides are present in first-
degree relatives of patients with T2DM, indicating that these
stores may be an early indication of insulin resistance [34].
Histochemical techniques have revealed that the volume
of lipid droplets in skeletal muscle is increased in T2DM. Ap-
proximately 1.5% of myocyte volume is occupied by lipid
droplets in healthy controls, and 3-4% of muscle volume is
occupied by lipid droplets in patients with T2DM [4]. Fur-
thermore, the distribution of lipid droplets differs between
healthy controls and patients with T2DM, where the latter
display lipid droplets more centrally located within the
muscle fiber [35]. The differing location of lipid droplets may
affect availability of the substrate for oxidation [28].
In addition to disrupting muscle metabolism, the accu-
mulation of lipid may have important functional implica-
tions. Examining a cohort of 2,979 participants from the
Health ABC study, Visser et al. [36] found that reduced mus-
cle attenuation (assessed via computed tomography; indica-
tor of fat infiltration into the muscle) was associated with
poorer lower extremity performance independent of muscle
area. Age-related fatty-infiltration of skeletal muscle is also
associated with the incidence of mobility disability [37].
2.2. Dysfunction in Bone in T2DM
2.2.1. Osteoporosis and Reduced Bone Quality. Several studies
suggest that diabetes negatively impacts skeletal health and
may increase one’s risk of skeletal dysfunction [38,39].
Osteoporosis is the most common metabolic skeletal disease
in the United States and is characterized by low bone mineral
density (BMD) resulting in an increased risk for fractures
[40]. The National Osteoporosis Foundation has indicated
that approximately 10 million Americans have osteoporosis
(T-scores ≤−2.5) and an additional 34 million are osteopen-
ic (T-scores between −1and−2.5) [8]. With more than 2
million osteoporotic fractures in 2005, osteoporosis-related
medical expenses reached $19 billion and are expected to
grow to $25.3 billion by 2025. Fracture rates are even higher
for diabetic populations [41,42]. The risk of fractures varies
by body site, with fracture risk being more than double
in certain sites and an overall fracture risk 29% higher in
diabetics compared to nondiabetics [7]. The drastic increase
in fracture risk strongly links compromised bone health with
diabetes. Findings in animal models indicate that fracture
risk may be related to a reduced ability of diabetic bone
to withstand load and bending. Reddy et al. [39]examined
the femur and tibia in experimentally induced diabetic rats
and found that diabetes reduced the femur and tibia mean
maximum load 37 and 30%, deformation at maximum load
25 and 30%, and energy absorbed 27 and 23% compared
to controls. Additionally, bending stiffness increased in the
diabetic rat bones: femur 57% and tibia 38%. Taken together,
these studies indicate a reduced bone quality in T2DM.
There are several potential causes for reduced bone quality
in T2DM including bone cell formation, advanced glycation
end products, and lipid accumulation.
2.2.2. Bone Cell Formation. Healthybonetissueundergoes
a constant state of remodeling, a coupled process involving
resorption and formation of bone through the activation of
osteoclasts, osteoblasts, and osteocytes [43,44]. Ideally, the
osteoclast resorption of bone is closely coupled with oste-
oblast bone formation in adults to maintain healthy bone
structure [45]. T2DM, however, may interfere with or alter
these processes resulting in compromised bone density and
quality, elevating one’s risk for osteoporosis and fractures
[8,46]. Mesenchymal stem cells (MSCs), located in the
bone marrow, are one form of multipotent cells having the
potential to give rise to a variety of cell types including bone,
fat, cartilage, and marrow [47]. The differentiation of MSC
to either osteoblasts or adipocytes is mediated by a variety
of molecular, biochemical, and physical stimuli [48]. Wang
et al. [9] utilized human osteoblast-like MG-63 cells to
determine the impact of high glucose levels on MSC. The dif-
ferentiation of MSC to either osteoblasts or adipocytes is reg-
ulated in part by runt-related transcription factor 2 (Runx2)
and peroxisome proliferator-activated receptor γ(PPARγ).
Runx2 favors osteoblast formation while PPARγfavors
adipocyte formation. Elevated glucose not only decreased the
development and maturation of MG-63 cells by 30–40% but
also reduced levels of osteogenic markers Runx2, collagen I,
osteonectin, and osteocalcin [9]. Though these findings have
4Journal of Nutrition and Metabolism
provided a potential contributor to reduced bone quality
in T2DM, future studies should examine whether hyper-
glycemia in T2DM impacts bone formation.
2.2.3. Advanced Glycation End-products (AGEs). AGE may
play a role in both bone cell formation and other factors
related to bone quality. AGEs result from the nonenzymatic
reaction of reducing sugars (such as glucose and fructose)
with proteins or lipids—a process called glycation. Contin-
ued glycation of these products leads to molecular rearrange-
ments and the ultimate production of AGE [49]. AGE can
produce reactive oxygen species, bind to specific cell surface
receptors, and form cross-links. Since advanced glycation
can take weeks to occur endogenously, the primary effectors
are long-lived proteins, including connective tissue such as
collagen [50]. Alikhani et al. [51] determined that AGEs
induce an apoptotic effect on osteoblast cells diminishing
bone formation which was found to be largely mediated
through AGE receptors. Saito et al. [52] investigated diabetic
induced alterations in collagen cross-links utilizing rats.
The two general divisions of collagen cross-links include
enzymatic cross-links, which have a positive effect on bone
function, and nonenzymatic cross-links, which impair bone
function. Saito et al. [52] reported that an elevation in
glycation-induced pentosidine (Pen), a common marker for
cross-linking AGE present in bone, impaired the mechanical
properties of bone in spontaneously diabetic rats. The level
of Pen and the Pen to total enzymatic cross-links (P/TECLs)
ratio had a significant relationship with the mechanical
properties of bone. Both Pen and Pen/TECL ratio were
associated with a decrease in the energy absorption, stiffness,
elasticity, and maximum load.
These findings support the idea that AGE and collagen
may be of particular importance in T2DM bone. Collagen
serves to enhance the toughness and tensile strength of bone
due to its capacity to absorb energy [52,53]. Non-enzy-
matic collagen cross-linking has been shown to impair the
mechanical properties of bone [51,54]therebymakingit
more susceptible to fractures. Additionally, AGE have been
shown to induced reductions in osteoblasts which can also
compromise bone health [55]. Thus, it has been speculated
that reducing AGE could help maintain bone quality and
reduce the diabetic associated fracture risk [56]. It is impor-
tant to note that assessments of BMD often do not detect
changes in bone quality, warranting alternative assessments
of bone health in diabetic populations.
2.2.4. Lipid Accumulation. Diabetes may also lead to an in-
crease in bone adiposity [8] thereby reducing bone quality.
Utilizing streptozotocin-induced diabetic mice, Botolin et al.
[57] reported an increase in marrow adiposity mediated by
an elevation in PPAR γ2, resistin, and adipocyte fatty acid
binding protein. Additionally, lipid-dense adipocytes were
noted in the tibia of the diabetic mice. Whether diabetes in-
duced differentiation of mesenchymal pluripotent cells to ad-
ipocytes, or if accumulation of lipid occurred in existing
adipocytes making them more visible, is unclear. The accu-
mulation of lipid in bone reportedly expands the marrow
cavity decreasing the cortical envelope [8].
The increase in adipogenic markers found under high
glucose conditions may be one factor contributing to the adi-
posity of bone with diabetes. Wang et al. [9] determined that
high glucose conditions suppressed osteogenic differentia-
tion of MG-63 cells and elevated adipogenic differentiation.
The increased adiposity was attributed to an elevation of
adipogenic markers: PPARγ, adipsin, resistin, and aP2 as the
result of high glucose levels. Thus, hyperglycemia associated
with diabetes may alter the normal regulation of bone and
lead to increased adiposity resulting in compromised bone
quality.
3. Role of Resistance Exercise in
Treating Musculoskeletal Dysfunction
The importance of exercise for patients with T2DM is em-
phasized by major organizations including the American
College of Sports Medicine and the American Diabetes
Association. Exercise is considered a cornerstone in the
therapeutic intervention for patients with T2DM, and the
importance of exercise is underscored by the costs and side
effects that accompany pharmacological intervention. Two
major modes of exercise are aerobic exercise and resistance
exercise. Aerobic exercise involves exercises performed with
large muscle groups over extended periods involving hun-
dreds of repetitions and limited by the delivery of oxygen
to the working muscles. Resistance exercise (also referred
to as resistance training) involves the movement of high
loads using resistance from either machines or weights for
a smaller number of repetitions [58,59].
Although cardiovascular exercise is often encouraged as
a nonpharmacological method to manage T2DM, com-
plications associated with diabetes often hinder cardio-
vascular capabilities [60,61] and only 39% of diabetics
meet the American Diabetes Association recommendations
of 150 min of moderate-intensity or 90 min of vigorous-
intensity cardiovascular exercise per week [55]. More re-
cently, resistance training has been found to be effective for
managing T2DM and may provide the additional benefit of
preventing or limiting musculoskeletal dysfunction associ-
ated with T2DM [54,60,62,63].
The majority of clinical trials that have examined the
impact of exercise on T2DM and associated comorbidities
have employed aerobic modes of exercise. Wang and Jin [58]
provided an excellent systematic review about the adapta-
tions to exercise training in skeletal muscle in T2DM; 78% of
the studies that met the inclusion criteria prescribed aerobic
training. Irvine and Taylor [11] conducted a systematic
review of resistance exercise on glycemic control in T2DM
and found nine trials that met inclusion criteria. Resistance
training appears to have an important impact on T2DM;
resistance exercise has been shown to improve HbA1C signif-
icantly more than performing no exercise at all and similarly
to aerobic exercise in patients with T2DM. Furthermore,
resistance exercise can cause significantly better improve-
ments in strength when compared to aerobic training [11].
The few trials that have included only resistance exercise
have focused largely onsystemic physiological and functional
Journal of Nutrition and Metabolism 5
responses more so than the direct impact of the training
on skeletal muscle and bone. Since resistance training has a
meaningful positive effect clinically on people with T2DM,
and given the substantial dysfunction present in skeletal
muscle and bone of people with T2DM, it is important to
explore the impact of resistance exercise on this dysfunction.
Although some direct evidence about the impact of resis-
tanceexerciseexistswithrespecttothedysfunctioninskele-
tal muscle with T2DM, there is little to no direct evidence
about the impact of resistance exercise on the dysfunction in
bone with T2DM. Therefore, the purpose of this section of
the review is (1) to examine how resistance exercise impacts
the aforementioned dysfunctional aspects of skeletal muscle
and (2) to hypothesize how resistance exercise may impact
the dysfunction found in bone in T2DM. Through these
hypotheses, we hope to highlight areas in need of additional
research with respect to bone dysfunction in T2DM. This
review does not include trials where aerobic exercise and
resistance exercise were combined or where aerobic exercise
alone was employed. Tab l e 1 provides a summary of the re-
sistance training protocol in trials with patients who had
T2DM.
3.1. Insulin-Independent Glucose Uptake in Exercising Muscle.
In addition to insulin-mediated glucose uptake, glucose can
also be taken up into muscle through insulin-independent
mechanisms (contraction-mediated uptake), which predom-
inate during exercise. It appears that there are distinct
contraction and insulin-responsive GLUT4 pools in skeletal
muscle [73,74], and contraction does not stimulate the
cascade of events in insulin signaling [75]. Two potential
mechanisms of insulin-independent glucose uptake have
been described, one mediated via intracellular calcium levels,
and the other dependent upon 5AMP-activated protein
kinase (AMPK) [76]. It appears that the extent to which
muscle glucose uptake increases during exercise is due to
exercise intensity [65], supporting the idea that both of these
proposed pathways may work in concert. Given the normal
reduction in serum insulin during exercise, these pathways
are a critical means of fuel delivery.
The insulin-independent uptake of blood glucose ap-
pears to function normally in people with T2DM even when
insulin action is impaired [77]. Musi et al. [68]demonstrated
that a single bout of aerobic exercise (45 minutes at 70% of
maximum work load) significantly reduced blood glucose,
and increased AMPK alpha2 activity to a similar degree as
compared to health controls. Since this pathway appears
to work normally in T2DM, exercise provides an excellent
opportunity to manage blood glucose. As such, exercise can
be an important means to improve glycemia in T2DM via
these mechanisms in addition to any impact exercise may
directly have on areas of dysfunction in skeletal muscle.
3.2. Resistance Exercise Effects on Dysfunction in
Muscle Identified in Section 2
3.2.1. Insulin Resistance. Whole-body insulin resistance, as
estimated by the homeostasis model assessment (HOMA-
IR), has been shown to improve by ∼25% after 16 weeks
of whole-body strength training three times per week in
older Hispanic adults with T2DM [54]. However, given that
HOMA-IR is calculated using fasting values of glucose and
insulin, this method is more indicative of hepatic insulin
sensitivity [3]. Dunstan et al. [67] randomized patients with
T2DM to circuit weight training program three times per
week for eight weeks or to a nonexercising control group. An
oral glucose tolerance test (OGTT) was performed at base-
line and week eight. Both glucose and insulin area under the
curve decreased significantly in the intervention group from
baseline to week eight, and reductions in insulin area under
the curve remained significant after adjusting for changes
in body mass. In contrast, Baldi and Snowling [64]found
that a 10-week resistance training program performed three
times per week did not change 2-hour glucose or insulin
but did lead to reductions in HbA1c and fasting insulin in
patients with T2DM. Iba˜
nez et al. [12] assigned nine older
men with T2DM to a progressive resistance training program
twice per week for 16 weeks. Insulin sensitivity, as measured
using the frequently sampled intravenous glucose tolerance
test, improved by 46.3%. Of note, these participants had
no significant change in body weight and increased energy
intake by 15% over the course of the study.
The euglycemic insulin clamp technique is considered
the gold standard for the in vivo measurement of insulin
action [78]. Insulin sensitivity measured using this technique
is primarily a reflection of skeletal muscle insulin sensitivity
as described by Ferrannini et al. [79]. As such, studies
employing this method to assess insulin sensitivity are best
suited to examine the effects of resistance training on skeletal
muscle insulin sensitivity. Ishii et al. [69] assigned 17 patients
with T2DM to either a resistance exercise group (2 sets of
9 exercises 5 times per week) or a nonexercising control
group for 4–6 weeks. The intervention group experienced a
48% increase in glucose disposal rate (as assessed using eug-
lycemic insulin clamp), indicating improved skeletal muscle
insulin sensitivity. Interestingly, VO2peak (a measurement of
aerobic capacity) was unchanged. Using similar techniques,
Holten et al. [70] found increased muscle glucose uptake
after single-leg strength training 30 minutes per day, three
times per week for six weeks. These studies indicate that
strength training increases skeletal muscle insulin sensitiv-
ity; notably, these changes occurred after only short-term
training (4–6 weeks). Furthermore, the improvements seen
in insulin sensitivity following resistance training are of a
similar magnitude seen following aerobic training [15,80].
3.2.2. Impaired Glycogen Synthesis. It appears that resistance
exercise may be an effective means for improving glycogen
and glycogen synthase in muscle. Holten et al. reported sig-
nificant increases in g lycogen content, glycogen synthase pro-
tein content, and glycogen synthase activity after six weeks
of resistance exercise in T2DM patients [70]. Similarly,
Castaneda et al. found that 16 weeks of resistance exercise
three times per week increased muscle glycogen by ∼32%;
interestingly, a control group who performed no exercise
experienced a significant reduction in muscle glycogen [66].
However, not all studies have shown improvements in mus-
cle glycogen levels following a resistance exercise program.
6Journal of Nutrition and Metabolism
Tab le 1: Summary of resistance training protocol in trials with patients who have type II diabetes.
Study [reference no.] Duration Training frequency Number of Exercises Sets ×Reps Intensity (%1RM) Compliance Training effect Body weight
Baldi and Snowling [64]10wks 3x/wk 10 Wk1: 1 ×12
Wk2–10: 2 ×12 NR 89.6% Upper and Lower Body
Strength ↑8–37% +1.7 kg
Rose and Richter [65]Paper reporting from same cohort presented in Castaneda et al. (Below)
Castaneda et al. [66]16wks 3x/wk 5 3
×8 60–80% 90 ±10% Upper body Strength ↑36%
Lower body Strength ↑51% +0.2 kg
Dunstan et al. [67]8wks 3x/wk 9 Wk1-2: 2 ×10–15
Wk2–8: 3 ×10–15 50–55% NR Strength ↑for all exercises
(↑range: 15–43%) −0.4 kg
Musi et al. [68]24wks3x/wk 9 3
×8–10 Wk1-2: 50–60%
Wk3–24: 75–85% 88% Upper body Strength ↑43%
Lower Body Strength ↑33% −2.5 kg
Iba˜
nez et al. [12]16wks 2x/wk 7-8 Wk1–8: 3-4 ×10–15
Wk9–16: 3–5 ×5-6
Wk1–8: 50–70%
Wk9–16: 70–80% 99.3% Upper Body Strength ↑18.2%
Lower Body Strength ↑17.1% n/c
Ishii et al. [69] 4–6 wks 5x/wk 9 2×10 Upper Body
2×20 Lower Body 40–50% 100% Lower Body Strength ↑16% BMI
↓0.6 kg/m2
Holten et al. [70] 6 wks 3x/wk 3∗Wk1-2: 3 ×10
Wk3–6: 4 ×8–12
50%
70–80% 100% Lower Body Strength ↑42–75% n/c
Ku et a l. [71]12wks5x/wk 10 3
×15–20 40–50% NR Upper body Strength ↑12%
Lower body Strength ↑11% −1.1 kg
Misra et al. [13]12wks3x/wk 6 2
×10 NR 100% NR n/c
Praet et al. [72]10wks3x/wk 5 2
×10 50–60% 83% Upper body Strength ↑16%
Lower body Strength ↑18% −0.1 kg
RM: repetition maximum; training frequency reported as times per week (x/wk); sets and repetitions reported as number of sets by the number of repetitions (sets ×reps); wks: weeks; wk: week; kg: kilograms;
BMI: body mass index; m2: meters squared; NR: not reported; n/c =no change; ∗strength training was performed on one leg only throughout the study; the other leg remained sedentary.
Journal of Nutrition and Metabolism 7
Praetetal.[72] trained patients with T2DM using a re-
sistance exercise program three times per week for 10
weeks and found no significant change in muscle glycogen
content, despite significant reductions in fasting glucose and
exogenous insulin requirements.
3.2.3. Mitochondrial Dysfunction. Although changes in skele-
tal muscle mitochondrial morphology and function after
aerobic training have been studied extensively, very few stud-
ies have examined the impact of resistance training on
mitochondrial quantity and size in T2DM. However, resis-
tance exercise has been shown to increase mitochondria in
other populations. Balakrishnan et al. [81]reportedthata
resistance exercise program completed three times per week
for 12 weeks significantly increased skeletal muscle mito-
chondrial content in older adults with chronic kidney dis-
ease. Resistance exercise has also been shown to improve
mitochondrial function in older adults [82].
The response of skeletal muscle oxidative activity to resis-
tance training in patients with T2DM has been examined,
but in very few studies. Holten et al. [70] found similar levels
of oxidative enzymes (citrate synthase and hydroxyl-acyl-
CoA dehydrogenase) in patients with T2DM and controls
previous to a 6-week resistance training intervention and
reported no significant changes in these enzymes following
the training program. In agreement, Praet et al. [72]reported
that resistance training performed three times per week for
10 weeks resulted in no significant change in skeletal muscle
succinate dehydrogenase activity.
The effects of resistance exercise on mitochondrial mor-
phology and function in healthy adults have been more
widely examined. Resistance exercise in healthy, untrained
males has been shown to reduce the relative skeletal muscle
volume of mitochondria and density [83,84]. However,
in both of these studies, muscle fiber cross-sectional area
increased significantly, leading to the conclusion (in both
cases) that resistance training results in a “dilution of the
mitochondrial volume” in skeletal muscle. Interestingly, and
similarly to patients with T2DM, the oxidative potential in
sedentary healthy adults has also been largely found unre-
sponsive to chronic resistance training [85–90]; however,
some reports of both increases [91–93]anddecreases[94]
in this population also exist.
3.2.4. Accumulation of Lipid. Very few interventions exist
to elucidate the effects of a resistance training program on
muscle lipid content in people with T2DM. After 10 weeks of
progressive resistance exercise in patients with T2DM, Praet
et al. [72] reported no change in the lipid content of Type
I, Type IIa, or Type IIx muscle fibers, and the lipid content
in Type I fibers was greater than that in Type IIa and Type
IIx fibers at both baseline and postintervention analyses. Ku
et al. [71]examinedtheeffects of strength training (using
elastic bands) at 40–50% of maximal strength five times
per week for 12 weeks in 44 Korean women with T2DM.
Subcutaneous, subfascial, and intramuscular adipose were
measured in the mid-thigh prior to and following the resist-
ance training program. No significant changes in any of these
adipose depots were detected after the training program.
There was also an aerobic-trained group in this study who
also had no changes in muscle lipid content.
The effects of resistance exercise alone on muscle lipid
content in other populations have also been scarcely re-
ported. Mueller et al. [95] assigned elderly men and women
to either an eccentric-based or conventionalstrength training
program twice per week for 12 weeks. Intramyocellular lipid
content decreased in the eccentric-based program, but not
in the conventional program—possibly indicating that the
tempo of resistance training may play a role in outcomes.
Given the numerous benefits of resistance exercise alone in
T2DM, future studies are needed to explore the effects of this
type of training on muscle lipid content.
3.3. Hypothesized Effects of Resistance Training on
Dysfunction in Bone
3.3.1. Weight Bearing, Resistance Training, and Bone. Bone
functions to withstand internal and external forces and is
able to adapt to enhance its ability to endure future loading
conditions. The mechanical loading of bone via weight-
bearing activities induces temporary bone deformation [96]
known as strain [97]. Weight-bearing exercise, including re-
sistance training, can provide the appropriate strain neces-
sary to the activate bone formation process through mechan-
otransduction. Mechanotransduction involves “the conver-
sion of a biophysical force into a cellular response” [97]. The
strain associated with resistance training results in mechani-
cal stretching of osteocytes and bone lining cells and hydro-
static pressure gradients causing the movement of interstitial
fluid within the canaliculae of bone. Fluid movement cre-
ates shear stress on the osteocytes, bone lining cells, and
osteoblasts. The stretching and shear stress placed on these
cells during this process leads to the formation and activation
of osteoblasts to form new bone in the affected area. Sub-
sequently over time, this process can lead to increases in
BMD. The potential influence that weight-bearing activities
have on bone can be affected by several factors including
strain magnitude, strain rate, strain frequency, and strain
variability [98,99].
Weight-bearing activities can induce varying degrees of
strain [100]. A minimal effective strain (MES), roughly
1,500 μstrain or greater, is necessary to stimulate bone for-
mation. When strain magnitudes are not of a sufficient
threshold, bone resorption can outweigh bone formation re-
sulting in a loss of bone [97]. Thus, presence or absence
of weight-bearing activities can impact bone health dra-
matically. Under extended conditions of unloading, such
as spaceflight or bed rest, the lack of mechanical loading
produces insufficient strain magnitudes, which can result
in excessive bone resorption and decreases in BMD [101],
thereby justifying the need for regular weight-bearing activ-
ity to maintain BMD and overall bone health. The magnitude
of strain necessary to reach MES can vary dramatically
when considering variables such as strain rate, frequency,
and variability [96]. Higher strain rates magnify the speed
of fluid movement enhancing shear stress creating a greater
osteogenic stimulus even at lower strain magnitudes [96].
8Journal of Nutrition and Metabolism
Greater strain frequency reduces the need for high strain
magnitudes to induce an osteogenic response [100]; however,
bone appears to lose sensitivity to loading after a certain
number of loading cycles and continued loading may not
provide any additional benefit [98]. Rest inserted between
loading has been shown to optimize the sensitivity of bone
to future loading, maximizing the osteogenic response [99].
Varying the direction of the strain creates differing force
vectors thus enhancing stimulation and the formation of new
bone in a greater diversity of locations.
Weight-bearing exercise is well recognized for its influ-
ence on the bone remodeling process enhancing BMD [96,
102]. This benefit is often observed through comparisons of
sports with diverse weight-bearing parameters and compari-
son made between athletes and nonathletes [102,103]. Ath-
letes in general tend to have higher BMD than nonathletes
and BMD tends to be greatest in athletes who participate
in sports that generate greater ground reaction forces [102].
Resistance training is a form of weight-bearing activity that
has osteogenic potential. Resistance training has been found
to alter biomarkers for bone formation and bone resorp-
tion [104]. Fujimura et al. [104]reportedanincreasein
osteogenic markers following 4 months of resistance train-
ing, but no changes in BMD were observed. It was speculated
that the changes in biomarkers preceded any detectable
changes in BMD.
Longer duration resistance training studies have however
reported improvements in BMD. Almstedt et al. [105]found
a 2.7 to 7.7% increase in the BMD of male participants fol-
lowing a 24-week resistance-training program but no signifi-
cant changes in the BMD of female participants. Nichols et al.
[106] reported significant increases in femoral neck BMD in
resistance trained females compared to nontrained controls.
Following a 9-month resistance training program Pruitt et al.
[107] found not only increases in BMD in resistance-trained
early postmenopausal female subjects but also a decline in
BMD in nontrained subjects. While not all studies report
increases in BMD with resistance training, resistance training
may help maintain existing bone mass or slow the loss of
BMD which may be just as beneficial with respect to prevent-
ing osteoporosis.
A substantial amount of research has identified the bene-
fits of weight-bearing exercise such as resistance training, on
bone in healthy populations [102–107]. Resistance training
has been found to have variable but often positive benefits on
BMD [108]. Limited research however exists examining the
impact of resistance training on diabetic skeletal dysfunction.
Diabetes was found to be a common exclusionary criterion
for resistance training and bone research. One study was
discovered that utilized diabetic subjects. Daly et al. [109]
determined that resistance training was beneficial at helping
maintain BMD in diabetic participants subjected to a
moderate weight loss program compared to a loss in BMD
seen in the weight loss only group. In diabetic populations
however, utilization of BMD as a mark of bone health
is not always appropriate because it does not equate to
fracture risk [43]. Thus, examining the impact of resistance
training on the factors associated with reduced bone quality
in diabetic populations may help shed light on the potential
benefits of resistance training in diabetic populations. This
is an important area of research that warrants exploration.
However, until such research is conducted utilizing diabetic
subjects, we can only hypothesize about the impact resistance
training has on bone quality by examining its impact on bone
in healthy subjects. The following studies provide evidence
regarding the benefits of resistance training to factors that
have been reported to compromise bone quality in diabetics.
So, although these studies do not utilize diabetic subjects,
they provide insight regarding the potential benefits resis-
tance training may serve to correct diabetic abnormalities
that impact bone.
3.3.2. Advanced Glycation Endproducts. Hyperglycemia and
AGE negatively impact bone in a variety of ways. Hyper-
glycemia reduces osteogenic cellular differentiation and os-
teogenic markers [9]. No research was found examining the
effect of resistance training on osteoblast differentiation or
osteogenic markers in diabetics; however, resistance training
has been found to promote osteogenic cellular differentiation
and osteogenic markers utilizing animal models and nondi-
abetic subjects, respectively. Menuki et al. [110]foundan
increase in osteoblast differentiation in bone marrow cells
from the tibia and femur of mice following 28 days of stair
climbing exercise. Humans with a history of resistance train-
ing also show increased osteogenic activity. Fujimura et al.
[104] reported an increase in biomarkers for osteogenesis,
including osteocalcin, and a decrease in urinary deoxypyridi-
noline (DPYR), a marker of bone resorption, in resistance
trained subjects. Osteocalcin levels increased significantly
from baseline each month during the four months of training
while DPYR decreased during the first three months and
then returned back toward baseline. BMD of the resistance-
trained subjects did not increase following the four-month
time period. The researchers concluded that increases in
the biomarkers for osteogenesis may precede any noticeable
changes in BMD. The positive changes in osteoblast differ-
entiation and osteogenic biomarkers via resistance training
have the potential to reduce the negative effect of diabetes on
these specific parameter that impact bone quality.
AGEs have a deleterious effect on bone by reducing oste-
oblast cells [51] and increasing nonenzymatic collagen cross-
links impairing bone quality [111]. No literature was found
examining the potential alterations to the influence of AGE
on bone with any form of exercise, including resistance train-
ing. Limited research appears to exist examining the impact
of exercise in general on AGE. Boor et al. [112]reporteda
decrease in AGE in obese Zucker rats following 10-weeks of
moderate aerobic exercise. Magalh˜
aes et al. [113] therefore
have speculated that exercise may aid in the reduction and
accumulation of AGE. Since resistance training has been
identified as an effective form of exercise for managing
T2DM [54,60,62,63], the potential exists for such training
to impact AGE; however, research is needed to fully elucidate
such a connection.
3.3.3. Lipid Accumulation. Compromised bone quality with
diabetes is due in part to an increase in bone adiposity [8].
Journal of Nutrition and Metabolism 9
Accelerated adipocyte differentiation coupled with a decrease
in osteoblast differentiation has been found under high
glucose conditions in animal models [9,57]. No research
exists to date examining the impact of resistance training
on the alterations to lipid accumulation in diabetic bone.
Menuki et al. [110] did however determine that mechanical
loading induced alterations to the cellular differentiation
of bone marrow cells utilizing an animal model. Menuki
et al. [110] examined bone samples taken from the tibias
and femurs of 70 mice following either 4, 7, or 28 days
of stair climbing. Adipocyte differentiation was significantly
lower in the 28-day stair climbing mice compared to con-
trol group mice, indicating that the mechanical loading had
apositiveeffect on decreasing bone adiposity. MSCs have
also been found to favor osteoblast differentiation when
exposed to a mechanical strain [114]. Sen et al. induced
a 2% mechanical strain at 10 cycles per minute for 3600
cycles total on cultured MSC. The researchers determined
that the mechanical strain reduced PPARγavailability,
thereby limiting bone adiposity and favoring osteogene-
sis, indicating that the functional loading of the skeleton
through exercise is important to bone mass and morphology.
Zayzafoon et al. [47] provide further support regarding
the necessity of mechanical loading to the maintenance
of bone quality. Zayzafoon et al. created a microgravity
(MG) environment to investigate the impact of unloading,
as occurred with space flight, on MSC differentiation. The
cells underwent 7 days of MG. The researchers determined
that the 7 days of MG totally suppressed osteoblast formation
mediated by a Runx2 inhibition, indicating the need for
mechanical stimulation to maintain MSC differentiation in
favor of bone formation. Although these studies did not
involve diabetic conditions, we hypothesize that these lend
support to the potential for resistance training to alter cel-
lular differentiation in favor of improving bone quality in
diabetics.
4. Conclusions
4.1. Summary. Diabetes effects more than 346 million people
worldwide [2] and has substantial impact on the develop-
ment of a wide array of comorbidities, subsequently decreas-
ing quality of life, and life-expectancy [115]. T2DM has been
identified as a contributing factor to musculoskeletal dys-
function. In muscle tissue, dysfunction occurs with insulin
sensitivity [3], mitochondrial function [6], and an accumu-
lation of triglycerides [4,5]. Some [66]butnotall[18]
studies indicate that glycogen synthesis is improved by resis-
tance training in T2DM. Both mitochondrial function and
accumulation of lipid have only been examined to a limited
capacity in T2DM, and the limited research indicates a
minimal impact of resistance training on these areas of dys-
function.
Skeletal dysfunction consists of altered bone quality me-
diated by hyperglycemia [9], AGE [51,52], and lipid accu-
mulation [8,9,57]. Despite T2DM potentially increasing
BMD, evidence of elevated fracture risk indicates poor bone
quality. Bone quality is compromised as a result of many
factors. Diabetes appears to increase nonenzymatic collagen
cross-linking [51,54] and decrease osteogenic activity by
reducing osteoblast cell growth and differentiation [9],
while promoting adipocyte differentiation and subsequently
increasing the adiposity of bone [8,57]. Given the limited
amount of research done with respect to resistance training
in T2DM, while taking into consideration the related find-
ings presented previously, we have hypothesized that (1) the
impact caused by resistance training may improve bone qual-
ity, and (2) the improvements in glycemic control resulting
from resistance training may cause a positive shift in bone
cell formation (and a shift away from lipid formation).
Pharmacological methods are often employed to help
manage T2DM; however some T2DM pharmaceuticals com-
promise the health of other body systems. For example,
thiazolidinedione has been implicated to suppress bone
formation and increase the risk for fractures [116,117].
The consequences associated with pharmacological diabetes
management further warrant the need for nonpharmacolog-
ical interventions. Although lifestyle interventions, such as
exercise, may have an associated financial cost, as do phar-
maceuticals, exercise also has expansive health and quality of
life benefits. As such, we acknowledge that a comprehensive
lifestyle intervention will impose some financial demand on
the patient, and that the cost-effectiveness of lifestyle-related
therapy in comparison to pharmacological therapy needs
further investigation.
It is also important to recognize that the majority of the
studies reviewed employed supervised resistance training
programs. As such, the results presented are only applicable
clinically when resistance training is supervised, particularly
in light of findings by Dunstan et al. [118]thatdemonstrated
a reduced adherence and training volume and intensity when
patients with T2DM switched from supervised strength
training to home-based strength training.
4.2. Suggestions for Future Research. In an effort to more
clearly understand the potential benefits of resistance train-
ing on musculoskeletal dysfunction with T2DM, future re-
search should focus on increasing the use of T2DM subjects
in resistance training studies. In addition to better under-
standing volume/intensity thresholds (for practical reasons),
the mechanistic examination of the unique effects of resis-
tance training in this population is important.
(1) There are several devastating health-related conse-
quences of diabetes including osteoporosis which
can dramatically alter one’s quality of life and have
medical costs. Research is strongly needed to help
fully understand diabetic skeletal dysfunction and to
explore the potential benefits of resistance training to
combat the dysfunction.
(2) As specifically identified by this review, a mechanistic
understanding about the effects of resistance training
in T2DM on the following is needed: mitochondrial
quantity and size, and lipid accumulation in muscle,
as well as AGE, osteoblast differentiation, and lipid
accumulation in bone.
10 Journal of Nutrition and Metabolism
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