The essential role of exercise in the management of type 2 diabetes

Exercise is typically one of the first management strategies advised for patients newly
diagnosed with type 2 diabetes. Together with diet and behavior modification, exercise is an
essential component of all diabetes and obesity prevention and lifestyle intervention programs.
Exercise training, whether aerobic or resistance training or a combination, facilitates improved
glucose regulation. High-intensity interval training is also effective and has the added benefit of
being very time-efficient. While the efficacy, scalability, and affordability of exercise for the
prevention and management of type 2 diabetes are well established, sustainability of exercise
recommendations for patients remains elusive.
Type 2 diabetes has emerged as a major public health and economic burden of the 21st
century. Recent statistics from the Centers for Disease Control and Prevention suggest that
diabetes affects 29.1 million people in the United States, 1 and the International Diabetes
Federation estimates diabetes effects 366 million people worldwide. As these shocking numbers
continue to increase, the cost of caring for patients with diabetes is placing enormous strain on
the economies of the US and other countries. In order to manage and treat a disease on the scale
of diabetes, the approaches need to be efficacious, sustainable, scalable, and affordable. Of all
the treatment options available, including multiple new medications and bariatric surgery (for
patients who meet the criteria, discussed elsewhere in this supplement),3–5 exercise as part of a
lifestyle approach is a strategy that meets the majority of these criteria. The health benefits of
exercise have a long and storied history. Hippocrates, the father of scientific medicine, was the
first physician on record to recognize the value of exercise for a patient with “consumption.”
Today, exercise is recommended as one of the first management strategies for patients newly
diagnosed with type 2 diabetes and, together with diet and behavior modification, is a central
component of all type 2 diabetes and obesity prevention programs.
The evidence base for the efficacy, scalability, and affordability of exercise includes
multiple large randomized controlled trials; and these data were used to create the recently
updated exercise guidelines for the prevention and treatment of type 2 diabetes, published by the
American Diabetes Association (ADA), American College of Sports Medicine (ACSM), and
other national organizations.
Herein, we highlight the literature surrounding the metabolic effects and clinical
outcomes in patients with type 2 diabetes following exercise intervention, and point to future
directions for translational research in the field of exercise and diabetes.
It is known that adults who maintain a physically active lifestyle can reduce their risk of
developing impaired glucose tolerance, insulin resistance, and type 2 diabetes. It has also been
established that low cardiovascular fitness is a strong and independent predictor of all-cause
mortality in patients with type 2 diabetes.11,12 Indeed, patients with diabetes are 2 to 4 times
more likely than healthy individuals to suffer from cardiovascular disease, due to the metabolic
complexity and underlying comorbidities of type 2 diabetes including obesity, insulin resistance,
dyslipidemia, hyperglycemia, and hypertension. Additionally, elevated hemoglobin A1c
(HbA1c) levels are predictive of vascular complications in patients with diabetes, and regular
exercise has been shown to reduce HbA1c levels, both alone and in conjunction with dietary
intervention. In a meta-analysis of 9 randomized trials comprising 266 adults with type 2
diabetes, patients randomized to 20 weeks of regular exercise at 50% to 75% of their maximal
aerobic capacity (VO2max) demonstrated marked improvements in HbA1c and cardiorespiratory
fitness.11 Importantly, larger reductions in HbA1c were observed with more intense exercise,
reflecting greater improvements in blood glucose control with increasing exercise intensity. In
addition to greater energy expenditure, which aids in reversing obesity-associated type 2
diabetes, exercise also boosts insulin action through short-term effects, mainly via insulin-
independent glucose transport. For example, our laboratory and others have shown that as little
as 7 days of vigorous aerobic exercise training in adults with type 2 diabetes results in improved
glycemic control, without any effect on body weight.15,16 Specifically, we observed decreased
fasting plasma insulin, a 45% increase in insulin-stimulated glucose disposal, and suppressed
hepatic glucose production (HGP) during carefully controlled euglycemic hyperinsulinemic
clamps. Although the metabolic benefits of exercise are striking, the effects are short-lived and
begin to fade within 48 to 96 hours.17 Therefore, an ongoing exercise program is required to
maintain the favorable metabolic milieu that can be derived through exercise.
EXERCISE MODALITIES
Aerobic exercise
The vast majority of the literature about the effects of exercise on glycemic parameters in
type 2 diabetes has been centered on interventions involving aerobic exercise. Aerobic exercise
consists of continuous, rhythmic movement of large muscle groups, such as in walking, jogging,
and cycling. The most recent ADA guidelines state that individual sessions of aerobic activity
should ideally last at least 30 minutes per day and be performed 3 to 7 days of the week (Table
1).18 Moderate to vigorous (65%–90% of maximum heart and rate) aerobic exercise training
improves VO2max cardiac output, which are associated with substantially reduced
cardiovascular and overall mortality risk in patients with type 2 diabetes.19

TABLE 1
American Diabetes Association recommendations for exercise in type 2 diabetes
Aerobic exercise: At least 150 minutes/week of moderate to vigorous exercise
Spread over 3 to 7 days/week, with no more than 2 consecutive days between exercise bouts
Daily exercise is suggested to maximize insulin action
Shorter durations (at least 75 minutes/week) of vigorous-intensity or interval training may be
sufficient for younger and more physically fit patients
May be performed continuously, or as high-intensity interval training
Resistance exercise: Progressive moderate to vigorous resistance training should be completed 2
to 3 times/week on nonconsecutive days.
At least 8 to 10 exercises, with completion of 1 to 3 sets of 10 to 15 repetitions
Flexibility and balance training are recommended 2 to 3 times/week for older adults
Participation in supervised training programs is recommended to maximize health benefits of
exercise in type 2 diabetes.
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Notably, aerobic exercise is a well-established way to improve HbA1c, and strong evidence
exists with regard to the effects of aerobic activity on weight loss and the enhanced regulation of
lipid and lipoprotein metabolism.8 For example, in a 2007 report, 6 months of aerobic exercise
training in 60 adults with type 2 diabetes led to reductions in HbA1c (−0.63% ± 0.41 vs 0.31% ±
0.10, P < .001), fasting plasma glucose (−18.6 mg/dL ± 4.4 vs 4.28 mg/dL ± 2.57, P < .001),
insulin resistance (−1.52 ± 0.6 vs 0.56 ± 0.44, P = .023; as measured by homeostatic model
assessment), fasting insulin (−2.91 mU/L ± 0.4 vs 0.94 mU/L ± 0.21, P = .031), and systolic
blood pressure (−6.9 mm Hg ± 5.19 vs 1.22 mm Hg ± 1.09, P = .010) compared with the control
group.
Furthermore, meta-analyses reviewing the benefits of aerobic activity for patients with
type 2 diabetes have repeatedly confirmed that compared with patients in sedentary control
groups, aerobic exercise improves glycemic control, insulin sensitivity, oxidative capacity, and
important related metabolic parameters.11 Taken together, there is ample evidence that aerobic
exercise is a tried-and-true exercise modality for managing and preventing type 2 diabetes.
Resistance training
During the last 2 decades, resistance training has gained considerable recognition as a viable
exercise training option for patients with type 2 diabetes. Synonymous with strength training,
resistance exercise involves movements utilizing free weights, weight machines, body weight
exercises, or elastic resistance bands. Primary outcomes in studies evaluating the effects of
resistance training in type 2 diabetes have found improvements that range from 10% to 15% in
strength, bone mineral density, blood pressure, lipid profiles, cardiovascular health, insulin
sensitivity, and muscle mass.18,20 Furthermore, because of the increased prevalence of type 2
diabetes with aging, coupled with age-related decline in muscle mass, known as sarcopenia,21
resistance training can provide additional health benefits in older adults.
Dunstan et al 21 reported a threefold greater reduction in HbA1c in patients with type 2
diabetes ages 60 to 80 compared with nonexercising patients in a control group. They also noted
an increase in lean body mass in the resistance-training group, while those in the nonexercising
control group lost lean mass after 6 months. In a shorter, 8-week circuit weight training study
performed by the same research group, patients with type 2 diabetes had improved glucose and
insulin responses during an oral glucose tolerance test.
These findings support the use of resistance training as part of a diabetes management
plan. In addition, key opinion leaders advocate that the resistance-training-induced increase in
skeletal muscle mass and the associated reductions in HbA1c may indicate that skeletal muscle is
a “sink” for glucose; thus, the improved glycemic control in response to resistance training may
be at least in part the result of enhanced muscle glycogen storage.
Based on increasing evidence supporting the role of resistance training in glycemic
control, the ADA and ACSM recently updated their exercise guidelines for treatment and
prevention of type 2 diabetes to include resistance training.

Combining aerobic and resistance training

The combination of aerobic and resistance training, as recommended by current ADA guidelines,
may be the most effective exercise modality for controlling glucose and lipids in type 2 diabetes.
Cuff et al 24 evaluated whether a combined training program could improve insulin sensitivity
beyond that of aerobic exercise alone in 28 postmenopausal women with type 2 diabetes. Indeed,
16 weeks of combined training led to significantly increased insulin-mediated glucose uptake
compared with a group performing only aerobic exercise, reflecting greater insulin sensitivity.

Balducci et al25 demonstrated that combined aerobic and resistance training markedly improved
HbA1c (from 8.31% ± 1.73 to 7.1% ± 1.16, P < .001) compared with the control group and
globally improved risk factors for cardiovascular disease, supporting the notion that combined
training for patients with type 2 diabetes may have additive benefits.
Of note, Snowling and Hopkins performed a head-to-head meta-analysis of 27 controlled
trials on the metabolic effects of aerobic, resistance, and combination training in a total of 1,003
patients with diabetes. All 3 exercise modes provided favorable effects on HbA1c, fasting and
postprandial glucose levels, insulin sensitivity, and fasting insulin levels, and the differences
between exercise modalities were trivial. In contrast, Schwingshackl and colleagues performed a
systematic review of 14 randomized controlled trials for the same 3 exercise modalities in 915
adults with diabetes and reported that combined training produced a significantly greater
reduction in HbA1c than aerobic or resistance training alone.
Future research is necessary to quantify the additive and synergistic clinical benefits of
combined exercise compared with aerobic or resistance training regimens alone; however,
evidence suggests that combination exercise may be the optimal strategy for managing diabetes.

High-intensity interval training

High-intensity interval training (HIIT) has emerged as one of the fastest growing exercise
programs in recent years. HIIT consists of 4 to 6 repeated, short (30-second) bouts of maximal
effort interspersed with brief periods (30 to 60 seconds) of rest or active recovery. Exercise is
typically performed on a stationary bike, and a single session lasts about 10 minutes.
HIIT increases skeletal muscle oxidative capacity, glycemic control, and insulin
sensitivity in adults with type 2 diabetes.28,29 A recent meta-analysis that quantified the effects
of HIIT programs on glucose regulation and insulin resistance reported superior effects for HIIT
compared with aerobic training or no exercise as a control.28 Specifically, in 50 trials with
interventions lasting at least 2 weeks, participants in HIIT groups had a 0.19% decrease in
HbA1c and a 1.3-kg decrease in body weight compared with control groups.
Alternative high-intensity exercise programs have also emerged in recent years such as
CrossFit, which we evaluated in a group of 12 patients with type 2 diabetes. Our proof-of-
concept study found that a 6-week CrossFit program reduced body fat, diastolic blood pressure,
lipids, and metabolic syndrome Z-score, and increased insulin sensitivity to glucose, basal fat
oxidation, VO2max, and high-molecular-weight adiponectin.30 HIIT appears to be another
effective way to improve metabolic health; and for patients with type 2 diabetes who can tolerate
HIIT, it may be a time-efficient, alternative approach to continuous aerobic exercise.

BENEFITS OF EXERCISE FOR SPECIFIC METABOLIC TISSUES

Within 5 years of the discovery of insulin by Banting and Best in 1921, the first report of
exercise-induced improvements in insulin action was published, though the specific cellular and
molecular mechanisms that underpin these effects remain unknown. There is general agreement
that the acute or short-term exercise effects are the result of insulin-dependent and insulin-
independent mechanisms, while longer-term effects also involve “organ crosstalk,” such as from
skeletal muscle to adipose tissue, the liver, and the pancreas, all of which mediate favorable
systemic effects on HbA1c, blood glucose levels, blood pressure, and serum lipid profiles

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FIGURE 1
Tissue-specific metabolic effects of exercise in patients with type 2 diabetes.

Skeletal muscle
Following a meal, skeletal muscle is the primary site for glucose disposal and uptake. Peripheral
insulin resistance originating in skeletal muscle is a major driver for the development and
progression of type 2 diabetes.
Exercise enhances skeletal muscle glucose uptake using both insulin-dependent and
insulin-independent mechanisms, and regular exercise results in sustained improvements in
insulin sensitivity and glucose disposal.
Of note, acute bouts of exercise can also temporarily enhance glucose uptake by the
skeletal muscle up to fivefold via increased (insulin-independent) glucose transport.33 As this
transient effect fades, it is replaced by increased insulin sensitivity, and over time, these 2
adaptations to exercise result in improvements in both the insulin responsiveness and insulin
sensitivity of skeletal muscle. The fuel-sensing enzyme adenosine monophosphate-activated
protein kinase (AMPK) is the major insulin-independent regulator of glucose uptake, and its
activation in skeletal muscle by exercise induces glucose transport, lipid and protein synthesis,
and nutrient metabolism.35 AMPK remains transiently activated after exercise and regulates
several downstream targets involved in mitochondrial biogenesis and function and oxidative
capacity.
In this regard, aerobic training has been shown to increase skeletal muscle mitochondrial
content and oxidative enzymes, resulting in dramatic improvements in glucose and fatty acid
oxidation10 and increased expression of proteins involved in insulin signaling.

Adipose tissue
Exercise confers numerous positive effects in adipose tissue, namely, reduced fat mass, enhanced
insulin sensitivity, and decreased inflammation. Chronic low-grade inflammation has been
integrally linked to type 2 diabetes and increases the risk of cardiovascular disease.
Several inflammatory adipokines have emerged as novel predictors for the development
of atherosclerosis, and fat-cell enlargement from excessive caloric intake leads to increased
production of pro-inflammatory cytokines, altered adipokine secretion, increased circulating
fatty acids, and lipotoxicity concomitant with insulin resistance.
It has been suggested that exercise may suppress cytokine production through reduced
inflammatory cell infiltration and improved adipocyte function. Levels of the key pro-
inflammatory marker C-reactive protein is markedly reduced by exercise and normalization of
adipokine signaling and related cytokine secretion has been validated for multiple exercise
modalities.

Moreover, Ibañez et al demonstrated that in addition to significant improvements in insulin

sensitivity, resistance exercise training reduced visceral and subcutaneous fat mass in patients
with type 2 diabetes.

Liver
The liver regulates fasting glucose through gluconeogenesis and glycogen storage. The liver is
also the primary site of action for pancreatic hormones during the transition from pre- to
postprandial states. As with skeletal muscle and adipose tissue, insulin resistance is also present
within the liver in patients with type 2 diabetes. Specifically, impaired suppression of HGP by
insulin is a hallmark of type 2 diabetes, leading to sustained hyperglycemia.
Approaches using fasting measures of glucose and insulin do not distinguish between peripheral
and hepatic insulin resistance. Instead, hepatic insulin sensitivity and HGP are best assessed by
the hyperinsulinemic-euglycemic clamp technique, along with isotopic glucose tracers.
Although more elaborate, magnetic resonance spectroscopy may also be used to assess
intrahepatic lipid content, as its accumulation has been shown to drive hepatic insulin resistance.
Indirect measures of hepatic dysfunction may be made from increased levels of the circulating
hepatic enzymes alkaline phosphatase, alanine transaminase, and aspartate transaminase.
From an exercise perspective, we have shown that 7 days of aerobic training, in the
absence of weight loss, improves hepatic insulin sensitivity. It has also been shown that hepatic
AMPK is stimulated during exercise, suggesting that an AMPK-induced adaptive response to
exercise may facilitate improved suppression of HGP. We have also shown that a longer 12-
week aerobic exercise intervention reduces hepatic insulin resistance, with and without restricted
caloric intake.48 Further, HGP correlated with reduced visceral fat, suggesting that this fat depot
may play an important mechanistic role in improved hepatic function.

Pancreas
Insulin resistance in adipose tissue, muscle, or the liver places greater demand on insulin
secretion from pancreatic beta cells. For many, this hypersecretory state is unsustainable, and the
subsequent loss of beta-cell function marks the onset of type 2 diabetes. Fasting plasma glucose,
insulin, and glucagon levels are generally poor indicators of beta-cell function.
Clinical research studies typically use the oral glucose tolerance test and hyperglycemic
clamp technique to more accurately measure the dynamic regulation of glucose homeostasis by
the pancreas.50 However, few studies have examined the effects of exercise on beta-cell function
in type 2 diabetes. Dela and colleagues showed that 3 months of aerobic training improved beta-
cell function in type 2 diabetes, but only in those who had some residual function and were less
severely diabetic. We have shown that a 12-week aerobic exercise intervention improves beta-
cell function in older obese adults and in patients with type 2 diabetes. We have also found that
improvements in glycemic control that occur with exercise are better predicted by changes in
insulin secretion as opposed to peripheral insulin sensitivity.54 It has also been shown that a
relatively short (8-week) HIIT program improved beta-cell function in patients with type 2
diabetes.55 And we recently found that a 6-week CrossFit training program improved beta-cell
function in adults with type 2 diabetes.
SUMMARY, CONCLUSIONS, AND FUTURE DIRECTIONS
Regular exercise produces health benefits beyond improvements in cardiovascular fitness. These
include enhanced glycemic control, insulin signaling, and blood lipids, as well as reduced low-
grade inflammation, improved vascular function, and weight loss.
Both aerobic and resistance training programs promote healthier skeletal muscle, adipose
tissue, liver, and pancreatic function.18 Greater whole-body insulin sensitivity is seen
immediately after exercise and persists for up to 96 hours. While a discrete bout of exercise
provides substantial metabolic benefits in diabetic cohorts, maintenance of glucose control and
insulin sensitivity are maximized by physiologic adaptations that only occur with weeks, months,
and years of exercise training. Exercise intensity,11 volume, and frequency are associated with
reductions in HbA1c; however, a consensus has not been reached on whether one is a better
determinant than the other. The most important consideration when recommending exercise to
patients with type 2 diabetes is that the intensity and volume be optimized for the greatest
metabolic benefit while avoiding injury or cardiovascular risk. In general, the risk of exercise-
induced adverse events is low, even in adults with type 2 diabetes, and there is no current
evidence that screening procedures beyond usual diabetes care are needed to safely prescribe
exercise in asymptomatic patients in this population.
Future clinical research in this area will provide a broader appreciation for the
interactions (positive and negative) between exercise and diabetes medications, the synergy
between exercise and bariatric surgery, and the potential to use exercise to reduce the health
burden of diabetes complications, including nephropathy, retinopathy, neuropathy, and
peripheral arterial disease. Moreover, basic research will likely identify the detailed molecular
defects that contribute to diabetes in insulin-targeted tissues. The emerging science surrounding
cytokines, adipokines, myokines, and, most recently, exerkines is likely to deepen our
understanding of the mechanistic links between exercise and diabetes management.
Finally, although we have ample evidence that exercise is an effective, scalable, and
affordable approach to prevent and manage type 2 diabetes, we still need to overcome the
challenge of discovering how to make exercise sustainable for patients.

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