American Journal of Medicine Open 9 (2023) 100031

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American Journal of Medicine Open

journal homepage: www.elsevier.com/locate/ajmo

Clinical Research Study

The importance of exercise for glycemic control in type 2 diabetes ✩

U.S. Afsheen Syeda a,1, Daniel Battillo b,1, Aayush Visaria c, Steven K. Malin b,c,d,e,∗
a
Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, United States
b
Department of Kinesiology and Health, Rutgers University, New Brunswick, NJ, United States
c
Center for Pharmacoepidemiology and Treatment Sciences, Rutgers Institute for Health, Health Care Policy, and Aging Research, New Brunswick, NJ, United States
d
New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, NJ, United States
e
Institute of Translational Medicine and Science, Rutgers University, New Brunswick, NJ, United States

a r t i c l e i n f o a b s t r a c t

Keywords: Exercise is a first-line therapy recommended for patients with type 2 diabetes (T2D). Although moderate to
Physical activity vigorous exercise (e.g. 150 min/wk) is often advised alongside diet and/or behavior modification, exercise is an
Glucose tolerance independent treatment that can prevent, delay or reverse T2D. Habitual exercise, consisting of aerobic, resistance
Insulin resistance
or their combination, fosters improved short- and long-term glycemic control. Recent work also shows high-
Obesity
intensity interval training is successful at lowering blood glucose, as is breaking up sedentary behavior with
Prediabetes
short-bouts of light to vigorous movement (e.g. up to 3min). Interestingly, performing afternoon compared with
morning as well as post-meal versus pre-meal exercise may yield slightly better glycemic benefit. Despite these
efficacious benefits of exercise for T2D care, optimal exercise recommendations remain unclear when considering,
dietary, medication, and/or other behaviors.

Introduction specific intent on gains in aerobic and/or muscular fitness. Most recom-
mendations by the American College of Sports Medicine (ACSM) and/or
Approximately 10.4% adults in the U.S. have type 2 diabetes (T2D), American Diabetes Association (ADA) for physical activity/exercise fo-
3.8% of whom are undiagnosed. In addition, nearly 45.8% of adults cus on frequency, intensity, and modality to favorably impact glycemic
are also categorized as having prediabetes, thereby placing major fi- control.5 , 6 Included within modality are considerations including vol-
nancial strains on the healthcare system.1 T2D (and prediabetes) is ume or the duration/repetitions of the exercise being completed. Addi-
mainly characterized by reduced whole-body insulin sensitivity and 𝛽- tionally, aerobic exercise intensity is primarily determined using a per-
cell dysfunction. Low insulin sensitivity initially induced by overnutr- centage of one’s maximal heart rate (%HRmax) and maximal oxygen
tion and/or physcil activity, for instance, promotes hypersecretion of consumption and utilization (%VO2 max).5 , 6 It is also worth mention-
insulin from pancreatic 𝛽-cells to regulate circulating glucose. When ing that rating of perceived exertion (RPE) is a practical tool people can
insulin secretion is no longer able to compensate for the prevailing use to estimate exercise intensity if they are unable to use heart rate or
low insulin sensitivity, blood glucose levels worsen towards predia- have maximal fitness tests conducted.5 , 6 Typically RPE correlates well
betes and T2D status. While the exact cause of T2D remains an area with heart rate (e.g. RPE of 12 would theoretically relate to a HR of 120
of intense research, excess body weight serves as a leading risk fac- bpm). Herein, we compare aerobic, resistance, and concurrent exercise,
tor. Indeed, excess lipid accumulation surrounding vital organs in the defined as completing aerobic and resistance exercise in combination,
abdomen (i.e. visceral fat), as well as within liver and muscle cells, as modalities to affect insulin sensitivity and cardiometabolic health.
are thought to impair insulin signaling and induce insulin resistance.2 We also discuss whether intensity or timing of exercise throughout the
Given that more than 42% of American adults have obesity,3 it is no day matters to yield optimal effects on glucose control. In turn, we dis-
surprise that identification of optimal treatment plans to combat obe- cuss high intensity interval versus continuous exercise for glycemia fol-
sity related insulin resistance is warranted to manage blood glucose.4 lowed by the timing at which exercise is performed. Recognizing that
One such treatment option is physical activity and/or exercise. Physical some people may find it challenging to dedicate time to exercise, we
activity is broadly defined as any bodily movement that is above resting also review breaks in sedentary behavior as a strategy to manage blood
conditions, whereas exercise is planned or structured movement with glucose. Further, since weight loss can be quite variable in response to

✩
Funding: SKM is supported by National Institutes of Health RO1-HL130296.
∗
Corresponding author at: Department of Kinesiology & Health, 70 Lipman Dr, Loree Gymnasium, New Brunswick, NJ 08091, United States.
E-mail address: [email protected] (S.K. Malin).
1
Shared first author responsibility.

https://doi.org/10.1016/j.ajmo.2023.100031
Received 28 April 2022; Received in revised form 1 December 2022; Accepted 10 January 2023
Available online 18 January 2023
2667-0364/© 2023 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
U.S.A. Syeda, D. Battillo, A. Visaria et al. American Journal of Medicine Open 9 (2023) 100031

exercise, we discuss current thoughts on weight loss variability, in ad- intensities: moderate-resistance-moderate-endurance, high-resistance-
dition to exercise benefits independent of weight loss, to help highlight moderate-endurance, and moderate-resistance-high-endurance. Follow-
benefits for people with T2D. Lastly, given many suggest individuals ing a 3-wk supervised program and continuing a self-management
progress from obesity with normoglyceemia to prediabetes to T2D, it compliance protocol for the remaining 11 months, participants in the
is understood that the pathology of insulin resistance is a continuum.7 high resistance exercise group lost the greatest amount of visceral fat
As such, the utlity of exercise in prediabetes and T2D will be discussed throughout the year-long combination program. This is consistent with
throughout. Together, future direction for the field and practical con- recent evidence from the DPP that physical activity, independent of
siderations is provided. weight loss, is an independent predictor in prevention of T2D in the orig-
inal cohort.20 Nearly 2 decades since the DPP was originally published,
Type 2 diabetes prevention and management this lifestyle program is now widely implanted in the U.S., with 1-on-1
counseling sessions both in-person and virtually. Many insurance pro-
It comes as no surprise that ACSM and ADA recommend comprehen- grams (including Medicaid and Medicare) cover such treatment. Still, it
sive lifestyle programs that increase physical activity in effort to pre- is worth noting that while weight loss is a significant predictor of T2D
vent glucose levels from detoriating as well as manage glycemia within prevention, the DPP standards have been updated. In fact, the goals
a given range.8 , 9 Indeed, lifestyle recommendations for individuals at of the program look to emphasize more the importance of physical ac-
risk for T2D often target weight loss of ∼ 5-10% and an increase in phys- tivity, as standard advice was originally focused on losing 5-7% body
ical activity to either 150 min/week or more of moderate intensity or 75 weight to elicit favorable HbA1c levels. Now, the goal of 4% weight loss
min/week of vigorous intensity aerobic exercise. Lifestyle interventions with 150 min/wk of physical activity, along with reduction in HbA1c
consisting of increased physical activity (i.e. aerobic and/or resistance of 0.2%, has been incorporated.19 Taken together, exercise favors glu-
exercise) and low-fat diet promotes ∼5 kg weight loss for 2 years or be- coregulatory effects via both weight-loss and weight loss-independent
yond and lowers T2D risk by ∼ 45%.10 Interestingly, there appears to be mechanisms18 and highlights exercise for glycemic management
a dose-response relationship with weight loss and glycemic control as (Fig. 1).
reflected by HbA1c, a measure of average blood glucose levels over an
8-12-week period. Indeed, a 2-10% reduction in body weight between Type 2 diabetes reversal
1-4 years is paralleled by decreases in HbA1c of 0.2-1.0%.6 , 10 This im-
provement in glycemic control is clinically meaningful as lifestyle pre- Classic work from nearly 4 decades ago highlight that 12 months of
scriptions of >5% weight loss via reductions in total fat under 30% high intensity exercise (about 85% HRmax 5 d/wk.) is capable of re-
of total calorie intake (with < 10% coming from saturated fat), ele- versing and normalizing blood glucose in people with prediabetes and
vation in fiber consumption (i.e. 15g per 1000 kcal) and increases in T2D.21 We too have shown that as little as 2 weeks of high intensity in-
physical activity (30 min/d) lowered the cumulative incidence of di- terval or moderate continuous exercise is able to reverse prediabetes in
abetes by 58% in people with prediabetes, compared with controls.11 nearly 40% of participants.22 Nevertheless, it should be acknowledged
In the landmark U.S. Diabetes Prevention Program (DPP),12 new cases that not all people with hyperglycemia may respond favorably to exer-
of T2D were reduced by 58% in people with prediabetes. This reduc- cise. In fact, some studies suggest upwards of 10-30% of people with T2D
tion was achieved using an intervention based on 150 min/wk of phys- may not improve fasting glucose and/or HbA1c following lifestyle ther-
ical activity and weight loss of approximately 7%,13 although subjects apy.23 This is consistent with recent work showing no glycemic benefit
who lost the most weight and met physical activity/diet targets had to lifestyle therapy in people with T2D versus control, although lifestyle
> 90% risk reductions of diabetes. Subsequently, it seems reasonable did reduce glucose medication numbers to a significant extent (about
to ask whether weight loss is best achieved by activity and/or diet, 75% vs. 47% discontinuation) in relation to greater exercise volume en-
provided its importance in promoting glycemic control. No random- gagement.24 This later work is of importance because it is consistent
ized controlled trials to date, though, have directly compared caloric with work comparing the DPP program with the optimal intensity of
restriction to exercise versus caloric restriction plus exercise in peo- exercise for preventing progression to T2D.25 In short, these later re-
ple with T2D. However, Weiss et al.14 observed that caloric restric- sults showcased that performing moderate intensity exercise of high
tion and exercise training in combination improved glucose tolerance volume (50% VO2 peak for about 287 min/wk) was most effective at
and increased insulin sensitivity, using a 2-hr frequently sampled oral improving glucose tolerance with only 2 kg of fat loss, when compared
glucose tolerance test (OGTT), more than caloric restriction or exercise with high intensity and volume (75% VO2 peak for about 195 min/wk)
alone, among overweight sedentary adults. Conversely, post-prandial or low volume moderate intensity (50% VO2 peak for 181 min/wk).
GLP-1 decreased in the caloric restriction group only, suggesting mech- While intensity effects may be somewhat unclear (see below), current
anisms affecting glucose tolerance may be different based on how weight work highlights higher volumes appear related to greater glucose reg-
loss is achieved. Interestingly, we identified similar observations to this ulation26-30 and cardiometabolic health.31 Indeed, a meta-analysis con-
in prior work after only 2 weeks of exercise, and this was correlated firmed that engaging in 5-7 hr/wk of leisure-time physical activity or
with gains in pancreatic 𝛽-cell function and GLP-1 increases,15 although moderate to vigorous exercise was inversely related with risk of devel-
improvements in circulating adipose-derived inflammation were simi- oping T2D.22 , 32 Furthermore, the Look AHEAD (Action for Health in Di-
lar in these women with obesity.16 In either case, adding exercise to abetes) trial,33 the longest running interventional study with median of
caloric restriction will yield gains in aerobic fitness, which benefits 9.6 years, tracked the development of cardiovascular disease among pa-
quality of life. Additionally, adding exercise to caloric restriction im- tients with T2D. Subjects were randomized to either Intensive Lifestyle
proved weight regulation, such as high intensity interval exercise (60 Intervention (ILI) including calorie restriction and increased physical
min/day alternating 3 min at 90 and 50% peak HR), suppressed acylated activity or a control group that received Diabetes Support and Educa-
ghrelin and increased fullness during caloric restriction, compared with tion (DSE). Under the monitoring of a registered dietitian, psychologist,
caloric restriction only,17 thereby favoring appetite suppression and in- and exercise physiologist, the intervention group ate a low calorie diet
creased satiety. This observation is consistent with exercise decreasing (LCD) between 1200-1500kcal/day, with <30% kcal from fat, setting
visceral fat during caloric restriction. Indeed, in the REverse metabolic a goal of 175 min of unsupervised exercise per week. By year 1, the
SyndrOme by Lifestyle and Various Exercises (RESOLVE) trial, middle- ILI participants achieved 20.4% increase in their fitness levels, com-
aged to older adults with obesity underwent different modalities of pared to the 5% in the DSE group. Throughout the trial period, the ILI
high-volume exercise (15-20 hr/wk) combined with a high protein, group accomplished 3 to 6 times more remission of T2D than the control
caloric-deficit diet to determine effects on visceral fat. Participants group among participants that were relatively healthy at baseline with a
between ages 50-70 yr were divided into three groups with varying lower HbA1c and had T2D for a shorter duration. Interestingly, though,

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U.S.A. Syeda, D. Battillo, A. Visaria et al. American Journal of Medicine Open 9 (2023) 100031

Fig. 1. Benefit of exercise on multiple bodily

tissues for blood glucose control.

there was no significant improvement in rate of CVD events between portantly, exercise further lowers subsequent risk of developing hypo-
the ILI and DSE groups. Nonetheless, the Diabetes Intervention Accen- glycemia among T2D patients who are non-insulin users.81 Thus, ac-
tuating Diet and Enhancing Metabolism (DIADEM-I)33 was a recent diet cumulating bouts of exercise will not only favor insulin sensitivity, but
and physical activity-based, randomized controlled trial among adults also contribute to gains in aerobic fitness for reducing CVD and all-cause
(mean age 42.1 yrs) with T2D in the Middle East and North African re- mortality in T2D, independent of body weight.39
gions. Participants were randomized into a control group on diabetes Convincing evidence demonstrates that exercise can improve
care or a lifestyle intervention group with total diet replacement (low- glycemic control. For instance, 6-months of aerobic training among
kcal/low glycemic index) and physical activity recommendations (target overweight individuals with T2D, comprised of 4 sessions/wk at 45-
10k steps/d for 150 min/wk), for a duration of 12 weeks. At the end of 60 min/session at 50-75% VO2 peak, reduced fasting plasma glucose (-
1 year follow-up, there was sustained weight loss, with 61% no longer 18.58 mg/dl) and insulin levels (-2.91 mU/l) measured, when compared
having T2D and 33% of participants going into remission. Weight-loss with a non-exercise control group.40 Further, aerobic exercise consist-
induced management of T2D in the lifestyle intervention group was also ing of 60 min at ∼75% VO2 peak intensity for 4-5 d/wk over 12-16 wk
associated with improved CVD health and quality of life.34 These find- reduced fasting blood glucose (-6.3 mg/dl) and increased insulin sen-
ings together highlight that T2D is not inevitable and can be delayed, sitivity in those with impaired glucose tolerance or T2D.34 These find-
prevented, and reversed by exercise. ings are clinically relevant as epidemiological studies report a 21% re-
duction in diabetes-related death following a 1% decrease in HbA1c.41
Aerobic compared with resistance exercise for glycemic control Moreover, a meta-analysis of 504 participants across 12 trials of aerobic
and 2 trials of resistance training demonstrated a significant decrease in
Most work surrounding exercise on glycemic control has focused on post-intervention HbA1c in the exercise groups by 0.66%, compared to
aerobic exercise in people with prediabetes or T2D. Aerobic exercise is the control group, independent of weight loss.42 Interestingly, recent
rhythmic in nature, with large muscle groups acting to support walking interest and advice on using continuous glucose monitoring (CGM) has
jogging, running, and cycling. Aerobic training increases insulin sensi- grown in the diabetes community, in effort to provide a more accurate
tivity and vascular function among other factors, such as aerobic fitness insight to acute changes in glycemia within individuals. A recent meta-
and reductions in body fat.6 ACSM and ADA guidelines recommend at analysis of 11 aerobic and resistance exercise interventions conveyed
least 150 mins/wk of moderate-to-vigorous intensity aerobic activity significantly decreased average glucose concentrations (-14.4 mg/dl) as
spread out over at least 3 d/wk, with no more than 2 consecutive days assessed by CGM.43 Importantly, this meta-analysis highlights that peo-
without activity (Table 1). This frequency recommendation is mainly ple spend on average approximately 129 minutes less in hyperglycemic
due to beneficial effects of aerobic exercise on insulin sensitivity last- ranges (i.e. >180 mg/dl), thereby reducing risk of complications. This
ing up to about 48 hr.35 , 36 Indeed, skeletal muscle plays a paramount aligns with findings that aerobic exercise also protects against CVD
role in glycemic control, by virtue of exercise-induced blood glucose risk, beyond glycemic improvements. A meta-analysis with 1,003 peo-
uptake and augmented insulin sensitivity, following an exercise bout. ple with T2D demonstrated that aerobic exercise training interventions
There are two primary pathways that promote skeletal muscle glucose lowered systolic blood pressure (-5.6 mmHg), diastolic blood pressure (-
uptake, insulin independent and insulin dependent.37 During bouts of 5.5 mmHg), triglyceride levels (-0.3 mmol/l), and total cholesterol (-0.3
aerobic exercise, skeletal muscle promotes GLUT-4, a key transporter, mmol/l).44
to translocate to the cell membrane, to increase glucose uptake indepen- Discerning the health benefits of resistance compared with aerobic
dent of insulin. Thereafter, these effects of exercise wane after about 3-6 exercise is useful for providing training diversity and augmenting exer-
hr, such that the muscle is now sensitized to insulin. This insulin sen- cise adherence. Given T2D is an independent risk factor for low muscu-
sitizing effect can last upwards of about 48 hr,35 , 36 based on intensity, lar strength and accelerated decline in muscle mass/functional status,
diet, and other factors (e.g. sleep, etc.). As such, single bouts of exer- resistance exercise could be a viable strategy to combat risk in falls and
cise are known to favorably impact insulin sensitivity and favor blood dissuade sarcopenic (age-associated decline in muscle mass) losses.45
glucose control, prior to weight loss or gains in aerobic fitness.38 Im- Resistance or strength training specifically involves the contraction of

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U.S.A. Syeda, D. Battillo, A. Visaria et al. American Journal of Medicine Open 9 (2023) 100031

Table 1
Exercise training recommendations for adults with type 2 diabetes.

Type of Training Type Intensity Frequency Duration

Aerobic - Rhythmic activities using - Moderate intensity exercise - 3-7 d/wk, with no more than - Minimum of 150 min/wk of
large muscle groups, like at 55-74% HRmax 2 consecutive days between moderate activity or 75-150
walking, jogging, and cycling - RPE 12-13 (somewhat hard) exercise bouts. Daily exercise min/wk of vigorous activity,
- Vigorous intensity exercise at is suggested to maximize or an equivalent combination
75-95% HRmax insulin action of the two
- RPE 14-16 (hard to very
hard)

Resistance - Contraction of muscle - For moderate intensity, - 2-3 nonconsecutive d/wk - 10-15 repetitions per set with
against an external force repetitions of an exercise at a 1-3 sets of each exercise.
using free weights, weight weight that can be repeated 8-10 exercises involving the
machines, body weight, or no more than 15 times. For major muscle groups in total
elastic resistance bands vigorous intensity,
repetitions of an exercise at a
weight that can be repeated
no more than 6-8 times

High Intensity Interval - Alternating vigorous - Vigorous intensity (75-95% - 3 d/wk for vigorous aerobic - 10 seconds to 4 min of
Training (HIIT) intensity exercise (aerobic or HRmax) exercise, followed training, with not more than vigorous intensity exercise,
strength training) with by active or passive recovery 2 consecutive days between with 12 seconds to 5 min of
recovery stages (30-60% HRmax) bouts active or passive recovery
- 2-3 nonconsecutive d/wk for
resistance training

Breaks in sedentary - Walking or simple resistance - Light to moderate intensity - Every 30 min for 8 hr, given - Replace sitting time with
behavior activities (half-squats, calf exercise at 45-55% HRmax the increased risk of standing time (2.5 hr/d)
raises, gluteal contractions - RPE 10-11 (very light to sedentary behavior beyond 8 - Light-intensity walking (2.2
and knee raises), or standing fairly light) hr/d hr/d), in 3-min segments
time in lieu of sitting time every 30 min

Note: Rating of perceived exertion (RPE) is a practical tool people can use to estimate exercise intensity. While not considered as accurate as using physiologic
markers (e.g. heart rate), RPE typically correlates with heart rate (e.g. RPE of 12 would theoretically relate to a HR of 120 bpm). Thus, it is an acceptable tool to
use.

muscle against an external force and includes using free weights, weight Given that the mechanisms by which aerobic and strength train-
machines, body weight, or elastic resistance bands. ACSM and ADA rec- ing may reduce HbA1c differ, combining training programs may yield
ommend resistance training at least 2-3 nonconsecutive d/wk with mod- greater benefit. A combined aerobic resistance training regimen (30 min
erate to vigorous training as determined by the number of repetitions aerobic at 40-80% HRR, plus 30 min resistance training at 40-60% 1-RM
an individual is doing per set (Table 1). If one can do a higher num- for 6 exercises of 12 reps) decreased fasting blood glucose (-36 mg/dl),
ber of repetitions at a given weight – closer to 15 reps at a weight that triglycerides (-106 mg/dl), and significantly increased fat free mass
can be repeated no more than 15 times – this is moderate exercise. Vig- (+0.4 kg).50 A meta-analysis of 915 participants across 14 trials com-
orous exercise follows the same principle around 6-8 reps. ACSM and pared the glycemic benefits across aerobic, resistance, and concurrent
ADA state that starting at moderate training involving 10-15 reps/set training, through reductions in HbA1c. While both modalities conveyed
and increasing weight only when the target number of reps can be com- reductions in HbA1c, concurrent training saw the greatest reduction in
pleted without reaching fatigue-induce failure is best practice. Vigorous HbA1c (-0.17%), fasting glucose (-35.82 mg/dl), and triglycerides (-0.28
exercise may be performed once technique and confidence in movement mmol/l).51 Together, this evidence supports the notion that concurrent
patterns occur.6 training may be the most efficacious modality to improve glycemic con-
Resistance training conveys potent benefits to glycemic control and trol and blood lipids. The Health Benefits of Aerobic and Resistance
provides additional benefits to muscular strength, bone density, and Training in Individuals with Type 2 Diabetes (HART-D) and Diabetes
quantity/quality of muscle. A meta-analysis of over 8500 patients with Aerobic and Resistance Exercise (DARE) randomized controlled trials
T2D found significant reductions in HbA1c of -0.57%, following struc- examined the effects of aerobic, resistance, and concurrent training reg-
tured resistance training, when compared with non-exercise control imens in people with T2D. While the DARE trial52 (Aerobic: 15-20 min
groups. This reduction in HbA1c, while clinically meaningful, is worth at 60% HRmax progressed to 45 min at 75% HRmax, resistance: eight
discussing since it reflects both fasting and post-prandial averages.46 weight bearing exercises with progressive load increase, 2-3 sets with
Recent work has suggested that resistance training does not signifi- eight rep max, aerobic + resistance) reported reductions in HbA1c across
cantly affect fasting glucose. As such, it appears that the benefit of re- all three exercise groups, the concurrent group reduced HbA1c the most
sistance exercise may be driven in the post-prandial state. This would (-0.46% vs. aerobic training alone and -0.59% compared with resis-
be consistent with studies reporting that resistance exercise training tance training alone), suggesting concurrent exercise was better than
augments insulin sensitivity by 48% as measured by the euglycemic- either training mode alone. However, a concern with this later trial was
hyperinsulinemic clamp (i.e. a “gold-standard” approach). Interestingly, the concurrent group performed twice the exercise volume than either
skeletal muscle is responsible for ∼80% of insulin mediated glucose up- group. As such, it was not clear if the groups would observe similar re-
take.47 Thus, targeting increased muscle mass and/or quality with re- ductions in HbA1c had aerobic or resistance training increased volume
sistance exercise seems appropriate to reduce blood glucose in T2D. In (or time). The HART-D trial,53 however, was designed to match exer-
parallel, a meta-analysis of 14 studies reported that resistance training cise volume among modalities of exercise (aerobic: 12 kcal/kg/wk at
in T2D lowered total cholesterol, LDL cholesterol, and triglycerides.48 50-80% VO2 max, resistance: 3 d/wk with 2 sets of 4 upper body exer-
Recently too, a supervised progressive high-intensity resistance training cises, 3 sets of 3 leg exercises, and 2 sets of each abdominal crunches
program performed 3 d/wk for 6 months in older patients with T2D and back extensions, combined: 10 kcal/kg/wk aerobic and 2 sessions
significantly decreased both systolic and diastolic blood pressure.49 of one set one the aforementioned resistance exercises). It was reported

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U.S.A. Syeda, D. Battillo, A. Visaria et al. American Journal of Medicine Open 9 (2023) 100031

that only concurrent training significantly reduced HbA1c when com- HOMA-b (an index of insulin secretion) as well as abdominal fat mass
pared with the control group (-0.34%). This is consistent with the Ital- compared to baseline.61 In a meta-analysis of ∼1400 patients with T2D,
ian Diabetes and Exercise Study showcasing concurrent exercise is effec- HIIT was shown to induce greater benefit to HbA1c, HOMA-IR, fasting
tive at lowering HbA1c, LDL cholesterol, and blood pressure, compared serum glucose, and VO2 peak than those exercising at moderate and low
with standard of care.54 It also corroborates evidence that short-term intensities.62 However, the meta-analysis did not compare standardized
high functional training (e.g. CrossFit) improved insulin sensitivity and energy expenditure across the groups, suggesting that groups potentially
pancreatic function in people with T2D.30 , 55 The relationship by which performed different levels of work that prompted exercise adaptations
exercise improves pancreatic function is beyond the scope of this re- across intensities.60 In either case, HIIT over 8 weeks, consisting of 3
view, but increases in GLUT2 transporter content, Akt signaling, and sessions/wk of cycling (between 80-110% of peak power output), in-
glucokinase activity. Further, mitochondrial function within the beta- creased aerobic capacity and reduced blood insulin concentrations and
cell cell may be involved,28 and muscles may relase cytokines that in- HOMA-IR in adults with T2D, when compared with non-insulin resis-
fluence beta-cell mass and/or function.56 In either case, these studies tance non-obese controls.63 Together, these findings suggest HITT is an
align with current ACSM and ADA guidelines recommending concur- effective program for glycemic control in T2D.
rent training and the inclusion of at least 2 resistance training days in a Whether HIIT is better than continuous training remains unclear.64
week, as part of reaching at least 150 min of moderate intensity exercise When compared with 3 d/wk of continuous endurance training (40 min
to impact glycemia. of cycling at 50% peak workload), HIIT (10, 1-min intervals at 95%
peak, interspersed with 1-min active recovery between working inter-
High intensity interval training for glycemic control vals) for 11 weeks promoted greater gains in VO2 max but similar ben-
efits in HbA1c, fasting glucose, postprandial glucose, and HOMA-IR in
While the benefit of physical activity/exercise on glycemic control T2D, despite lower total energy expenditure and time requirement.65
in T2D is established, time constraints are a commonly reported bar- These findings are consistent with a recent meta-analysis identifying
rier to exercise,57 as only ∼20% of U.S. adults currently meet physical 345 patients over 13 HIIT trials in patients with T2D had significant re-
activity guidelines. High-intensity interval training (HIIT) has garnered ductions in HbA1c (mean difference: -0.37%), when compared to a non-
attention over recent years, providing a time-efficient means of improv- training control group.66 Further, no significant differences were found
ing glycemic control and cardiovascular health in those with T2D. In between groups in HOMA-IR or reducing CVD risk. In particular, a HIIT
comparison to other continuous high intensity exercise options, HIIT cycling exercise regimen of 1 × 4 min of cycling at 90% peak VO2 peak,
was reported may bee enjoyable for some, despite the stronger feeling 3 sessions/wk for 12 wk, in T2D decreased pulse wave velocity (PWV), a
of fatigue.58 To this extent, some overuse injuries have been reported measure of arterial stiffness, as well as improved systolic blood pressure
during HIIT trials, although HIIT does not appear to place exercisers at to comparable levels of that of moderate intensity continuous training
greater injury risk than traditional continuous exercise. Rather, as with (MICT).67 Moreover, flow mediated dilation (FMD), a non-invasive ap-
any exercise program, initial fitness level should be taken into consider- proach to measure endothelial function, had similar benefits between
ation, so exercise acclimation periods are appropriate, and inclusion of HIIT and MICT in T2D.68
warmups and cool-downs are warranted. Thus, for those who are med- While aerobic HIIT has incorporated treadmill vs. cycling modalities,
ically cleared for a vigorous exercise program, HIIT can provide bene- newer work has begun examining the utility of resistance HIIT to foster
fits as an alternative to traditional, moderate intensity exercise.59 Addi- fitness and glycemia. A year-long trial comparing the effects of moder-
tional risk with high intensity training is exercise-related hypoglycemia, ate intensity to high intensity resistance training found more vascular
particularly among insulin users. Non-insulin (or insulin secretagogue) benefit in those completing resistance HIIT. The HIIT group completed
users on the other hand have minimal risk and would benefit from high 10-12 repetitions of upper (seated row, seated lat pulldown, seated chest
intensity training to maintain glycemic status.81 Importantly though, the press, and standing shoulder press) and lower limb (less press, one leg
long-term utllity and adherence rates of HIIT has not been adequately in- lunge, and plank) exercises at 90% HR reserve (HRR), followed by 1
vestigated among people with prediabetes and T2D. Thus, incorporation min of resting at 40-60% HRR, for 3 sessions/wk. The MICT group com-
of HIIT is fair along with continuous exeercise for promoting exercise pleted continuous cycling at 40-60% HRR. Carotid intima-media thick-
volume. ness (cIMT), a measure used to diagnose the extent of carotid atheroscle-
Interval training consists of alternating exercise and recovery stages. rotic vascular disease, decreased in both groups, but only HIIT reduced
In HIIT, one may alternate 10 seconds to 4 min of high intensity aero- PWV, thereby favoring reduced arterial stiffness.69 Additional work ex-
bic exercise (e.g., 75-95% HRmax) with 12 seconds to 5 min of active or amining resistance HIIT versus other combinations of continuous or HIIT
passive recovery (e.g., 30-60% HRmax; Table 1). This contrasts with tra- aerobic training in T2D awaits to be established for maximal glycemic
ditional continuous exercise, during which individuals maintain a given benefit.
intensity for a set period. In fact, high-intensity exercise often elicits a
heart rate response around 75-95% HRmax, and current guidelines from Exercise timing relative to daytime and meals
ACSM recommend at least 75 min of vigorous activity per week, with
no more than 2 consecutive days between bouts of activity. To date, ev- The timing of physical activity/exercise for optimal glycemic control
idence has emerged highlighting HIIT, similar to traditional continuous has recently become an area of intense research. Timing of activity im-
high intensity exercise, can yield favorable glycemic control. Short-term plicates both the time of day and before/after meals as being important
HIIT consisting of six sessions of 10 × 60-s cycling bouts, each reaching for long-term glycemic control and postprandial glucose spikes across
∼90% HRmax, on the cycle ergometer over 2 weeks was shown to de- the day. To identify the best time to exercise, it is worth noting that cir-
crease average 24 hr blood glucose readings when measured with CGM. cadian physiology has underlying influence on glucose homeostasis. In-
Additionally, short-term HIIT training improved mitochondrial capac- deed, our body has circadian clocks as evidenced by diurnal oscillations
ity measured via muscle biopsies, suggesting that skeletal muscle has in a variety of physiologic processes that include body temperature, glu-
greater oxidative capacity to utilize glucose as an energy source.60 In cose tolerance, circulating insulin, and adipose tissue-related hormones
addition, pancreatic function in response to HIIT was examined in an (e.g. adiponectin, leptin, etc.). Interestingly, these processes all tend to
8-week cycling intervention in T2D. Participants were placed in a HIIT collectively be worse in the afternoon/evening compared with morning
exercise regimen (3 sessions/wk of 10 × 60-s cycling at ∼90% HRmax for among healthy individuals.70 In turn, some reports suggest consuming
8 weeks). Compared to a matched healthy control group, HIIT reduced smaller meals may be beneficial for glycemia next day compared with
fasting glucose concentrations, HbA1c, HOMA-IR (Homeostatic Model traditional large dinner meals (e.g.. > 30% total kcals)69 Furthermore,
of Assessment of Insulin Resistance, a proxy for insulin resistance), and people with T2D have a disrupted circadian rhythm such that insulin

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U.S.A. Syeda, D. Battillo, A. Visaria et al. American Journal of Medicine Open 9 (2023) 100031

sensitivity is relatively better in the evening but gets worse throughout erally defined as any waking behavior characterized by a low level of
sleep and into the morning, thereby raising plasma glucose (often called energy expenditure (less than or equal to 1.5 METs) while sitting, re-
the dawn phenomena).71 This circadian misalignment may be improved clining, or lying (e.g. TV-watching, screen time).90,91 This is clinically
with exercise, although specific exercise work in T2D is needed. Such concerning since high sedentary activity (e.g. generally ≥ 8 hrs) is asso-
diurnal oscillations suggest that glucose metabolism is “better” at spe- ciated with increased risk of all-cause mortality, cardiovascular disease,
cific times during the day, and incorporating exercise based on this tim- and T2D.92 Remarkably, every 1 hr increase in sedentary activity above
ing may result in greater glycemic control. To date, some71-74 but not 8 hr/d was associated with an 8% increased risk of cardiovascular mor-
all75 , 76 research suggest physical activity in the afternoon or evening tality and 1% increase in risk of T2D.92 In another cohort, 1 extra hr of
may be more beneficial for circulating glucose and insulin sensitivity, sedentary time over an 8 d period was associated with 22% increased
compared to equivalent physical activities done in the morning in peo- odds of T2D adults aged 45-70 yr.93 Additionally, greater sedentary time
ple with and without T2D, on or off insulin therapy. Importantly, not was associated with hyperglycemia and incident T2D independent of
all outcomes seem to respond to afternoon exercise better than morning physical activity levels in a multi-ethnic U.S. population.94
exercise. In fact, work on body weight and food intake have recently Given the alarming public health implications of sedentary activity,
suggested morning exercise is better for weight management as well as independent of physical activity, health professionals and researchers
activity adherence.77 Thus, determining the best time of exercise may be have revised the 2nd edition95 of the U.S. Physical Activity Guidelines
outcome dependent. Practically speaking, though, activity should be en- for American to include sedentary activity as an independent risk factor
couraged whenever the patient is consistently able to fit in their sched- for all-cause and cardiovascular mortality and incident T2D. This recom-
ule. Indeed, a retrospective cohort study78 of the National Health and mendation is, in part, based on interventional studies showing benefits
Nutrition Examination Survey (NHANES) reported that physical activ- in glycemic control upon breaking up sedentary activity and/or replac-
ity amount, regardless of timing, was associated with lower all-cause ing sedentary time with light-intensity or moderate-intensity activity.
mortality in men and women. Thus, considering exercise timing to fos- For example, interrupting prolonged sitting with activity breaks, such
ter engagement and adherence is seemingly most relevant for glycemic as light-intensity walking or simple resistance activities (half-squats, calf
benefit. raises, gluteal contractions, and knee raises) for 3 min every 30 min over
It should be noted that several studies have found post-prandial glu- 8 hr, decreased postprandial glucose incremental area under the curve
cose to be a stronger predictor of future CVD than fasting glucose.79 As by ∼14 mmol/h/L among previously inactive adults with T2D.96 Re-
a result, it might be appropriate to wonder whether people should exer- placing sitting time with standing (2.5 hr/d) and light-intensity walking
cise before or after a meal to further refine the glycemic response, inde- (totaling 2.2 hr/d) every 30 min also improved 24hr glucose levels and
pendent of time of day. This effect could have concomitant benefit on insulin sensitivity, even more so than structured, moderate-level cycling
vascular physiology by lowering postprandial glycemia-related endothe- activity for 1.1 hr/d in individuals with T2D.97 However, Loh et al.,98
lial dysfunction and oxidative stress.80 However, few studies have been in a meta-analysis of trials comparing breaking up sedentary activity to
conducted on whether fasted states of exercise confer greater glycemic continuous sitting to prevent T2D demonstrated only a small decrease
benefit than fed states in people with T2D. A consensus statement from in standardized mean plasma glucose for breaking up sedentary activity
ACSM81 concluded that current evidence suggests postprandial exercise after matching for energy expenditure. Similarly, the evidence is unclear
provides better glucose control by attenuating acute glycemic spikes, whether breaks from sitting have clinically relevant impacts on hyper-
regardless of exercise intensity or type, with a longer duration (≥45 glycemia in free-living environments.99 , 100 Interestingly, less-frequent
min) providing the most consistent benefits.78 However, it should be active interruptions (sitting interrupted with 6 min of simple resistance
mentioned that, of studies, only Francois et al.82 showed that “exercise exercises every 60 min) improved acute post-prandial glycemic control
snacking” (6 × 1 min intense incline walking at 90% HRmax on a tread- post-lunch, while more-frequent interruptions (3 min resistance exer-
mill) 30 min before a meal reduced 3-h postprandial blood glucose af- cises every 30 min) were more beneficial for nocturnal glucose in those
ter breakfast and dinner among patients with T2D or insulin resistance, with medication-controlled T2D.101
compared to traditional 30 min moderate-intensity (60% HRmax). Ad- Although less researched, short, high-intensity exercises may also
ditionally, Edinburgh et al.83 found that moderate-intensity cycling (60 have glycemic control and other cardiometabolic benefits as seen in
min performed at 65% VO2 peak for 6 weeks) prior to carbohydrate in- light- and moderate-intensity exercises. For example, a review on “ex-
gestion improved postprandial insulin sensitivity and reduced insuline- ercise snacks” (isolated bouts of vigorous exercise lasting ≤1 min)102
mia and lipemia, but not plasma glucose, among overweight/obese men. summarized several RCTs describing improvements in cardiorespiratory
Other studies showed that brief exercises after meals blunted glucose fitness (e.g. VO2 peak and peak power output).102-104 The exercise pre-
spikes. For instance, these brief exercises included (a) 3 sets of 1-min scriptions for these studies included: 1) three daily bouts of vigorous
light intensity jogging + 30 s of rest; total duration of 4 min for each stair climbing (climbing 60 steps as fast as possible)105 ; 2) three isolated
exercise bout, every 30 min throughout the day, 20 times in total; (b) 20-second “all-out” cycling bouts, about 1-4 hr apart daily; 3) stair-based
3 sets of 15 min bouts at 3 METs after a meal84 ; (c) resistance exercise exercise snacks (∼15–30 sec)106 ; and 4) 5 × 4-second maximal cycling
(up to 40% of their bodyweight)85 (d) 10 × 1 min HIIT (10 × 1 min sprints on a specialized ergometer, once per hour.107
work-bouts at 95–120% of individual peak power output, separated by In addition to exercises, it is also of interest to investigate the effects
1 min low-intensity cycling)72 ; and (e) 4 bouts including 3 min at 56.5 of ‘domestic’ physical activity on glycemic control as domestic chores
± 3.9 % VO2 max after breakfast.86 Interestingly, postprandial exercise are the main contributors to total daily physical activity in older patients
also reduced acute elevations in serum triglyceride levels after high-fat with T2D.106 Few studies have been done isolating household activity
meals and reduced functional derangements from lipid-induced oxida- effects on glycemic control, with even fewer to none among patients
tive stress87-89 , suggesting post-meal exercise may benefit both glucose with T2D. Li et al.107 in a cohort study of the UK Biobank among partic-
and lipids to support cardiovascular health. Collectively, these findings ipants without diabetes, reported that replacing 30 min/d of sedentary
suggest “exercise desserts” immediately post-meal may yield optimal activity with daily activities (e.g. walking for pleasure, pruning, water-
benefit for attenuating postprandial spikes. ing the lawn, weeding, lawn mowing, car maintenance etc.) resulted in
a 6-31% risk reduction in T2D. Stair climbing (6 continuous repetitions
Breaking up sedentary activity with physical activity of climbing to the second floor (21 steps) at a rate of 80-110 steps/min)
significantly reduced postprandial glycemia at 150 min post meal com-
Sedentary behavior is now recognized as an independent risk fac- pared to resting,108 but not necessarily 24 hr glucose or long-term hy-
tor for chronic disease. Based on a NHANES analysis, U.S. adults spend perglycemia, as evidenced by minimal change in 24 hr glucose compar-
nearly 8 hr/d on average being sedentary.88 Sedentary behavior is gen- ing 60-sec pulses of vigorous stair-climbing to resting over 6 weeks.109

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When taking together, it seems reasonable to conclude that interven- (>250min/wk) moderate intensity physical activity was associated with
tions breaking up sedentary activity are favorable in at least providing significant weight loss including loss in VAT. It is worth noting though
acute glycemic benefit. that aerobic exercise may be more beneficial on reducing VAT when
Observational and some experimental studies110-114 , but not compared with resistance exercise, although both lower subcutaneous
all,115 , 116 on breaks in sedentary time affecting blood pressure and lipid fat.130 Either way, low impact aerobic exercises, like walking 3 d/wk,
levels have implied similar improvements on other cardiovascular risk can be extremely beneficial for decreasing VAT among women with T2D
factors. For example, Dempsey et al.114 reported that interrupting seden- between 50-70 yr when performed at a 65-70% VO2 max for 50 min.131
tary time with brief bouts of walking among patients with T2D produced Thus, performing exercise with current ACSM and ADA recommenda-
small yet significant decreases in blood pressure (SBP/DBP: 14±1/8±1 tions seems effective at reducing total body fat and VAT in people with
mmHg). Champion et al.,112 among healthy adults aged 18-55yr, found obesity.132
that sitting time interrupted hourly with 20 min light-intensity treadmill Another consideration is that many people with obesity/T2D also de-
desk walking between 1.2-3.5 km/h acutely reduced plasma glucose, velop concurrent non-alcoholic fatty liver disease (NAFLD), character-
triglycerides, and blood pressure modestly (3-4% decrease). Certainly, ized by ectopic fat accumulation in the liver. NAFLD is believed to result
more long-term work is needed as well as investigation on other car- from overnutrition and lack of exercise, leading to insulin resistance,
diovascular risk factors and measurements in patients with T2D such as lipogenesis, and inflammation. People with T2D and NAFLD have ex-
blood pressure, LDL cholesterol, endothelial function, coronary artery aggerated hyperinsulinemia and dyslipidemia compared to those with-
calcium, and arterial stiffness. Importantly, these breaks in sedentary out NAFLD, signifying that the amount of liver fat is germane towards
behavior with physical activity need not be structured exercise sessions health. Interestingly, moderate to vigorous intensity aerobic exercise
(e.g. 30-60 min of moderative vigorous movement), and light-intensity around 150-300 min/wk, including brisk walking and jogging, as well
activities (e.g. household activities) and/or resistance exercise may be as HIIT training at 80-85% VO2 max 3 d/wk, significantly reduces liver
feasible for impacting cardiometabolic health. Thus, in individuals who fat and provides hepatoprotective effects. Indeed, increasing physical
are unable to do conventional moderate or vigorous exercise for 150 activity, whether aerobic or resistance based without caloric restriction,
min/wk or 75 min/wk, respectively, other modes of movement broken reduces liver fat,132 although aerobic exercise may be more potent.130
up throughout the day may serve as suitable alternatives provided they Importantly, though, it has been demonstrated that aerobic exercise at
are done consistently. approximately 85% HRmax for 60min/d shifts hepatic fat away from
saturated and towards polyunsaturated fat, independent of changes in
Exercise cardiometabolic benefit beyond weight loss total weight or liver fat. The shift in liver fat composition is relevant
as well since it correlated with whole-body insulin sensitivity.133 This
Exercise as a part of lifestyle recommendations promotes weight loss suggests exercise benefits on the liver occurs well before changes in fat
of 5-10%. Yet, many acknowledge that increases in energy expenditure content per se.
via exercise alone may not induce weight loss if energy intake is not Systemic inflammation impairs glucose regulation through, in part,
kept constant and/or if alterations in non-exercise physical activity oc- disruption in insulin signaling.134 Exercise reduces pro-inflammatory
cur such that people sit more. In fact, recent work highlights that despite cytokines prior to clinically meaningful weight loss135 and favors se-
high energy expenditure from exercise, adaptative thermogenesis (i.e. cretion of anti-inflammation molecules into the general circulation that
metabolic adaptation) occurs during weight loss in some people such are considered “exerkines”.136 Indeed, exercise, with or without caloric
that their resting metabolism declines, and this makes losing weight restriction, reduces several pro-inflammatory mediators of dysglycemia
and/or maintaining weight loss challenging.117 , 118 Thus, it is essential (e.g. leptin, feutin-A and CRP).16 , 137-139 Furthermore, moderate and
to acknowledge that weight loss is just one measure of T2D and CVD short-term HIIT interventions reduce circulating free-fatty acids that
risk reduction that does not exclude other health benefits. are key promoters of not only reduced insulin action but also inflam-
One the main health benefits observed from exercise, independent of mation.134 Newer work has also highlighted that acute or short-term
weight loss, is the shift in body composition. Specifically, exercise often exercise may reduce circulating levels of extracellular vesicles (among
maintains/increases fat-free mass (e.g. muscle mass) and reduces total others; see review Chow et al.136 ) in people with obesity140 or pre-
body fat and/or visceral fat (VAT). Indeed, a recent meta-analysis119 hypertension141 to favor cardiometabolic health. When coupled with
revealed that exercise interventions that follow ACSM-based moderate observations that exercise also increases anti-inflammatory hormones
to high intensity exercise (40-90% VO2 max) for 30-60 min/d, showed from skeletal muscle, (e.g. IL-6, IL-8, BAIBA, lactate, etc.) adipose tissue
a marked reduction in total body fat, accompanied with a significant (e.g. adiponectin),16 , 137 and liver (e.g. follistan) for promotion of car-
decrease in triglycerides. Others120 have also showed that high inten- diometabolic health,136 , 142 it is clear exercice has wide ranging benefit
sity exercise (60-75% VO2 max) for 3-5 d/wk was more effective than beyond that of weight loss.
continuous moderate exercise in reducing total body fat percent in peo- It is important to acknowledge that exercise is also a valuable tool for
ple with obesity, independent of BMI, along with 17% higher VO2 max. emotional and mental health. Many patients with T2D develop depres-
These findings suggest intensity of exercise may be ideal for body fat sion, possibly due to impact of insulin resistance on reward and learning
reduction. In fact, several studies121-124 report effects of aerobic exer- centers in the brain.143 Regular engagement in some form of moderate
cise on reducing VAT, while emphasizing that adherence and intensity intensity aerobic exercise or exercise ‘snacks’ has been shown to improve
of exercise may play a significant role. This is clinically relevant since mood, reduce anxiety and stress, boost self-esteem, and improve sleep
VAT is the fat deposited around the abdominal organs and is considered quality and cognition.144 , 145 Together, these finding support views that
tightly associated with insulin resistance, chronic inflammation.125 hy- exercise can reduce depression in people with T2D,146 independent of
pertension, metabolic syndrome and T2D,126 , 127 But, recent work from weight loss, via changes in inflammation.147
a large clinical trial demonstrated there is no difference in fat loss when
intensity of exercise is matched on energy expenditure,128 suggesting ex- Perspectives and conclusions
ercise volume/time is key. Interestingly too this later work shows that
aerobic exercise maintains lower body muscle mass, while high intensity Physical activity and/or exercise is essential to improve glucose lev-
plus volumes of exercise may be associated with declines in upper body els as well as other cardiometabolic risk factors. Activities that favor
muscle mass.128 In turn, resistance exercise is important to consider for glucose reductions include taking breaks between long periods of sit-
increasing fat-free mass specifically.129 This is consistent with a meta- ting, scheduling workouts after meals to avoid hyperglycemia, and in-
analysis122 describing that, compared to strength training, low intensity corporating some form of aerobic and high-intensity resistance exercise
aerobic exercise, or a combination of both, performed at high volume in the week. While it is important to recognize the lack of information

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on sex and/or race specific recommendations as well as pediatric deci- 10. Ebbert JO, Elrashidi MY, Jensen MD. Managing overweight and obesity in adults to
sions for engaging in exercise and physical activity is an area worthy reduce cardiovascular disease risk. Curr Atheroscler Rep. 2014;16(10) 445-445.
11. Tuomilehto J, et al. Prevention of type 2 diabetes mellitus by changes in
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In addition, exercise also reduces body fat, lipids, and blood pressure. 12. Diabetes Prevention Program Research, G.The diabetes prevention program (DPP):
description of lifestyle intervention. Diabetes Care. 2002;25(12):2165–2171.
Both aerobic and resistance exercise offer unique opportunities to in- 13. Diabetes Prevention Program Research GroupReduction in the incidence of type 2 di-
duce gains in glycemic control. While exercise intensity, volume, and abetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403.
frequency are associated with improved glycemic control, the evidence 14. Weiss EP, et al. Calorie restriction and matched weight loss from exercise: indepen-
dent and additive effects on glucoregulation and the incretin system in overweight
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tion, people with T2D often take medications when advised to exercise, during caloric restriction in women with obesity. Physiol Behav. 2020;223:112978.
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tion diabetes prevention recognition program standards and operating procedures.
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Declaration of Competing Interests function in adults with type 2 diabetes. Am J Physiol. Endocrinol Metabol.
2017;313(3):E314–E320.
We declare no competing interests. 31. Hamer M, Stamatakis E. Low-dose physical activity attenuates cardiovascular dis-
ease mortality in men and women with clustered metabolic risk factors. Circulation.
2012;5(4):494–499.
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