The Importance of Exercise for Glycemic Control in Type 2 Diabetes

Abstract

Exercise is a first-line therapy recommended for patients with type 2 diabetes (T2D). Although moderate to vigorous exercise (e.g. 150 min/wk) is often advised alongside diet and/or behavior modification, exercise is an independent treatment that can prevent, delay or reverse T2D. Habitual exercise, consisting of aerobic, resistance or their combination, fosters improved short- and long-term glycemic control. Recent work also shows high-intensity interval training is successful at lowering blood glucose, as is breaking up sedentary behavior with 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.

Full text

American Journal of Medicine Open 9 (2023) 100031
Contents lists available at ScienceDirect
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
          
Keywords:
Physical activity
Glucose tolerance
Insulin resistance
Obesity
Prediabetes
       
Exercise is a rst-line therapy recommended for patients with type 2 diabetes (T2D). Although moderate to
vigorous exercise (e.g. 150 min/wk) is often advised alongside diet and/or behavior modication, exercise is an
independent treatment that can prevent, delay or reverse T2D. Habitual exercise, consisting of aerobic, resistance
or their combination, fosters improved short- and long-term glycemic control. Recent work also shows high-
intensity interval training is successful at lowering blood glucose, as is breaking up sedentary behavior with
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 benet. Despite these
ecacious benets of exercise for T2D care, optimal exercise recommendations remain unclear when considering,
dietary, medication, and/or other behaviors.
Introduction
Approximately 10.4% adults in the U.S. have type 2 diabetes (T2D),
3.8% of whom are undiagnosed. In addition, nearly 45.8% of adults
are also categorized as having prediabetes, thereby placing major -
nancial strains on the healthcare system.
1 T2D (and prediabetes) is
mainly characterized by reduced whole-body insulin sensitivity and 𝛽-
cell dysfunction. Low insulin sensitivity initially induced by overnutr-
tion and/or physcil activity, for instance, promotes hypersecretion of
insulin from pancreatic 𝛽-cells to regulate circulating glucose. When
insulin secretion is no longer able to compensate for the prevailing
low insulin sensitivity, blood glucose levels worsen towards predia-
betes and T2D status. While the exact cause of T2D remains an area
of intense research, excess body weight serves as a leading risk fac-
tor. Indeed, excess lipid accumulation surrounding vital organs in the
abdomen (i.e. visceral fat), as well as within liver and muscle cells,
are thought to impair insulin signaling and induce insulin resistance.
2
Given that more than 42% of American adults have obesity,
3 it is no
surprise that identication of optimal treatment plans to combat obe-
sity related insulin resistance is warranted to manage blood glucose.
4
One such treatment option is physical activity and/or exercise. Physical
activity is broadly dened as any bodily movement that is above resting
conditions, whereas exercise is planned or structured movement with
✩ 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: steven.malin@rutgers.edu (S.K. Malin) .
1 Shared rst author responsibility.
specic intent on gains in aerobic and/or muscular tness. Most recom-
mendations by the American College of Sports Medicine (ACSM) and/or
American Diabetes Association (ADA) for physical activity/exercise fo-
cus on frequency, intensity, and modality to favorably impact glycemic
control.
5 , 6 Included within modality are considerations including vol-
ume or the duration/repetitions of the exercise being completed. Addi-
tionally, aerobic exercise intensity is primarily determined using a per-
centage of one’s maximal heart rate (%HRmax) and maximal oxygen
consumption and utilization (%VO
2
max).
5 , 6 It is also worth mention-
ing that rating of perceived exertion (RPE) is a practical tool people can
use to estimate exercise intensity if they are unable to use heart rate or
have maximal tness tests conducted.
5 , 6
Typically RPE correlates well
with heart rate (e.g. RPE of 12 would theoretically relate to a HR of 120
bpm). Herein, we compare aerobic, resistance, and concurrent exercise,
dened as completing aerobic and resistance exercise in combination,
as modalities to aect insulin sensitivity and cardiometabolic health.
We also discuss whether intensity or timing of exercise throughout the
day matters to yield optimal eects on glucose control. In turn, we dis-
cuss high intensity interval versus continuous exercise for glycemia fol-
lowed by the timing at which exercise is performed. Recognizing that
some people may nd it challenging to dedicate time to exercise, we
also review breaks in sedentary behavior as a strategy to manage blood
glucose. Further, since weight loss can be quite variable in response to
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-
dition to exercise benets independent of weight loss, to help highlight
benets for people with T2D. Lastly, given many suggest individuals
progress from obesity with normoglyceemia to prediabetes to T2D, it
is understood that the pathology of insulin resistance is a continuum.
7
As such, the utlity of exercise in prediabetes and T2D will be discussed
throughout. Together, future direction for the eld and practical con-
siderations is provided.
Type 2 diabetes prevention and management
It comes as no surprise that ACSM and ADA recommend comprehen-
sive lifestyle programs that increase physical activity in eort to pre-
vent glucose levels from detoriating as well as manage glycemia within
a given range.
8 , 9 Indeed, lifestyle recommendations for individuals at
risk for T2D often target weight loss of ∼5-10% and an increase in phys-
ical activity to either 150 min/week or more of moderate intensity or 75
min/week of vigorous intensity aerobic exercise. Lifestyle interventions
consisting of increased physical activity (i.e. aerobic and/or resistance
exercise) and low-fat diet promotes ∼5 kg weight loss for 2 years or be-
yond and lowers T2D risk by ∼45%.
10
Interestingly, there appears to be
a dose-response relationship with weight loss and glycemic control as
reected by HbA1c, a measure of average blood glucose levels over an
8-12-week period. Indeed, a 2-10% reduction in body weight between
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-
scriptions of > 5% weight loss via reductions in total fat under 30%
of total calorie intake (with < 10% coming from saturated fat), ele-
vation in ber consumption (i.e. 15g per 1000 kcal) and increases in
physical activity (30 min/d) lowered the cumulative incidence of di-
abetes by 58% in people with prediabetes, compared with controls.
11
In the landmark U.S. Diabetes Prevention Program (DPP),
12
new cases
of T2D were reduced by 58% in people with prediabetes. This reduc-
tion was achieved using an intervention based on 150 min/wk of phys-
ical activity and weight loss of approximately 7%,
13
although subjects
who lost the most weight and met physical activity/diet targets had
> 90% risk reductions of diabetes. Subsequently, it seems reasonable
to ask whether weight loss is best achieved by activity and/or diet,
provided its importance in promoting glycemic control. No random-
ized controlled trials to date, though, have directly compared caloric
restriction to exercise versus caloric restriction plus exercise in peo-
ple with T2D. However, Weiss et al.
14 observed that caloric restric-
tion and exercise training in combination improved glucose tolerance
and increased insulin sensitivity, using a 2-hr frequently sampled oral
glucose tolerance test (OGTT), more than caloric restriction or exercise
alone, among overweight sedentary adults. Conversely, post-prandial
GLP-1 decreased in the caloric restriction group only, suggesting mech-
anisms aecting glucose tolerance may be dierent based on how weight
loss is achieved. Interestingly, we identied similar observations to this
in prior work after only 2 weeks of exercise, and this was correlated
with gains in pancreatic 𝛽-cell function and GLP-1 increases,
15
although
improvements in circulating adipose-derived inammation were simi-
lar in these women with obesity.
16 In either case, adding exercise to
caloric restriction will yield gains in aerobic tness, which benets
quality of life. Additionally, adding exercise to caloric restriction im-
proved weight regulation, such as high intensity interval exercise (60
min/day alternating 3 min at 90 and 50% peak HR), suppressed acylated
ghrelin and increased fullness during caloric restriction, compared with
caloric restriction only,
17
thereby favoring appetite suppression and in-
creased satiety. This observation is consistent with exercise decreasing
visceral fat during caloric restriction. Indeed, in the REverse metabolic
SyndrOme by Lifestyle and Various Exercises (RESOLVE) trial, middle-
aged to older adults with obesity underwent dierent modalities of
high-volume exercise (15-20 hr/wk) combined with a high protein,
caloric-decit diet to determine eects on visceral fat. Participants
between ages 50-70 yr were divided into three groups with varying
intensities: moderate-resistance-moderate-endurance, high-resistance-
moderate-endurance, and moderate-resistance-high-endurance. Follow-
ing a 3-wk supervised program and continuing a self-management
compliance protocol for the remaining 11 months, participants in the
high resistance exercise group lost the greatest amount of visceral fat
throughout the year-long combination program. This is consistent with
recent evidence from the DPP that physical activity, independent of
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,
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-
grams (including Medicaid and Medicare) cover such treatment. Still, it
is worth noting that while weight loss is a signicant predictor of T2D
prevention, the DPP standards have been updated. In fact, the goals
of the program look to emphasize more the importance of physical ac-
tivity, as standard advice was originally focused on losing 5-7% body
weight to elicit favorable HbA1c levels. Now, the goal of 4% weight loss
with 150 min/wk of physical activity, along with reduction in HbA1c
of 0.2%, has been incorporated.
19
Taken together, exercise favors glu-
coregulatory eects via both weight-loss and weight loss-independent
mechanisms
18 and highlights exercise for glycemic management
( Fig. 1 ).
Type 2 diabetes reversal
Classic work from nearly 4 decades ago highlight that 12 months of
high intensity exercise (about 85% HRmax 5 d/wk.) is capable of re-
versing and normalizing blood glucose in people with prediabetes and
T2D.
21
We too have shown that as little as 2 weeks of high intensity in-
terval or moderate continuous exercise is able to reverse prediabetes in
nearly 40% of participants.
22
Nevertheless, it should be acknowledged
that not all people with hyperglycemia may respond favorably to exer-
cise. In fact, some studies suggest upwards of 10-30% of people with T2D
may not improve fasting glucose and/or HbA1c following lifestyle ther-
apy.
23
This is consistent with recent work showing no glycemic benet
to lifestyle therapy in people with T2D versus control, although lifestyle
did reduce glucose medication numbers to a signicant extent (about
75% vs. 47% discontinuation) in relation to greater exercise volume en-
gagement.
24 This later work is of importance because it is consistent
with work comparing the DPP program with the optimal intensity of
exercise for preventing progression to T2D.
25 In short, these later re-
sults showcased that performing moderate intensity exercise of high
volume (50% VO
2
peak for about 287 min/wk) was most eective at
improving glucose tolerance with only 2 kg of fat loss, when compared
with high intensity and volume (75% VO
2
peak for about 195 min/wk)
or low volume moderate intensity (50% VO
2
peak for 181 min/wk).
While intensity eects may be somewhat unclear ( see below ), current
work highlights higher volumes appear related to greater glucose reg-
ulation
26-30
and cardiometabolic health.
31
Indeed, a meta-analysis con-
rmed that engaging in 5-7 hr/wk of leisure-time physical activity or
moderate to vigorous exercise was inversely related with risk of devel-
oping T2D.
22 , 32
Furthermore, the Look AHEAD (Action for Health in Di-
abetes) trial,
33
the longest running interventional study with median of
9.6 years, tracked the development of cardiovascular disease among pa-
tients with T2D. Subjects were randomized to either Intensive Lifestyle
Intervention (ILI) including calorie restriction and increased physical
activity or a control group that received Diabetes Support and Educa-
tion (DSE). Under the monitoring of a registered dietitian, psychologist,
and exercise physiologist, the intervention group ate a low calorie diet
(LCD) between 1200-1500kcal/day, with < 30% kcal from fat, setting
a goal of 175 min of unsupervised exercise per week. By year 1, the
ILI participants achieved 20.4% increase in their tness levels, com-
pared to the 5% in the DSE group. Throughout the trial period, the ILI
group accomplished 3 to 6 times more remission of T2D than the control
group among participants that were relatively healthy at baseline with a
lower HbA1c and had T2D for a shorter duration. Interestingly, though,
2

U.S.A. Syeda, D. Battillo, A. Visaria et al. American Journal of Medicine Open 9 (2023) 100031
Fig. 1. Benet of exercise on multiple bodily
tissues for blood glucose control.
there was no signicant improvement in rate of CVD events between
the ILI and DSE groups. Nonetheless, the Diabetes Intervention Accen-
tuating Diet and Enhancing Metabolism (DIADEM-I)
33
was a recent diet
and physical activity-based, randomized controlled trial among adults
(mean age 42.1 yrs) with T2D in the Middle East and North African re-
gions. Participants were randomized into a control group on diabetes
care or a lifestyle intervention group with total diet replacement (low-
kcal/low glycemic index) and physical activity recommendations (target
10k steps/d for 150 min/wk), for a duration of 12 weeks. At the end of
1 year follow-up, there was sustained weight loss, with 61% no longer
having T2D and 33% of participants going into remission. Weight-loss
induced management of T2D in the lifestyle intervention group was also
associated with improved CVD health and quality of life.
34
These nd-
ings together highlight that T2D is not inevitable and can be delayed,
prevented, and reversed by exercise.
Aerobic compared with resistance exercise for glycemic control
Most work surrounding exercise on glycemic control has focused on
aerobic exercise in people with prediabetes or T2D. Aerobic exercise is
rhythmic in nature, with large muscle groups acting to support walking
jogging, running, and cycling. Aerobic training increases insulin sensi-
tivity and vascular function among other factors, such as aerobic tness
and reductions in body fat.
6
ACSM and ADA guidelines recommend at
least 150 mins/wk of moderate-to-vigorous intensity aerobic activity
spread out over at least 3 d/wk, with no more than 2 consecutive days
without activity ( Table 1 ). This frequency recommendation is mainly
due to benecial eects of aerobic exercise on insulin sensitivity last-
ing up to about 48 hr.
35 , 36
Indeed, skeletal muscle plays a paramount
role in glycemic control, by virtue of exercise-induced blood glucose
uptake and augmented insulin sensitivity, following an exercise bout.
There are two primary pathways that promote skeletal muscle glucose
uptake, insulin in dependent and insulin dependent.
37 During bouts of
aerobic exercise, skeletal muscle promotes GLUT-4, a key transporter,
to translocate to the cell membrane, to increase glucose uptake indepen-
dent of insulin. Thereafter, these eects of exercise wane after about 3-6
hr, such that the muscle is now sensitized to insulin. This insulin sen-
sitizing eect can last upwards of about 48 hr,
35 , 36
based on intensity,
diet, and other factors (e.g. sleep, etc.). As such, single bouts of exer-
cise are known to favorably impact insulin sensitivity and favor blood
glucose control, prior to weight loss or gains in aerobic tness.
38 Im-
portantly, exercise further lowers subsequent risk of developing hypo-
glycemia among T2D patients who are non-insulin users.
81 Thus, ac-
cumulating bouts of exercise will not only favor insulin sensitivity, but
also contribute to gains in aerobic tness for reducing CVD and all-cause
mortality in T2D, independent of body weight.
39
Convincing evidence demonstrates that exercise can improve
glycemic control. For instance, 6-months of aerobic training among
overweight individuals with T2D, comprised of 4 sessions/wk at 45-
60 min/session at 50-75% VO
2
peak, reduced fasting plasma glucose (-
18.58 mg/dl) and insulin levels (-2.91 mU/l) measured, when compared
with a non-exercise control group.
40
Further, aerobic exercise consist-
ing of 60 min at ∼75% VO
2
peak intensity for 4-5 d/wk over 12-16 wk
reduced fasting blood glucose (-6.3 mg/dl) and increased insulin sen-
sitivity in those with impaired glucose tolerance or T2D.
34
These nd-
ings are clinically relevant as epidemiological studies report a 21% re-
duction in diabetes-related death following a 1% decrease in HbA1c.
41
Moreover, a meta-analysis of 504 participants across 12 trials of aerobic
and 2 trials of resistance training demonstrated a signicant decrease in
post-intervention HbA1c in the exercise groups by 0.66%, compared to
the control group, independent of weight loss.
42 Interestingly, recent
interest and advice on using continuous glucose monitoring (CGM) has
grown in the diabetes community, in eort to provide a more accurate
insight to acute changes in glycemia within individuals. A recent meta-
analysis of 11 aerobic and resistance exercise interventions conveyed
signicantly decreased average glucose concentrations (-14.4 mg/dl) as
assessed by CGM.
43
Importantly, this meta-analysis highlights that peo-
ple spend on average approximately 129 minutes less in hyperglycemic
ranges (i.e. > 180 mg/dl), thereby reducing risk of complications. This
aligns with ndings that aerobic exercise also protects against CVD
risk, beyond glycemic improvements. A meta-analysis with 1,003 peo-
ple with T2D demonstrated that aerobic exercise training interventions
lowered systolic blood pressure (-5.6 mmHg), diastolic blood pressure (-
5.5 mmHg), triglyceride levels (-0.3 mmol/l), and total cholesterol (-0.3
mmol/l).
44
Discerning the health benets of resistance compared with aerobic
exercise is useful for providing training diversity and augmenting exer-
cise adherence. Given T2D is an independent risk factor for low muscu-
lar strength and accelerated decline in muscle mass/functional status,
resistance exercise could be a viable strategy to combat risk in falls and
dissuade sarcopenic (age-associated decline in muscle mass) losses.
45
Resistance or strength training specically involves the contraction of
3

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
large muscle groups, like
walking, jogging, and cycling
- Moderate intensity exercise
at 55-74% HRmax
- RPE 12-13 (somewhat hard)
- Vigorous intensity exercise at
75-95% HRmax
- RPE 14-16 (hard to very
hard)
- 3-7 d/wk, with no more than
2 consecutive days between
exercise bouts. Daily exercise
is suggested to maximize
insulin action
- Minimum of 150 min/wk of
moderate activity or 75-150
min/wk of vigorous activity,
or an equivalent combination
of the two
Resistance - Contraction of muscle
against an external force
using free weights, weight
machines, body weight, or
elastic resistance bands
- For moderate intensity,
repetitions of an exercise at a
weight that can be repeated
no more than 15 times. For
vigorous intensity,
repetitions of an exercise at a
weight that can be repeated
no more than 6-8 times
- 2-3 nonconsecutive d/wk - 10-15 repetitions per set with
1-3 sets of each exercise.
8-10 exercises involving the
major muscle groups in total
High Intensity Interval
Training (HIIT)
- Alternating vigorous
intensity exercise (aerobic or
strength training) with
recovery stages
- Vigorous intensity (75-95%
HRmax) exercise, followed
by active or passive recovery
(30-60% HRmax)
- 3 d/wk for vigorous aerobic
training, with not more than
2 consecutive days between
bouts
- 2-3 nonconsecutive d/wk for
resistance training
- 10 seconds to 4 min of
vigorous intensity exercise,
with 12 seconds to 5 min of
active or passive recovery
Breaks in sedentary
behavior
- Walking or simple resistance
activities (half-squats, calf
raises, gluteal contractions
and knee raises), or standing
time in lieu of sitting time
- Light to moderate intensity
exercise at 45-55% HRmax
- RPE 10-11 (very light to
fairly light)
- Every 30 min for 8 hr, given
the increased risk of
sedentary behavior beyond 8
hr/d
- Replace sitting time with
standing time (2.5 hr/d)
- Light-intensity walking (2.2
hr/d), in 3-min segments
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
machines, body weight, or elastic resistance bands. ACSM and ADA rec-
ommend resistance training at least 2-3 nonconsecutive d/wk with mod-
erate to vigorous training as determined by the number of repetitions
an individual is doing per set ( Table 1 ). If one can do a higher num-
ber of repetitions at a given weight –closer to 15 reps at a weight that
can be repeated no more than 15 times –this is moderate exercise. Vig-
orous exercise follows the same principle around 6-8 reps. ACSM and
ADA state that starting at moderate training involving 10-15 reps/set
and increasing weight only when the target number of reps can be com-
pleted without reaching fatigue-induce failure is best practice. Vigorous
exercise may be performed once technique and condence in movement
patterns occur.
6
Resistance training conveys potent benets to glycemic control and
provides additional benets to muscular strength, bone density, and
quantity/quality of muscle. A meta-analysis of over 8500 patients with
T2D found signicant reductions in HbA1c of -0.57%, following struc-
tured resistance training, when compared with non-exercise control
groups. This reduction in HbA1c, while clinically meaningful, is worth
discussing since it reects both fasting and post-prandial averages.
46
Recent work has suggested that resistance training does not signi-
cantly aect fasting glucose. As such, it appears that the benet of re-
sistance exercise may be driven in the post-prandial state. This would
be consistent with studies reporting that resistance exercise training
augments insulin sensitivity by 48% as measured by the euglycemic-
hyperinsulinemic clamp (i.e. a “gold-standard ” approach). Interestingly,
skeletal muscle is responsible for ∼80% of insulin mediated glucose up-
take.
47 Thus, targeting increased muscle mass and/or quality with re-
sistance exercise seems appropriate to reduce blood glucose in T2D. In
parallel, a meta-analysis of 14 studies reported that resistance training
in T2D lowered total cholesterol, LDL cholesterol, and triglycerides.
48
Recently too, a supervised progressive high-intensity resistance training
program performed 3 d/wk for 6 months in older patients with T2D
signicantly decreased both systolic and diastolic blood pressure.
49
Given that the mechanisms by which aerobic and strength train-
ing may reduce HbA1c dier, combining training programs may yield
greater benet. A combined aerobic resistance training regimen (30 min
aerobic at 40-80% HRR, plus 30 min resistance training at 40-60% 1-RM
for 6 exercises of 12 reps) decreased fasting blood glucose (-36 mg/dl),
triglycerides (-106 mg/dl), and signicantly increased fat free mass
( + 0.4 kg).
50 A meta-analysis of 915 participants across 14 trials com-
pared the glycemic benets across aerobic, resistance, and concurrent
training, through reductions in HbA1c. While both modalities conveyed
reductions in HbA1c, concurrent training saw the greatest reduction in
HbA1c (-0.17%), fasting glucose (-35.82 mg/dl), and triglycerides (-0.28
mmol/l).
51
Together, this evidence supports the notion that concurrent
training may be the most ecacious modality to improve glycemic con-
trol and blood lipids. The Health Benets of Aerobic and Resistance
Training in Individuals with Type 2 Diabetes (HART-D) and Diabetes
Aerobic and Resistance Exercise (DARE) randomized controlled trials
examined the eects of aerobic, resistance, and concurrent training reg-
imens in people with T2D. While the DARE trial
52
(Aerobic: 15-20 min
at 60% HRmax progressed to 45 min at 75% HRmax, resistance: eight
weight bearing exercises with progressive load increase, 2-3 sets with
eight rep max, aerobic + resistance) reported reductions in HbA1c across
all three exercise groups, the concurrent group reduced HbA1c the most
(-0.46% vs. aerobic training alone and -0.59% compared with resis-
tance training alone), suggesting concurrent exercise was better than
either training mode alone. However, a concern with this later trial was
the concurrent group performed twice the exercise volume than either
group. As such, it was not clear if the groups would observe similar re-
ductions in HbA1c had aerobic or resistance training increased volume
(or time). The HART-D trial,
53 however, was designed to match exer-
cise volume among modalities of exercise (aerobic: 12 kcal/kg/wk at
50-80% VO
2
max, resistance: 3 d/wk with 2 sets of 4 upper body exer-
cises, 3 sets of 3 leg exercises, and 2 sets of each abdominal crunches
and back extensions, combined: 10 kcal/kg/wk aerobic and 2 sessions
of one set one the aforementioned resistance exercises). It was reported
4

U.S.A. Syeda, D. Battillo, A. Visaria et al. American Journal of Medicine Open 9 (2023) 100031
that only concurrent training signicantly reduced HbA1c when com-
pared with the control group (-0.34%). This is consistent with the Ital-
ian Diabetes and Exercise Study showcasing concurrent exercise is eec-
tive at lowering HbA1c, LDL cholesterol, and blood pressure, compared
with standard of care.
54 It also corroborates evidence that short-term
high functional training (e.g. CrossFit) improved insulin sensitivity and
pancreatic function in people with T2D.
30 , 55
The relationship by which
exercise improves pancreatic function is beyond the scope of this re-
view, but increases in GLUT2 transporter content, Akt signaling, and
glucokinase activity. Further, mitochondrial function within the beta-
cell cell may be involved,
28
and muscles may relase cytokines that in-
uence beta-cell mass and/or function.
56 In either case, these studies
align with current ACSM and ADA guidelines recommending concur-
rent training and the inclusion of at least 2 resistance training days in a
week, as part of reaching at least 150 min of moderate intensity exercise
to impact glycemia.
High intensity interval training for glycemic control
While the benet of physical activity/exercise on glycemic control
in T2D is established, time constraints are a commonly reported bar-
rier to exercise,
57
as only ∼20% of U.S. adults currently meet physical
activity guidelines. High-intensity interval training (HIIT) has garnered
attention over recent years, providing a time-ecient means of improv-
ing glycemic control and cardiovascular health in those with T2D. In
comparison to other continuous high intensity exercise options, HIIT
was reported may bee enjoyable for some, despite the stronger feeling
of fatigue.
58 To this extent, some overuse injuries have been reported
during HIIT trials, although HIIT does not appear to place exercisers at
greater injury risk than traditional continuous exercise. Rather, as with
any exercise program, initial tness level should be taken into consider-
ation, so exercise acclimation periods are appropriate, and inclusion of
warmups and cool-downs are warranted. Thus, for those who are med-
ically cleared for a vigorous exercise program, HIIT can provide bene-
ts as an alternative to traditional, moderate intensity exercise.
59
Addi-
tional risk with high intensity training is exercise-related hypoglycemia,
particularly among insulin users. Non-insulin (or insulin secretagogue)
users on the other hand have minimal risk and would benet from high
intensity training to maintain glycemic status.
81
Importantly though, the
long-term utllity and adherence rates of HIIT has not been adequately in-
vestigated among people with prediabetes and T2D. Thus, incorporation
of HIIT is fair along with continuous exeercise for promoting exercise
volume.
Interval training consists of alternating exercise and recovery stages.
In HIIT, one may alternate 10 seconds to 4 min of high intensity aero-
bic exercise (e.g., 75-95% HRmax) with 12 seconds to 5 min of active or
passive recovery (e.g., 30-60% HRmax; Table 1 ). This contrasts with tra-
ditional continuous exercise, during which individuals maintain a given
intensity for a set period. In fact, high-intensity exercise often elicits a
heart rate response around 75-95% HRmax, and current guidelines from
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-
idence has emerged highlighting HIIT, similar to traditional continuous
high intensity exercise, can yield favorable glycemic control. Short-term
HIIT consisting of six sessions of 10 ×60-s cycling bouts, each reaching
∼90% HRmax, on the cycle ergometer over 2 weeks was shown to de-
crease average 24 hr blood glucose readings when measured with CGM.
Additionally, short-term HIIT training improved mitochondrial capac-
ity measured via muscle biopsies, suggesting that skeletal muscle has
greater oxidative capacity to utilize glucose as an energy source.
60 In
addition, pancreatic function in response to HIIT was examined in an
8-week cycling intervention in T2D. Participants were placed in a HIIT
exercise regimen (3 sessions/wk of 10 ×60-s cycling at ∼90% HRmax for
8 weeks). Compared to a matched healthy control group, HIIT reduced
fasting glucose concentrations, HbA1c, HOMA-IR (Homeostatic Model
of Assessment of Insulin Resistance, a proxy for insulin resistance), and
HOMA-b (an index of insulin secretion) as well as abdominal fat mass
compared to baseline.
61
In a meta-analysis of ∼1400 patients with T2D,
HIIT was shown to induce greater benet to HbA1c, HOMA-IR, fasting
serum glucose, and VO
2
peak than those exercising at moderate and low
intensities.
62
However, the meta-analysis did not compare standardized
energy expenditure across the groups, suggesting that groups potentially
performed dierent levels of work that prompted exercise adaptations
across intensities.
60 In either case, HIIT over 8 weeks, consisting of 3
sessions/wk of cycling (between 80-110% of peak power output), in-
creased aerobic capacity and reduced blood insulin concentrations and
HOMA-IR in adults with T2D, when compared with non-insulin resis-
tance non-obese controls.
63
Together, these ndings suggest HITT is an
eective program for glycemic control in T2D.
Whether HIIT is better than continuous training remains unclear.
64
When compared with 3 d/wk of continuous endurance training (40 min
of cycling at 50% peak workload), HIIT (10, 1-min intervals at 95%
peak, interspersed with 1-min active recovery between working inter-
vals) for 11 weeks promoted greater gains in VO
2
max but similar ben-
ets in HbA1c, fasting glucose, postprandial glucose, and HOMA-IR in
T2D, despite lower total energy expenditure and time requirement.
65
These ndings are consistent with a recent meta-analysis identifying
345 patients over 13 HIIT trials in patients with T2D had signicant re-
ductions in HbA1c (mean dierence: -0.37%), when compared to a non-
training control group.
66
Further, no signicant dierences were found
between groups in HOMA-IR or reducing CVD risk. In particular, a HIIT
cycling exercise regimen of 1 ×4 min of cycling at 90% peak VO
2
peak,
3 sessions/wk for 12 wk, in T2D decreased pulse wave velocity (PWV), a
measure of arterial stiness, as well as improved systolic blood pressure
to comparable levels of that of moderate intensity continuous training
(MICT).
67
Moreover, ow mediated dilation (FMD), a non-invasive ap-
proach to measure endothelial function, had similar benets between
HIIT and MICT in T2D.
68
While aerobic HIIT has incorporated treadmill vs. cycling modalities,
newer work has begun examining the utility of resistance HIIT to foster
tness and glycemia. A year-long trial comparing the eects of moder-
ate intensity to high intensity resistance training found more vascular
benet in those completing resistance HIIT. The HIIT group completed
10-12 repetitions of upper (seated row, seated lat pulldown, seated chest
press, and standing shoulder press) and lower limb (less press, one leg
lunge, and plank) exercises at 90% HR reserve (HRR), followed by 1
min of resting at 40-60% HRR, for 3 sessions/wk. The MICT group com-
pleted continuous cycling at 40-60% HRR. Carotid intima-media thick-
ness (cIMT), a measure used to diagnose the extent of carotid atheroscle-
rotic vascular disease, decreased in both groups, but only HIIT reduced
PWV, thereby favoring reduced arterial stiness.
69
Additional work ex-
amining resistance HIIT versus other combinations of continuous or HIIT
aerobic training in T2D awaits to be established for maximal glycemic
benet.
Exercise timing relative to daytime and meals
The timing of physical activity/exercise for optimal glycemic control
has recently become an area of intense research. Timing of activity im-
plicates both the time of day and before/after meals as being important
for long-term glycemic control and postprandial glucose spikes across
the day. To identify the best time to exercise, it is worth noting that cir-
cadian physiology has underlying inuence on glucose homeostasis. In-
deed, our body has circadian clocks as evidenced by diurnal oscillations
in a variety of physiologic processes that include body temperature, glu-
cose tolerance, circulating insulin, and adipose tissue-related hormones
(e.g. adiponectin, leptin, etc.). Interestingly, these processes all tend to
collectively be worse in the afternoon/evening compared with morning
among healthy individuals.
70
In turn, some reports suggest consuming
smaller meals may be benecial for glycemia next day compared with
traditional large dinner meals (e.g.. > 30% total kcals)
69
Furthermore,
people with T2D have a disrupted circadian rhythm such that insulin
5

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
sleep and into the morning, thereby raising plasma glucose (often called
the dawn phenomena).
71
This circadian misalignment may be improved
with exercise, although specic exercise work in T2D is needed. Such
diurnal oscillations suggest that glucose metabolism is “better ”at spe-
cic times during the day, and incorporating exercise based on this tim-
ing may result in greater glycemic control. To date, some
71-74
but not
all
75 , 76 research suggest physical activity in the afternoon or evening
may be more benecial for circulating glucose and insulin sensitivity,
compared to equivalent physical activities done in the morning in peo-
ple with and without T2D, on or o insulin therapy. Importantly, not
all outcomes seem to respond to afternoon exercise better than morning
exercise. In fact, work on body weight and food intake have recently
suggested morning exercise is better for weight management as well as
activity adherence.
77
Thus, determining the best time of exercise may be
outcome dependent. Practically speaking, though, activity should be en-
couraged whenever the patient is consistently able to t in their sched-
ule. Indeed, a retrospective cohort study
78
of the National Health and
Nutrition Examination Survey (NHANES) reported that physical activ-
ity amount, regardless of timing, was associated with lower all-cause
mortality in men and women. Thus, considering exercise timing to fos-
ter engagement and adherence is seemingly most relevant for glycemic
benet.
It should be noted that several studies have found post-prandial glu-
cose to be a stronger predictor of future CVD than fasting glucose.
79
As
a result, it might be appropriate to wonder whether people should exer-
cise before or after a meal to further rene the glycemic response, inde-
pendent of time of day. This eect could have concomitant benet on
vascular physiology by lowering postprandial glycemia-related endothe-
lial dysfunction and oxidative stress.
80
However, few studies have been
conducted on whether fasted states of exercise confer greater glycemic
benet than fed states in people with T2D. A consensus statement from
ACSM
81
concluded that current evidence suggests postprandial exercise
provides better glucose control by attenuating acute glycemic spikes,
regardless of exercise intensity or type, with a longer duration ( ≥ 45
min) providing the most consistent benets.
78 However, it should be
mentioned that, of studies, only Francois et al.
82
showed that “exercise
snacking ”(6 ×1 min intense incline walking at 90% HRmax on a tread-
mill) 30 min before a meal reduced 3-h postprandial blood glucose af-
ter breakfast and dinner among patients with T2D or insulin resistance,
compared to traditional 30 min moderate-intensity (60% HRmax). Ad-
ditionally, Edinburgh et al.
83
found that moderate-intensity cycling (60
min performed at 65% VO
2
peak for 6 weeks) prior to carbohydrate in-
gestion improved postprandial insulin sensitivity and reduced insuline-
mia and lipemia, but not plasma glucose, among overweight/obese men.
Other studies showed that brief exercises after meals blunted glucose
spikes. For instance, these brief exercises included (a) 3 sets of 1-min
light intensity jogging + 30 s of rest; total duration of 4 min for each
exercise bout, every 30 min throughout the day, 20 times in total; (b)
3 sets of 15 min bouts at 3 METs after a meal
84
; (c) resistance exercise
(up to 40% of their bodyweight)
85 (d) 10 ×1 min HIIT (10 ×1 min
work-bouts at 95–120% of individual peak power output, separated by
1 min low-intensity cycling)
72
; and (e) 4 bouts including 3 min at 56.5
± 3.9 % VO
2
max after breakfast.
86
Interestingly, postprandial exercise
also reduced acute elevations in serum triglyceride levels after high-fat
meals and reduced functional derangements from lipid-induced oxida-
tive stress
87-89
, suggesting post-meal exercise may benet both glucose
and lipids to support cardiovascular health. Collectively, these ndings
suggest “exercise desserts ” immediately post-meal may yield optimal
benet for attenuating postprandial spikes.
Breaking up sedentary activity with physical activity
Sedentary behavior is now recognized as an independent risk fac-
tor for chronic disease. Based on a NHANES analysis, U.S. adults spend
nearly 8 hr/d on average being sedentary.
88
Sedentary behavior is gen-
erally dened as any waking behavior characterized by a low level of
energy expenditure (less than or equal to 1.5 METs) while sitting, re-
clining, or lying (e.g. TV-watching, screen time).
90,91
This is clinically
concerning since high sedentary activity (e.g. generally ≥ 8 hrs) is asso-
ciated with increased risk of all-cause mortality, cardiovascular disease,
and T2D.
92
Remarkably, every 1 hr increase in sedentary activity above
8 hr/d was associated with an 8% increased risk of cardiovascular mor-
tality and 1% increase in risk of T2D.
92
In another cohort, 1 extra hr of
sedentary time over an 8 d period was associated with 22% increased
odds of T2D adults aged 45-70 yr.
93
Additionally, greater sedentary time
was associated with hyperglycemia and incident T2D independent of
physical activity levels in a multi-ethnic U.S. population.
94
Given the alarming public health implications of sedentary activity,
independent of physical activity, health professionals and researchers
have revised the 2
nd
edition
95
of the U.S. Physical Activity Guidelines
for American to include sedentary activity as an independent risk factor
for all-cause and cardiovascular mortality and incident T2D. This recom-
mendation is, in part, based on interventional studies showing benets
in glycemic control upon breaking up sedentary activity and/or replac-
ing sedentary time with light-intensity or moderate-intensity activity.
For example, interrupting prolonged sitting with activity breaks, such
as light-intensity walking or simple resistance activities (half-squats, calf
raises, gluteal contractions, and knee raises) for 3 min every 30 min over
8 hr, decreased postprandial glucose incremental area under the curve
by ∼14 mmol/h/L among previously inactive adults with T2D.
96 Re-
placing sitting time with standing (2.5 hr/d) and light-intensity walking
(totaling 2.2 hr/d) every 30 min also improved 24hr glucose levels and
insulin sensitivity, even more so than structured, moderate-level cycling
activity for 1.1 hr/d in individuals with T2D.
97
However, Loh et al.,
98
in a meta-analysis of trials comparing breaking up sedentary activity to
continuous sitting to prevent T2D demonstrated only a small decrease
in standardized mean plasma glucose for breaking up sedentary activity
after matching for energy expenditure. Similarly, the evidence is unclear
whether breaks from sitting have clinically relevant impacts on hyper-
glycemia in free-living environments.
99 , 100 Interestingly, less-frequent
active interruptions (sitting interrupted with 6 min of simple resistance
exercises every 60 min) improved acute post-prandial glycemic control
post-lunch, while more-frequent interruptions (3 min resistance exer-
cises every 30 min) were more benecial for nocturnal glucose in those
with medication-controlled T2D.
101
Although less researched, short, high-intensity exercises may also
have glycemic control and other cardiometabolic benets as seen in
light- and moderate-intensity exercises. For example, a review on “ex-
ercise snacks ”(isolated bouts of vigorous exercise lasting ≤ 1 min)
102
summarized several RCTs describing improvements in cardiorespiratory
tness (e.g. VO
2
peak and peak power output).
102-104
The exercise pre-
scriptions for these studies included: 1) three daily bouts of vigorous
stair climbing (climbing 60 steps as fast as possible)
105
; 2) three isolated
20-second “all-out ”cycling bouts, about 1-4 hr apart daily; 3) stair-based
exercise snacks ( ∼15–30 sec)
106
; and 4) 5 ×4-second maximal cycling
sprints on a specialized ergometer, once per hour.
107
In addition to exercises, it is also of interest to investigate the eects
of ‘domestic’ physical activity on glycemic control as domestic chores
are the main contributors to total daily physical activity in older patients
with T2D.
106
Few studies have been done isolating household activity
eects on glycemic control, with even fewer to none among patients
with T2D. Li et al.
107
in a cohort study of the UK Biobank among partic-
ipants without diabetes, reported that replacing 30 min/d of sedentary
activity with daily activities (e.g. walking for pleasure, pruning, water-
ing the lawn, weeding, lawn mowing, car maintenance etc.) resulted in
a 6-31% risk reduction in T2D. Stair climbing (6 continuous repetitions
of climbing to the second oor (21 steps) at a rate of 80-110 steps/min)
signicantly reduced postprandial glycemia at 150 min post meal com-
pared to resting,
108
but not necessarily 24 hr glucose or long-term hy-
perglycemia, as evidenced by minimal change in 24 hr glucose compar-
ing 60-sec pulses of vigorous stair-climbing to resting over 6 weeks.
109
6

U.S.A. Syeda, D. Battillo, A. Visaria et al. American Journal of Medicine Open 9 (2023) 100031
When taking together, it seems reasonable to conclude that interven-
tions breaking up sedentary activity are favorable in at least providing
acute glycemic benet.
Observational and some experimental studies
110-114
, but not
all,
115 , 116
on breaks in sedentary time aecting blood pressure and lipid
levels have implied similar improvements on other cardiovascular risk
factors. For example, Dempsey et al.
114
reported that interrupting seden-
tary time with brief bouts of walking among patients with T2D produced
small yet signicant decreases in blood pressure (SBP/DBP: 14 ± 1/8 ± 1
mmHg). Champion et al.,
112
among healthy adults aged 18-55yr, found
that sitting time interrupted hourly with 20 min light-intensity treadmill
desk walking between 1.2-3.5 km/h acutely reduced plasma glucose,
triglycerides, and blood pressure modestly (3-4% decrease). Certainly,
more long-term work is needed as well as investigation on other car-
diovascular risk factors and measurements in patients with T2D such as
blood pressure, LDL cholesterol, endothelial function, coronary artery
calcium, and arterial stiness. Importantly, these breaks in sedentary
behavior with physical activity need not be structured exercise sessions
(e.g. 30-60 min of moderative vigorous movement), and light-intensity
activities (e.g. household activities) and/or resistance exercise may be
feasible for impacting cardiometabolic health. Thus, in individuals who
are unable to do conventional moderate or vigorous exercise for 150
min/wk or 75 min/wk, respectively, other modes of movement broken
up throughout the day may serve as suitable alternatives provided they
are done consistently.
Exercise cardiometabolic benefit beyond weight loss
Exercise as a part of lifestyle recommendations promotes weight loss
of 5-10%. Yet, many acknowledge that increases in energy expenditure
via exercise alone may not induce weight loss if energy intake is not
kept constant and/or if alterations in non-exercise physical activity oc-
cur such that people sit more. In fact, recent work highlights that despite
high energy expenditure from exercise, adaptative thermogenesis (i.e.
metabolic adaptation) occurs during weight loss in some people such
that their resting metabolism declines, and this makes losing weight
and/or maintaining weight loss challenging.
117 , 118
Thus, it is essential
to acknowledge that weight loss is just one measure of T2D and CVD
risk reduction that does not exclude other health benets.
One the main health benets observed from exercise, independent of
weight loss, is the shift in body composition. Specically, exercise often
maintains/increases fat-free mass (e.g. muscle mass) and reduces total
body fat and/or visceral fat (VAT). Indeed, a recent meta-analysis
119
revealed that exercise interventions that follow ACSM-based moderate
to high intensity exercise (40-90% VO
2
max) for 30-60 min/d, showed
a marked reduction in total body fat, accompanied with a signicant
decrease in triglycerides. Others
120 have also showed that high inten-
sity exercise (60-75% VO
2
max) for 3-5 d/wk was more eective than
continuous moderate exercise in reducing total body fat percent in peo-
ple with obesity, independent of BMI, along with 17% higher VO
2
max.
These ndings suggest intensity of exercise may be ideal for body fat
reduction. In fact, several studies
121-124 report eects of aerobic exer-
cise on reducing VAT, while emphasizing that adherence and intensity
of exercise may play a signicant role. This is clinically relevant since
VAT is the fat deposited around the abdominal organs and is considered
tightly associated with