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Exercise in the Prevention and Treatment of
Type 2 Diabetes
John P. Kirwan,* Elizabeth C. Heintz, Candida J. Rebello, and Christopher L. Axelrod

ABSTRACT
Type 2 diabetes is a systemic, multifactorial disease that is a leading cause of morbidity and
mortality globally. Despite a rise in the number of available medications and treatments avail-
able for management, exercise remains a first-line prevention and intervention strategy due to
established safety, efficacy, and tolerability in the general population. Herein we review the pre-
disposing risk factors for, prevention, pathophysiology, and treatment of type 2 diabetes. We
emphasize key cellular and molecular adaptive processes that provide insight into our evolving
understanding of how, when, and what types of exercise may improve glycemic control. © 2023
American Physiological Society. Compr Physiol 13:1-27, 2023.

Didactic Synopsis low-income nations (44, 153, 263). Furthermore, diabetes is

a primary risk factor for the onset and progression of numer-
Major teaching points ous conditions such as cardiovascular disease, neuropathy,
nephropathy, retinopathy, Alzheimer’s disease, depression,
• Physical activity is a safe and practical lifestyle interven-
cancer, and coronavirus disease 2019 (COVID-19) (102,
tion for the treatment, prevention, and management of
334). Despite increasing prevalence and socioeconomic
type 2 diabetes across the lifespan.
burden its incidence has decreased from 0.9% to 0.6% of the
• Exercise improves whole-body glucose uptake primarily population over the past 10 years (44), indicating that current
by enhancing multi-organ insulin sensitivity and glucose preventative, diagnostic, interventional, and treatment are
disposal. effective in limiting the course of the disease.
Lifestyle and behavioral modifications are first-line therapy
• Both aerobic and resistance exercise improves biochem-
for preventing new-onset and transition from prediabetes to
ical markers of type 2 diabetes and multi-modal training
diabetes (7). Lifestyle and behavioral interventions such as
approaches result in synergistic and additive benefit.
dietary restriction and exercise training remain an essential
• Exercise training decreases the risk of cardiovascular dis- strategy for disease management due to well-established
ease, excessive adiposity, and systemic inflammation in safety, efficacy, tolerability, and accessibility in the general
patients with type 2 diabetes. population. More specifically, these interventions are gen-
erally easy to prescribe, making them preferable as a first
• Combined pharmacological, surgical, and lifestyle
option for disease prevention and management (7). Despite
approaches yield maximal biochemical remission of type
the potential glycemic benefits, there are numerous drawbacks
2 diabetes. However, additional research on the effects of
and limitations that often restrict real-world implementation
exercise in combination with medication is required to
of exercise training regimens for the treatment and manage-
determine safety and population-level efficacy.
ment of the disease. As such, the ability to provide precise
guidelines and recommendations for exercise in the treat-
ment and management remains essential to enhance clinical
Introduction utility and outcomes.
Herein we review the role of exercise in the treatment
Adult-onset type 2 diabetes, in contrast to juvenile or insulin- and management of diabetes with an emphasis on targeting
dependent diabetes, is a chronic, multifactorial disease pathophysiological mechanisms of disease. Additionally,
characterized by sustained impairments in glycemic con-
trol resulting from multi-organ metabolic derangements. The
prevalence of type 2 diabetes, hereafter referred to as diabetes, *Correspondence to [email protected]
continues to rise, affecting approximately 7% of the popula- Integrative Physiology and Molecular Medicine Laboratory,
tion globally and approximately 10% or 34 million adults in Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
the United States alone (44, 153). It is the ninth leading cause Published online, April 2023 (comprehensivephysiology.com)
of death worldwide and the seventh in the United States, DOI:10.1002/cphy.c220009
presenting a large socioeconomic burden on both high- and Copyright © American Physiological Society.

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Exercise and Type 2 Diabetes Comprehensive Physiology

we provide insight on how, when, and what types of exercise to TCF7L2, PPARG, IRS1, IGF1, CPT1A, and KCNQ1,
may improve glycemic control, compare exercise to gold among others (24, 185, 186). Furthermore, recent studies
standard and standard-of-care therapies, and address possible have investigated the role of ethnicity on type 2 diabetes
and known interactions between multiple treatment methods. incidence and heritability, specifically for minority popu-
lations in the United States and the United Kingdom, to
better characterize disease risk in historically understudied
Pathophysiology of Type 2 Diabetes populations (1, 65, 98).

Glucose is a tightly regulated metabolite that is maintained

through multi-organ hormonal feedback systems. Low glu- Impact of environmental factors on diabetes
cose conditions promote the release of glucagon, a hormone development
secreted by pancreatic alpha cells, to stimulate glycogenol- Environment includes a diversity of factors related to the sur-
ysis until homeostasis is achieved. High glucose conditions roundings and/or conditions in which an individual operates.
promote the release of insulin, a hormone secreted by pan- A number of environmental factors are associated with
creatic β-cells, to stimulate glucose uptake into the brain and risk of diabetes, including air and water quality, degree of
peripheral tissues such as skeletal muscle, adipose tissue, and urbanization, noise pollution, food accessibility and secu-
liver. Additionally, glucose can self-regulate production and rity, income status, home and neighborhood safety, exercise
uptake in the absence of insulin and glucagon, referred to as safety and accessibility, and health services. While low
glucose effectiveness. In a simplistic view, diabetes reflects socioeconomic status has long been identified as a significant
a state when glucose homeostasis is no longer defended. predictor of obesity development and subsequent diabetes
However, diabetes is preceded by an extended period, often risk (137, 317), this factor is largely tied to other environ-
10 to 20 years in adult humans, where the rise in fasting mental factors that contribute to overall poorer health quality.
glucose is prevented by hyperinsulinemia, or the chronic Despite having healthcare access and insurance, compo-
excess release of insulin. During this state, insulin secretion nents such as transportation and proximity of a patient’s
acts as a compensatory mechanism to maintain blood glu- primary treatment facility remain barriers to receiving health
cose. Over time, however, cells develop insulin resistance, a services (248). A lack of access to recreational facilities
maladaptive process characterized by the inability of insulin and concerns regarding neighborhood safety have been
to stimulate glucose uptake and/or restrict hepatic glucose shown to further hinder lifestyle modifications that aid in
production. This occurs through decreased insulin sensitivity, prevention and deter diagnosed patients from exercise as a
where higher concentrations of insulin are required to induce treatment (228). More recently, environmental factors related
a similar biologic response, or through decreased responsive- to urbanization and climate change have been indicated
ness, where the overall dose-response to insulin is decreased, to increase risk (224), as causative links between dysreg-
or a combination of the two (142). Near the onset of diabetes, ulated glycemic control and air pollution; light exposure
progressive insulin resistance, loss of glucose effectiveness, and noise levels are also developing areas of investigation
and hyperinsulinemia contribute to β-cell fatigue, ultimately (2, 147, 300).
leading to insufficient insulin production to support glucose
homeostasis. As the disease progresses, β-cell fatigue results
in functional decline and eventual apoptosis, death, and/or Lifestyle and behavioral risk factors associated with
cellular senescence. At this stage, endogenous glucose home- type 2 diabetes
ostasis is rendered dysfunctional and clinical intervention Lifestyle and behavior are primary contributors to the onset,
is necessary to prevent uncontrolled hyperglycemia and progression, and severity of diabetes. Sedentarism, broadly
associated morbidities. defined as spending <10% of daily energy expenditure on
movement, physical activity, and/or exercise, is indepen-
dently associated with risk of developing the disease and
Genetic factors of type 2 diabetes its related complications (95, 108, 180, 325). The impact
Type 2 diabetes can result from individual and/or combined of sedentary behavior on diabetes is generally attributable
genetic, environmental, lifestyle, and behavioral factors. In to the central role of skeletal muscle contraction in energy
adults, there are more than 150 known DNA mutations as utilization. For example, skeletal muscle accounts for >80%
well as countless epigenetic factors associated with type 2 of whole-body glucose disposal in adults, and this can be
diabetes. The predictive power of such genes and epigenetic augmented by vigorous physical activity.
modifications is limited since the majority of patients with Excessive energy intake without increased energy expen-
this type of diabetes have obesity, which is associated with diture is the primary lifestyle contribution to diabetes risk.
distinct genetic and epigenetic traits. Nevertheless, genetic Western dietary patterns are associated with increased risk of
and epigenetic alterations account for approximately 10% of diabetes in the general population. Specific dietary macronu-
the heritability of type 2 diabetes (24). These mutations are trients such as long-chain free fatty acids can induce insulin
commonly linked to β-cell function and include alterations resistance in the absence of other risk factors such as obesity.

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Comprehensive Physiology Exercise and Type 2 Diabetes

Of note, factors such as food preference, eating behavior, and

meal timing are not strictly the function of lifestyle but are
Exercise and Type 2 Diabetes Risk
heavily influenced by individual genetic and proteomic make- Regular exercise can induce both phenotypic and metabolic
ups, particularly in the brain, that regulate desire, disinhibi- improvements, and thus, it is often prescribed for both the
tion, impulse control, and food preferences (178). treatment and prevention of T2D and other cardiometabolic
diseases. Similar to insulin, a single bout of exercise has
been shown to increase the rate of skeletal muscle glucose
Clinical Diagnosis and Management of uptake via glucose transporter type 4 (GLUT4) regulation
(68, 167). While exercise and insulin act through different
Type 2 Diabetes pathways, both are capable of leading to increased glucose
Type 2 diabetes is formally diagnosed based upon several bio- transport by activating GLUT4, leading to increased muscle
chemical determinations: (i) glycated hemoglobin (HbA1c ) glucose uptake (188). The fact that skeletal muscle con-
levels ≥6.5% (48 mmol/mol), (ii) fasting plasma glucose traction is capable of inducing substantial improvements
(FPG) ≥126 mg/dL (7.0 mmol/liter) on two separate occa- in insulin sensitivity and glucose uptake, while physical
sions, glucose levels ≥200 mg/dL (11.1 mmol/L) 2 h after a inactivity causes decreased insulin action, is a phenomenon
75 g oral glucose tolerance test (OGTT), or a random glucose that highlights the necessity of exercise in maintaining glu-
≥200 mg/dL (11.1 mmol/liter) in symptomatic patients (8). cose homeostasis (290), specifically in the case of diabetes
Prediabetes, or a state of chronically impaired glycemic development due to compounding lifestyle and behavioral
control that precedes the onset of diabetes, is diagnosed factors. Furthermore, there is evidence that long-term regular
using the same tests with the following criteria: HbA1c exercise can reduce diabetes risk and that exercise train-
5.7% to 6.4% (39–47 mmol/mol), FPG 100 to 125 mg/dL ing is a critical primary treatment and adjunct therapy for
(5.6–6.9 mmol/L) on two separate occasions, and glucose improving clinical markers of diabetes (100). Additionally,
levels 140 to 199 mg/dL (7.8–11.0 mmol/liter) (8). as insulin resistance is associated with high levels of lipid
Patients with impaired glucose tolerance (IGT), predi- stored in skeletal muscle (135, 227), exercise, particularly
abetes, or diabetes are counseled at the time of diagnosis aerobic exercise, has been reported to decrease skeletal
on the need to engage in a healthy and balanced diet muscle lipid products and increase lipid oxidative capacity
and regular physical activity to achieve glycemic control. with as little as a single bout of exercise (308). Therefore,
First-line pharmacotherapy consists of the biguanide met- aerobic exercise may prevent insulin resistance by correcting
formin combined with comprehensive lifestyle management. the mismatch between fatty acid uptake and oxidation in
If glycemic targets are not achieved with metformin, skeletal muscle (307). Muscle contraction may also protect
treatment is escalated according to patient goals, co- against lipid-induced insulin resistance by stimulating glu-
morbidities, severity of disease, affordability, and acces- cose uptake and preventing the inhibitory effect of palmitate
sibility. Food and Drug Administration (FDA)-approved on insulin signaling (220), providing evidence that muscle
pharmacotherapies include alpha-glucosidase inhibitors, contraction and exercise may be an effective stimulus to
biguanides, bile acid sequestrants, dopamine-2 agonists, prevent lipid-induced obesity and diabetes. Regular exercise
dipeptidyl peptidase-4 (DPP-4) inhibitors, meglitinides, also induces phenotypic shifts in adipose tissue, which may
sodium-glucose cotransporter-2 (SGLT2) inhibitors, sulfony- underlie the generally superior health of physically active
lureas, thiazolidinediones (TZDs), glucagon-like peptide 1 populations (5), further supporting the role of exercise in
(GLP1) analogs, and oral combination therapy. Metformin disease prevention.
is the primary antidiabetic drug intervention, with approx-
imately 79% of patients prescribed metformin as an initial
treatment, while sulfonylureas glipizide, glimepiride, or Impact of exercise type, intensity, and timing
glyburide are currently the most common secondary and The most commonly prescribed forms of structured physical
combined pharmacological intervention (207). activity are aerobic exercise, where whole body oxygen con-
For persons with obesity, diabetes may also be treated sumption rate is increased; resistance exercise, where muscle
by surgical therapy. Bariatric and metabolic surgery (BMS) strength training modalities are targeted; or a combination of
procedures include vertical sleeve gastrectomy (VSG) and the two. While each confers different physiological benefits,
Roux-en-Y gastric bypass (RYGB); less frequently used as resistance exercise leads to greater increases in muscle
surgeries include adjustable gastric banding (AGB), biliopan- mass and strength while aerobic exercise confers greater
creatic diversion (BPD) with Duodenal switch, and single benefits to cardiorespiratory function, both are effective at
anastomosis duodeno-ileal bypass with sleeve gastrectomy. improving overall health (166).
As of 2021, VSG (∼65%) and RYGB (∼18%) account Multiple large-scale randomized controlled trials have
for the majority of operations. BMS procedures are often been conducted to evaluate the impacts of different types
combined with lifestyle and behavioral intervention and of exercise on metabolic improvements. One of the earliest,
pharmacotherapies to maximize efficacy and durability of the Diabetes Aerobic and Resistance Exercise (DARE) trial,
glycemic benefit. investigated the effects of aerobic, resistance, or combined

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Exercise and Type 2 Diabetes Comprehensive Physiology

training in patients with diabetes for 6 months, concluded Exercise timing may also have an impact on associated
that combination exercise conferred greater benefits and disease improvements. A randomized cross-over trial found
induced significantly more robust decreases in HbA1c than that HIIT in the afternoon had greater impact on lowering
either exercise type alone (269). Likewise, a follow-up study, blood glucose than morning HIIT sessions (257). Another
the Health Benefits of Aerobic and Resistance Exercise study found that postdinner exercise improved postprandial
Training in individuals with type 2 diabetes (HART-D) trail glucose and triglycerides, while predinner exercise only
controlled for work intensity between groups, and discovered improved glucose levels, indicating that postfeeding exercise
that aerobic exercise is more efficacious than resistance may be more optimal for improving diabetes symptoms
exercise in terms of HbA1c reduction, but the combination (119). While more research is needed on how timing impacts
of both aerobic and resistance exercise was still more ben- the benefits of exercise, especially with larger-scale studies,
eficial (52). Interestingly, the Resistance versus Aerobic exercise timing should be a consideration when planning and
Exercise training in type 2 diabetes (RAED2) trial showed evaluating the impacts of exercise interventions, as it may
that both resistance and aerobic exercise training for 4 months influence outcomes.
induced similar increases in hyperinsulinemic-euglycemic
clamp-derived insulin sensitivity while functional improve-
ments such as VO2max and maximum strength were specific Exercise as a prevention approach for type 2
to each training group (15). However, as VO2max is an diabetes
independent and significant predictor of insulin sensitivity In general, regular exercise improves cardiorespiratory fit-
(278), aerobic exercise is often assumed to be slightly more ness, lipid profiles, and glycemic control in individuals in
beneficial than resistance exercise in regulating diabetes both healthy and diseased states (183). A meta-analysis
symptoms. Nevertheless, the impacts of resistance exercise evaluating physical activity and diabetes incidence found that
cannot be discounted, as resistance exercise still confers there is a nonlinear relationship between exercise and disease
benefits in glucose and insulin signaling and is necessary for outcomes, with the greatest benefits of exercise occurring in
the maintenance of muscle mass and hypertrophy. Though those who were previously sedentary (273). Similarly, another
both aerobic and resistance exercise alone are capable of study on exercise and disease incidence reported that the rela-
lowering HbA1c , greatest improvements seem to occur with tionship between exercise frequency and lower disease risk
combination training (52, 269). Thus, the American Diabetes follows a J-shaped curve, with even moderate levels of phys-
Association (ADA) recommends combined aerobic and resis- ical activity significantly reducing diabetes risk in healthy
tance exercise for controlling glucose and lipids in diabetes individuals (155). Specifically, 16 weeks of exercise training
(58). However, more research is needed on the additive and improved insulin sensitivity in a dose-dependent manner
synergistic effects of combination exercise training (159). independent of age and gender, with no evidence of a maxi-
Collectively, despite disparities in the types and intensities mal dose response to exercise (70), providing strong evidence
of exercise that are best for treating and preventing diabetes, that exercise conveys health benefits and may prevent
some form of regular physical activity is far more favorable disease development even in healthy individuals. Further-
to none. more, endurance exercise training improved adipose tissue
It is also important to consider exercise intensity when insulin sensitivity and metabolic flexibility in healthy men
examining health outcomes associated with exercise, as and is associated with better insulin profiles and responses
intensity has been shown to greatly impact exercise benefits, compared to untrained healthy individuals (78, 245).
despite exercise modality. For example, aerobic high-intensity While exercise training appears to be an effective preven-
interval training (HIIT) has been reported to be more effec- tion strategy for healthy individuals, there is also evidence
tive than continuous aerobic training in both db/db mice that exercise may slow or even prevent diabetes onset in
and humans, with greater improvements in HbA1c , VO2max , patients who are overweight or have obesity and prediabetes.
body weight, and adipose tissue and skeletal muscle insulin In patients who are overweight, short-term exercise training
signaling resulting from interval training (45, 64, 302). Addi- has been shown to improve body mass index (BMI), fat mass,
tionally, interval training was more effective than continuous glucose tolerance, and insulin sensitivity, as well as reduce
training in improving lipoprotein profiles and reducing liver hepatic and skeletal muscle insulin resistance and C-reactive
lipid content in both prediabetic and patients with diabetes protein levels (115, 151, 193, 218). Additionally, VO2max has
despite similar alterations in substrate oxidation and lipid been shown to be inversely associated with HbA1c , fasting
metabolism (144, 211). Furthermore, interval training has glucose, and glucose tolerance responses in a mixed popula-
been shown to improve glucose effectiveness significantly tion of healthy individuals and patients with prediabetes or
more than continuous training in patients with diabetes diabetes (278), further suggesting that exercise may protect
(143); therefore, it is important to consider the intensity of against diabetes outcomes. Likewise, a meta-analysis on
exercise interventions when examining the corresponding adults with prediabetes found that long-term lifestyle inter-
impacts on metabolism and overall health improvements, as vention including regular exercise lowered diabetes incidence
higher intensity exercise appears to be associated with more in a 23-year follow-up (181), suggesting preventative actions
favorable outcomes. of exercise on diabetes development. Another meta-analysis

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Comprehensive Physiology Exercise and Type 2 Diabetes

reported that 100 min/week of physical activity decreased phosphatidylinositol 3-kinase (PI3K) docking to IRS. PI3K
both fasting glucose and HbA1c in participants across the glu- stimulates membrane recruitment of phosphatidylinositol-
cose tolerance spectrum, with the positive effects of exercise 3,4,5-triphosphate (PIP3), which reciprocally recruits
being more profound in individuals with worse glucose phosphatidylinositol-3,4,5-triphosphate-dependent kinase
tolerance (29). Furthermore, in obese adults with prediabetes, (PDK1) and protein kinase B (AKT). PDK1 triggers a
12 weeks of exercise intervention enhanced β-cell function phosphorylation cascade, initiated with AKT and followed
and glucose-stimulated insulin secretion in association with by Akt substrate of 160 kDa (AS160), facilitating plasma
improvements in VO2max despite no change in body fat (194), membrane GLUT4 vesicle translocation, uptake of glucose,
providing evidence that exercise may play a significant role and glycogen synthesis (162, 244, 252). Preceding the onset
in mediating diabetes onset independent of weight loss. of diabetes, muscle cells become resistant to endogenous
Importantly, the beneficial effects of exercise to lower HbA1c insulin action while receptor and binding activity remain
occur in a dose-dependent manner, with 150 min/week of normal. This condition, known as insulin resistance, is an
physical activity inducing significantly greater improvements early pathogenic trait that contributes to hyperglycemia by
than exercising for less than 150 min/week (310). While this increasing the amount of insulin (and subsequently β-cell
highlights the added benefits of increased exercise duration, output) required to maintain plasma glucose homeostasis.
increasing the intensity of shorter exercise sessions has also Proximal signaling factors such as IRS-1, PI3K, AKT, and
been shown to have a similar effect on improving markers GLUT4 have augmented activity in patients with diabetes
of glycemic control in patients with prediabetes (64). Taken (132). These augmentations may entirely account for the
together, these findings highlight exercise for the prevention diminished sensitivity to insulin observed in patients with
and treatment of diabetes in both healthy and prediabetic IGT, prediabetes, or diabetes, though the net contribution
populations. remains somewhat unclear.
Exercise is one of the most rapid and effective means of
improving skeletal muscle insulin sensitivity (243), with
Impacts of Exercise on Glycemic Control measurable adaptation within days of initiating training (49).
Unlike endogenous insulin, which requires receptor signaling
in Type 2 Diabetes to activate AKT, muscle contraction can directly increase
Both aerobic and resistance exercise training have been glucose uptake via AMP-activated protein kinase (AMPK)
shown to improve glycemic control (15, 159, 269), and even activation of the GLUT4 cascade (26, 161, 221, 235). Like
small changes in habitual physical activity, such as increases any treatment, the effects of a single “dose” of exercise on
in daily walking by 400 steps, convey benefits on glucose insulin sensitivity dissipate within 48 to 72 h; thus, regular
regulation in patients with diabetes (332, 333). Exercise has and repeated exercise is necessary to induce chronic benefits
been shown to increase insulin action (117, 172), mediate in insulin sensitivity (40, 113, 117, 158, 322). Furthermore,
the secretion of cytokines such as interleukin 6 (IL-6) from the magnitude and extent of exercise-induced insulin sen-
skeletal muscle that can stimulate insulin secretion via GLP1 sitivity depend largely on exercise volume, intensity, and
production (77), improve β-cell function by reducing non- mode. While aerobic and resistance exercise increase insulin
pulsatile basal insulin secretion while enhancing pulsatile signaling via phosphorylation of AS160 and activation of
secretion (78), and resynchronize the circadian rhythmicity IRS-1 in skeletal muscle, the greatest effects are observed
of hormones and related physiology (328). Moreover, it with combination training (92, 130, 140).
can be broadly concluded that the benefits of exercise for
patients with diabetes can be achieved by aerobic, resistance,
and combination training (140), though different exercise
Aerobic exercise and glycemic control in type 2
modalities may have greater impacts on discrete metabolic diabetes
outcomes. Aerobic exercise facilitates numerous metabolic improve-
ments, including enhanced glucose regulation and insulin
sensitivity (Table 1), primarily through the recruitment of
Exercise training and insulin sensitivity in patients large muscle groups and associated cardiorespiratory func-
with type 2 diabetes tional improvements (120). Short-term increases in aerobic
Skeletal muscle glucose uptake is predominantly mediated by exercise via interval walking have been shown to improve
action of the insulin receptor, a concept that has been reviewed glucose effectiveness by approximately 50% in patients
extensively elsewhere (290). Rapid substrate exchange at with diabetes (143). However, while this robust improve-
the cellular level is maintained by a high affinity and sen- ment was associated with an amelioration of mean and
sitivity to the peptide hormone insulin and/or molecules peak glucose levels over a 24-h period, insulin sensitivity
mimicking its structure and activity. Insulin, insulin mimet- remained unchanged. Interestingly, longer intervention peri-
ics, and/or analogs activate the insulin receptor tyrosine ods report improvements in insulin sensitivity as well (145).
kinase, resulting in insulin receptor substrate (IRS) recruit- For example, 12 weeks of aerobic training has been shown to
ment and phosphorylation at multiple residues, triggering concurrently improve insulin sensitivity and reduce fasting

Volume 13, April 2023 5

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Table 1 Effects of Aerobic Exercise Training on Glycemic Control in Type 2 Diabetes

Aerobic exercise study Exercise prescription Duration Impact on glycemic control Secondary outcomes

Bacchi et al. (15) 60 min/day, 3 days/wk on cardiovascular training 4 months ↓ HbA1c , ↓ FPG, ↑ GDR ↑ VO2peak , ↓ BMI, ↓ fat mass, ↓ VAT, ↓ SAT,
equipment, progression to 60%–65% HRR ↑ lean mass
Church et al. (52) 12 kcal/kg at 50%–80% VO2max per wk 9 months ↔ HbA1c ↓ Waist circumference
Earnest et al. (73) 12 kcal/kg at 50%–80% VO2max per wk 9 months ↓ Metabolic syndrome score ↓ Waist circumference, ↓ SBP, ↑ VO2peak
Exercise and Type 2 Diabetes

Haus et al. (114) 1 h/day, 5 days/wk at 65% VO2max 12 wks ↓ Basal HGP, ↓ insulin-stimulated HGP, ↓ Body weight, ↓ abdominal fat, ↓ VAT
↓ hepatic insulin resistance
Jorge et al. (140) 1 h/day, 3 days/wk of cycling at HR corresponding 12 wks ↓ FPG, ↓ PPG, ↔ HbA1c , ↔ HOMA-IR, ↔ BMI, ↓ total cholesterol, ↓ TG, ↑ VO2peak ,
to lactate threshold ↑ IRS-1 ↓ blood pressure, ↓ c-reactive protein,
Karstoft et al. (144) 1 h/day, 5 days/wk of continuous (75%–80% 2 wks ↑ Glucose effectiveness, ↔ FPG, ↔ FPI ↔ Body mass, ↔ fat mass, ↔ RER, ↔ c-peptide
VO2max ) or interval (alternating 3 min sets of ∼60%
and ∼90% VO2max ) treadmill walking
Kasumov et al. (145) 1 h/day, 5 days/wk of treadmill or cycle ergometer, 12 wks ↓ Fasting insulin, ↑ glucose-stimulated ↓ Body weight, ↓ BMI, ↓ fat mass, ↓ TG, ↓ total
progression from 60% MHR to 80% MHR insulin disposal cholesterol, ↑ VO2max , ↓ plasma ceramides
Kirwan et al. (160) 50–60 min/day of cycling or treadmill walking at 7 days ↓ FPG, ↓ FPI, ↑ GDR, ↓ HGP ↔ Body weight, ↔ BMI, ↔ % body fat
80%–85% MHR
Ku et al. (168) 1 h/day, 5 days/wk of walking at 3–5 METs 12 wks ↔ HbA1c , ↔ FPG ↓ Body weight, ↓ fat mass, ↑ adiponectin,
↓ leptin, ↓ c-peptide
Li et al. (182) 30 min/day of cycle ergometer at 50%–70% MHR, 12 wks ↓ HbA1c , ↓ FPG, ↓ FPI ↑ VO2max (both groups), ↓ BMI, ↓ body mass
5 days/wk or 15 min/day (7 rounds of 1 min (continuous training only)
intervals at 80%–95% MHR followed by 1 min of
20%–30% MHR) of cycle ergometer, 5 days/wk
LookAHEAD Research 175 min/wk of moderate-intensity exercise 1 year ↓ HbA1c ↓ Body weight, ↓ waist circumference, ↔ CVD
Group (298) risk
Savikj et al. (257) ∼30 min/day (7 min warm-up followed by 6 rounds 2 wks ↔ HbA1c ↔ Total cholesterol, ↔ TG
of 1 min pulses over 220 W at 75 rpm with 1 min
rest between), 3 days/wk of cycling either in the
morning or afternoon
Sigal et al. (269) Treadmill or cycle ergometer, progression from 15 22 wks ↓ HbA1c ↓ Body weight, ↓ waist circumference, ↑ thigh
to 20 min/day at 60% MHR to 45 min/day at 75% muscle CSA, ↔ total cholesterol, ↔ blood
MHR, 3 days/wk pressure
Solomon et al. (276) 1 h/day, 5 days/wk at 60%–65% MHR; intensity 3 months ↓ FPG, ↓ 2 h OGTT, ↑ GDR, ↓ glucose ↓ Body weight, ↓ BMI, ↓ % body fat, ↓ VAT,
increased to 80%–85% at wk 4 AUC, ↑ insulin AUC, ↑ β-cell function ↓ leptin, ↓ TG, ↓ total cholesterol
Solomon et al. (277) 1 h/day, 4–5 days/wk of cycling or treadmill 12–16 wks ↔ HbA1c , ↓ FPG, ↓ 2 h OGTT, ↓ insulin ↓ Body weight, ↓ BMI, ↓ % body fat, ↑ VO2max
walking at ∼75% VO2max AUC

AUC, area under the curve; BMI, body mass index; FPG, fasting plasma glucose; FPI, fasting plasma insulin; GDR, glucose disposal rate; HbA1c , hemoglobin A1c ; HGP, hepatic glucose production;
HOMA-IR, homeostatic model assessment of insulin resistance; MHR, maximum heart rate; OGTT, oral glucose tolerance test; PPG, postprandial glucose; RER, respiratory exchange ratio; SAT,
subcutaneous adipose tissue; SBP, systolic blood pressure; TG, triglyceride; VAT, visceral adipose tissue.
Comprehensive Physiology

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Comprehensive Physiology Exercise and Type 2 Diabetes

glucose, oral glucose tolerance, and HbA1c in patients with extent than aerobic or combined exercise training (Table 2).
diabetes (277). Furthermore, the benefits of resistance exercise are largely
While exercise is known to enhance GLP1 secretion in related to its role in preserving or increasing muscle mass and
healthy and obese individuals (122, 198), the impacts of physical function (25, 48).
exercise on GLP1 in patients with diabetes remains unclear
(107). Both aerobic HIIT and moderate-intensity continuous
training improved GLP1 secretion in men with obesity (200), Combination training and glycemic control in type 2
and short-term aerobic exercise training has been shown diabetes
to improve GLP1 sensitivity in patients with nonalcoholic Evidence supports aerobic and resistance training programs
fatty liver disease (NAFLD) (169), collectively indicating a for the greatest benefit in ameliorating diabetes symptoms,
favorable role of exercise in regulating GLP1. While acute as effects of both training modalities combined are additive
aerobic exercise did not enhance GLP1 secretion in patients (Table 3). Long-term combination training decreases HbA1c
with diabetes (80), both aerobic HIIT and low-intensity in patients with diabetes significantly more than either aero-
continuous exercise interventions induced improvements in bic or resistance exercise alone, in conjunction with inducing
GLP1 after a period of 12 weeks, with the greatest improve- greater improvements in clinical markers of metabolic
ments occurring after HIIT (175). Given the favorable syndrome (52, 73, 269). Similarly, 6 weeks of short-term
evidence around GLP1 in healthy individuals and those with functional high-intensity training improved β-cell function
obesity, it is plausible that long-term exercise intervention and insulin sensitivity with concurrent decreases in fat mass
may also enhance GLP1 secretion in patients with diabetes and preservation of lean mass (85, 219), and more recently,
as well. However, further research is needed to fully eluci- short-term combination aerobic and resistance exercise has
date the impacts of regular exercise on GLP1 secretion and been shown to significantly decrease HbA1c , fasting glucose,
to understand possible differential mechanistic actions of and fasting insulin in patients with diabetes (294). Impor-
exercise in healthy individuals and patients with diabetes. tantly, improvements in HbA1c with short-term combination
In contrast, gastric inhibitory polypeptide (GIP) secretion exercise intervention are associated with better mental health
seems to decrease with chronic aerobic exercise training, and quality of life in patients with diabetes (305). Longer-
although this effect may be dependent on combined lifestyle term combination training has also been shown to reduce
interventions (149, 197). Nevertheless, evidence suggests prescribed medication doses (139). Interestingly, differences
overall improvements in incretin secretion in response to in resistance training volume and intensity have not been
exercise; however, GIP remains understudied compared to shown to further impact improvements in HbA1c associated
GLP-1 in the context of diabetes. This is another area that with combination training (74, 331), although it is likely that
is ripe for future research and the opportunity to explore increases in resistance training volume or intensity in com-
the interactions of exercise and GLP-1 with GIP so as to bination with aerobic exercise would have additive benefits
better understand the overall impacts of exercise on incretin for secondary outcomes. Therefore, combined aerobic and
hormone secretion in patients with diabetes. resistance exercise induces greater enhancement of glycemic
control than either modality alone and thus is most effective
for managing diabetes symptoms (Figure 1).
Impacts of resistance exercise on clinical markers of
type 2 diabetes
Resistance exercise favors the neuromuscular system over Impact of exercise-associated weight loss on
cardiovascular adaptation (251). As such, improvements in glycemic control
glucose control are more directly attributable to improved Improvements in primary diabetes symptoms with exercise
substrate uptake and utilization, as the change in energy often occur in conjunction with weight loss and associated
expenditure is typically insufficient to decrease body weight improvements in body composition (15, 145, 277). Thus, it
(82, 236). The effects of resistance exercise in patients has been suggested that enhancements in glycemic control
with diabetes have been studied to a lesser extent than both with exercise training are the result of weight loss rather than
aerobic and combined exercise training; however, resis- stimulatory actions of exercise itself (276). Though it is often
tance training has been shown to mediate improvements difficult to distinguish improvements in glycemic control
in glucose tolerance (111, 119). For example, 16 weeks of associated with exercise from exercise-induced weight loss,
resistance exercise three times per week significantly lowered there are data to support exercise-induced enhancement of
HbA1c and the amount of medication required for diabetes glucose regulation independent of weight loss. One week of
control in high-risk older adults (41). Similarly, 12 weeks walking or cycling for 30 min/day increased glucose disposal
of moderate-intensity resistance training improved fasting rates and peripheral insulin sensitivity while reducing HGP
glucose, glycemic control, and components of the metabolic without inducing weight loss (160). Additionally, 12 weeks of
syndrome independent of body weight in adults with dia- HIIT training in men with diabetes improved HbA1c without
betes (205). Therefore, resistance training appears to convey inducing significant decreases in BMI or body mass (182).
benefits for glycemic control in diabetes, although to a lesser Contrarily, 12 weeks of moderate-intensity aerobic exercise

Volume 13, April 2023 7

8
Table 2 Effects of Resistance Exercise Training on Glycemic Control in Type 2 Diabetes

Resistance exercise study Exercise prescription Duration Impact on glycemic control Secondary outcomes

Bacchi et al. (15) 9 exercises/day on weight machines or with free 4 months ↓ HbA1c , ↓ FPG, ↑ GDR ↓ BMI, ↓ fat mass, ↓ VAT, ↓ SAT, ↑ lean mass,
weights, 3 sets of 10 reps, progression from 30% to ↑ leg extension 1RM, ↑ chest press 1RM
50% 1RM to 70%–80% 1RM
Castaneda et al. (41) 5 exercises/session on weight machines, 3 sets of 8 16 wks ↓ HbA1c , ↓ dose of prescribed T2D ↑ Muscle glycogen, ↑ lean mass, ↓ SBP, ↓ trunk
Exercise and Type 2 Diabetes

reps, progression from 60% to 80% baseline 1RM medication fat mass
to 70%–80% mid-study 1RM, 3 days/wk
Chen et al. (48) 5 exercises/day with resistance bands or isometric 12 wks ↔ HbA1c ↑ Muscle strength, ↑ balance, ↑ physical function
holds, 5 sets of 10 reps, 3 days/wk
Church et al. (52) 3 days/wk, 2 sets of 4 upper body exercises, 3 sets 9 months ↔ HbA1c ↑ Lean mass, ↓ fat mass, ↓ waist circumference
of 3 leg exercises, 2 sets of 2 core exercises,
10–12 reps/set
Earnest et al. (73) 3 days/wk, 2 sets of 4 upper body exercises, 3 sets 9 months ↔ Metabolic syndrome score ↓ Waist circumference
of 3 leg exercises, 2 sets of 2 core exercises,
10–12 reps/set
Hangping et al. (111) 4 isometric exercises/day on weight machines at 6 months ↓ HbA1c , ↓ FPG ↓ Total cholesterol, ↓ LDL,
progressively increasing maximal contraction for
5 s, 5–10 min/day, 1 day/wk
Heden et al. (119) 3 sets of 10 reps at RM of 8 upper and lower body Single bout ↓ Glucose AUC, ↓ insulin AUC ↓ TG AUC
exercises
Jorge et al. (140) full-body, 7-exercise circuit 3 days/wk 12 wks ↓ FPG, ↓ PPG, ↔ HbA1c , ↔ HOMA-IR, ↔ BMI, ↓ total cholesterol, ↓ TG
↓ c-reactive protein, ↑ IRS-1
Ku et al. (168) 3 sets of 15–20 reps at 40%–50% maximal 12 wks ↔ HbA1c , ↔ FPG ↓ Body weight, ↓ fat mass, ↑ adiponectin,
capacity of 10 upper and lower body exercises ↑ muscle mass, ↓ RBP4
with resistance bands, 5 days/wk
Misra et al. (205) 6 exercises/day at RM, 2 sets of 10 reps, 12 wks ↑ Insulin sensitivity, ↓ HbA1c , ↓ blood ↓ Total cholesterol, ↓ TG, ↓ SAT, ↔ BMI, ↔ lean
3 days/wk glucose, ↔ c-reactive protein mass, ↔ total body fat
Sigal et al. (269) 7 exercises/day on weight machines, progression 22 wks ↓ HbA1c ↓ Body weight, ↓ waist circumference, ↑ thigh
to 2–3 sets of 7–9 reps, 3 days/wk muscle CSA, ↔ total cholesterol, ↔ blood
pressure

1RM, one repetition maximum; AUC, area under the curve; BMI, body mass index; CSA, cross-sectional area; FPG, fasting plasma glucose; GDR, glucose disposal rate; HbA1c , hemoglobin
A1c ; HGP, hepatic glucose production; HOMA-IR, homeostatic model assessment of insulin resistance; LDL, low-density lipoprotein; RBP4, retinol-binding protein 4; RM, repetition maximum; SAT,
subcutaneous adipose tissue; SBP, systolic blood pressure; TG, triglyceride; VAT, visceral adipose tissue.
Comprehensive Physiology

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 Table 3 Effects of Combination Exercise Training on Glycemic Control in Type 2 Diabetes

Combination exercise study Exercise prescription Duration Impact on glycemic control Secondary outcomes

Church et al. (52) 10 kcal/kg at 50%–80% VO2max per wk plus 9 months ↓ HbA1c ↑ VO2max , ↓ body weight, ↓ fat mass, ↓ waist
2 days/wk, 1 set of 4 upper body exercises, 3 leg circumference
exercises and 2 core exercises, 10–12 reps/set

Volume 13, April 2023

Comprehensive Physiology

Earnest et al. (73) 10 kcal/kg at 50%–80% VO2max per wk plus 9 months ↓ Metabolic syndrome score ↑ VO2peak , ↓ waist circumference
2 days/wk, 1 set of 4 upper body exercises, 3 leg
exercises and 2 core exercises, 10–12 reps/set
Egger et al. (74) 2 days/wk of 1 h/day of cycle ergometer at 70% HRR 8 wks ↓ HbA1c , ↓ FPG ↓ Body weight, ↓ BMI, ↓ SAT, ↓ SBP, ↓ DBP
and 50 min/day of 6 exercises of either hypertrophy
(2 sets of 10–12 reps at 70% 1RM) or endurance
(2 sets of 20–30 reps at 40% 1RM) resistance exercise
on weight machines
Fealy et al. (85) 3 days/wk of CrossFit training >85% MHR for 6 wks ↑ Insulin sensitivity ↓ Fat mass, ↓ DBP, ↓ TG, ↑ fat oxidation,
8–20 min ↑ adiponectin
Johansen et al. (139) 30–60 min/day of aerobic exercise 5–6 days/wk, with 12 months ↔ HbA1c , ↓ 2 h OGTT, ↓ Body mass, ↓ BMI, ↓ fat mass, ↑ lean mass,
2–3 sessions/wk combined with resistance exercise ↓ prescribed T2D medication use ↓ abdominal fat, ↑ VO2max
Jorge et al. (140) 3 days/wk of alternating 1 h/day of cycling at HR 12 wks ↓ FPG, ↓ PPG, ↔ HbA1c , ↔ BMI, ↓ total cholesterol, ↓ TG
corresponding to lactate threshold or full-body, ↔ HOMA-IR, ↓ c-reactive protein,
7-exercise circuit ↑ IRS-1
Nieuwoudt et al. (219) 3 days/wk of CrossFit training with at least one session 6 wks ↔ FPG, ↔ FPI, ↑ β-cell function ↔ Body weight, ↓ fat mass, ↑ VO2max
at >85% MHR for 10–20 min
Sigal et al. (269) 3 days/wk of treadmill or cycle ergometer, progression 22 wks ↓ HbA1c ↓ Body weight, ↓ waist circumference, ↑ thigh
from 15 to 20 min/day at 60% MHR to 45 min/day at muscle CSA, ↔ cholesterol, ↔ blood pressure
75% MHR plus 7 exercises/day on weight machines,
progression to 2–3 sets of 7–9 reps
Terauchi et al. (294) 3 days/wk of aerobic (30 min/session at increasing 12 wks ↓ HbA1c , ↓ FPG, ↓ FPI, ↓ HOMA-IR ↓ HDL
intensity from light to vigorous) and resistance (at
repetition maximum) exercise
Tomas-Carus et al. (305) 25 min/day of aerobic exercise at 60%–65% MHR 12 wks ↓ HbA1c ↑ Maximal strength, ↑ physical function,
and 15 min/day of resistance exercise of 2–4 sets of ↑ mental health
10 reps, 3 days/wk
Yang et al. (331) 5 days/wk of walking at 75% HRR and 2 days/wk of 6 months ↓ HbA1c , ↓ FPI ↓ BMI, ↓ body fat, ↑ VO2peak
10 resistance exercises of 2–3 sets of 7–15 reps

1RM, one repetition maximum; AUC, area under the curve; BMI, body mass index; DBP, diastolic blood pressure; FPG, fasting plasma glucose; FPI, fasting plasma insulin; GDR, glucose disposal
rate; HbA1c , hemoglobin A1c ; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; IRS-1, insulin receptor substrate 1; MHR, maximum heart rate; OGTT,
oral glucose tolerance test; PPG, postprandial glucose; RM, repetition maximum; SAT, subcutaneous adipose tissue; SBP, systolic blood pressure; T2D, type 2 diabetes; TG, triglyceride; VAT,
visceral adipose tissue.

9
Exercise and Type 2 Diabetes

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Exercise and Type 2 Diabetes Comprehensive Physiology

impacts on the microbiome, metabolome, and genome that

serve to improve secondary health consequences, thus medi-
ating multiple systemic health improvements for patients
with diabetes (Figure 2).

Combination exercise
Exercise and skeletal muscle mass and function in
patients with type 2 diabetes

Insulin secretion
Exercise and skeletal muscle atrophy

Insulin sensitivity
Aerobic exercise Maintenance of muscle mass is an intricate balance between
anabolism and catabolism (89). In healthy skeletal muscle,
Hepatic glucose production degradation of damaged or denatured proteins is necessary
Resistance exercise
Glucose effectiveness for maintaining homeostasis (173, 179); however, dysregula-
tion of this homeostatic function induced by the acceleration
Figure 1 Exercise improves glucose homeostasis. Exercise improves
of protein degradation or reduced protein synthesis results in
glucose effectiveness by increasing insulin secretion and sensitivity while muscle atrophy (57, 81). Molecular mechanisms of muscle
lowering hepatic glucose production. Aerobic, resistance, and combi- wasting include inappropriately adapted anabolic growth
nation exercise training improve glucose homeostasis in varying magni- hormone and insulin-like growth factor-1 (IGF-1), as well as
tudes based on the volume, intensity, duration, and mode, with greatest
benefits seen with combination training. dysregulation of catabolic proteins such as tumor necrosis
factor-alpha (TNFα) and myostatin, can shift protein balance
toward muscle degradation (81). In atrophic muscles, ubiq-
in women with diabetes led to a lower BMI without altering uitin ligase activation regulates protein degradation through
glucose regulation or insulin sensitivity (168). While these subsequent activation of muscle RING-finger protein-1
differences may be due to variations in study design, sex, (MuRF-1) and atrogin-1 (28, 254). Simultaneously, down-
and race, determining the role of weight loss and exercise in regulation of the PI3K/AKT pathway can activate forkhead
mediating improvements in diabetes remains elusive as the transcription factors (FoxO), specifically FoxO1, leading
two are typically accomplished simultaneously. to an increase in transcription of MuRF-1 and atrogin-1
There is also evidence that the positive health outcomes (28, 254).
from exercise are associated more with weight loss than Type 2 diabetes can trigger muscle atrophy via prolonged
fitness (299); thus, it can also be argued that weight loss activation of degradative pathways, leading to reduced mus-
mediates the greatest effects of exercise on diabetes symp- cle content, quality, and function (89, 231). Insulin resistance
toms. Furthermore, there is substantial evidence that exercise is a key contributor to muscle atrophy, as it activates the
alleviates primary symptoms whether weight-loss mediated PI3K/AKT pathway and mammalian target of rapamycin
or not. While determining the weight-loss-dependent and (mTOR), which also drives glucose metabolism (171). Thus,
independent effects of exercise on glycemic control should impairments in this pathway have been implicated in reduced
be further examined to enhance current understandings of protein synthesis (17, 28). Likewise, insulin and IGF-1 act
the mechanistic effects of exercise as a treatment modality through the PI3K/AKT pathway to suppress FoxO1 activa-
for diabetes, weight loss is generally beneficial and recom- tion and downstream MuRF-1 and atrogin-1 transcription to
mended for patients who are overweight (326). Therefore, attenuate muscle wasting (254, 286). Patients with diabetes
regardless of whether the impacts of exercise on glucose are also reported to have 60% above normal expression of
regulation and insulin sensitivity are weight-loss mediated, FoxO1 (231), collectively indicating heightened atrophic
regular exercise is an effective treatment for diabetes. signaling in diabetes.
Exercise counteracts muscle atrophy and promotes muscle
hypertrophy via increased protein synthesis (3). Exercise
Impacts of Exercise on Comorbidities in activates extracellular receptor kinase (ERK) and mTOR
Patients with Type 2 Diabetes to increase ribosomal biogenesis and subsequently increase
the capacity for protein synthesis (86). Resistance exercise
While regular exercise training is effective for maintaining specifically has been shown to increase p70S6K, conse-
and regulating glucose homeostasis in patients with diabetes, quently activating the AKT/mTOR signaling pathway to
the powerful effects of exercise extend beyond glycemic induce anabolic processes in skeletal muscle (6, 99). Never-
control. Exercise enhances mitochondrial function, increases theless, both aerobic and resistance exercise have been shown
skeletal muscle mass and function, augments cardiovascular to prevent muscle wasting in typically atrophic conditions
health, attenuates inflammatory signaling, alleviates diabetic such as spaceflight and bedrest (3, 6), and thus, it is not sur-
neuropathies, and helps prevent diabetes-associated neu- prising that exercise can elucidate similar effects in diseased
rodegenerative diseases. In addition, exercise exerts positive states known to induce atrophy (321).

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Comprehensive Physiology Exercise and Type 2 Diabetes

Lipolysis
Insulin Insulin
Glucose

Insulin IRS-
1

PI3K PI3K
Glucose
uptake Signal
cascade
Akt
Akt GLUT4
TNFα
TNFα

IL-6 IL-1β
IFN-γ IL-1β
mTOR

Vasodilation Inflammation Muscle atrophy

Figure 2 Mechanistic actions of exercise on the treatment of multiorgan symptoms of type 2 diabetes. Exercise
induces tissue-specific effects that contribute to improvements of whole-body markers of type 2 diabetes. Primary
systemic improvements are achieved via activated pathways in skeletal muscle, adipose tissue, and the car-
diorespiratory system. Exercise-mediated enhancements in glucose regulation, insulin sensitivity, and substrate
utilization at the tissue level contribute to the reduction of inflammatory cytokine production and systemic inflam-
mation and improvements in whole-body outcomes. AKT, protein kinase B; GLUT4, glucose transporter type 4;
IFN-γ, interferon gamma; IL-1β, interleukin 1 beta; IL-6, interleukin 6; IRS-1, insulin receptor substrate 1; PI3K,
phosphatidylinositol 3-kinase; mTOR, mammalian target of rapamycin; TNF-α, tumor necrosis factor-alpha.

In patients with diabetes, 6 weeks of resistance training improvements in muscle quality mediated improvements in
have been shown to induce qualitative changes in skeletal metabolic control (34). However, metabolic improvements
muscle and increases in muscle fiber diameter (125). Impor- in conjunction with increased muscle mass may depend on
tantly, these improvements are accompanied by increases disease severity. Another study found that resistance training
in the expression of proteins involved in skeletal muscle improved body composition and muscle mass across the
insulin signaling and glucose uptake, namely GLUT4 (125). glucose tolerance spectrum, but improvements in glycemic
Similar effects were seen after 16 weeks of strength training control seen in healthy individuals or those with prediabetes
in older adults with diabetes, as increases in muscle mass and were not observed in patients with diagnosed disease (97).

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Exercise and Type 2 Diabetes Comprehensive Physiology

Thus, while exercise improves muscle mass and function shown that exercise intervention increased mitochondrial
in patients with diabetes, the evidence demonstrating these content in patients across the glucose tolerance spectrum
effects in conjunction with improvements in glycemic control without significantly impacting mitochondrial respiratory
are inconsistent. function (292). It has also been proposed that mitochondrial
Nevertheless, maintenance of muscle mass and prevention localization and membrane plasticity may contribute to the
of muscle wasting are crucial for many disease outcomes. bioenergetic adaptations to exercise (83), which is primarily
Although it may not significantly regulate improvements in achieved by the activation of fission and fusion machinery
glycemic control, resistance training is important for muscle (13). Impairments in mitochondrial quality control have been
mass and function. Given the known effects of aerobic and linked to skeletal muscle insulin sensitivity across the glucose
resistance exercise on glucose regulation and skeletal mus- tolerance continuum, with most favorable mitonuclear protein
cle maintenance, combined aerobic and resistance training balances and mitochondrial protein folding found in active
in patients with diabetes appears to be the most favorable individuals (129). Furthermore, twelve weeks of exercise
approach for maintaining muscle quality while also inducing training in previously sedentary patients with obesity resulted
favorable outcomes in glycemic control. This is particularly in reduced mitochondrial fission independent of changes in
important for older patients who face compounding effects of mitochondrial content (13, 84), suggesting a role for exercise
sarcopenia from both age and disease (18). Being overweight in mediating mitochondrial-induced improvements in dia-
induces progressive imbalance of muscle protein toward betes symptoms. However, recent findings also reveal the
breakdown in older adults, leading to decreased muscle impacts of race on the relationship between mitochondrial
content and quality (238), and diabetes further accelerates dynamics and insulin sensitivity, thus highlighting the need
age-related sarcopenia (17). However, long-term resistance for further investigation on the role of mitochondrial plasticity
training in older patients with diabetes increased muscle and diabetes development in diverse populations (69).
mass and decreased adiposity with associated reductions
in systemic inflammation and C-reactive protein (201).
Furthermore, combined aerobic and resistance training in Exercise and adipose tissue function
older patients with obesity led to maintenance of muscle
mass despite weight loss (59). Thus, exercise training elicits Derangements in adipose tissue insulin responsiveness and
metabolic improvements in older adults while also mediating inflammatory signaling, particularly visceral and ectopic fat,
increased or sustained muscle mass during aging, making are another pathological feature of diabetes. Adipose tissue
it an effective intervention for diabetes and age-related insulin resistance, the inability of insulin to inhibit lipolysis
sarcopenia. in adipocytes, is increased nearly threefold above normal in
patients with diabetes (96). A progressive decline in β-cell
function is associated with incremental increases in free fatty
acids (FFAs) and fasting adipose tissue insulin resistance (96).
Exercise and skeletal muscle mitochondrial plasticity
Additionally, GLP1 receptors that stimulate lipolysis corre-
Early studies on patients with diabetes revealed a number late positively with insulin resistance in patients with severe
of mitochondrial abnormalities in skeletal muscle including obesity (313). Consequently, this causes a cycle of dysregu-
reduced content, size, density, respiratory function, and lation, as increased FFA levels further contribute to the loss
subtype distribution (148, 187, 246). It was proposed that of glucose effectiveness in poorly controlled diabetes (116).
these changes resulted in sustained bioenergetic impair- Obesity-related diabetes is also characterized by alterations
ments, ultimately contributing to impaired insulin action. in adipose tissue cytokine secretion, namely overexpression
Reductions in skeletal muscle mitochondrial content and of TNFα, which is further associated with the development of
size have been consistently observed in obese patients with insulin resistance (128, 234, 311).
diabetes (118, 246), largely due to deficiencies in mitochon- Regular exercise is associated with numerous improve-
drial fission proteins and mitonuclear protein imbalances ments in adipose tissue that contribute to attenuating markers
(129). However, the functional intactness of mitochondria of diabetes. Although exercise mediates improvements in
remains highly debated, with contrasting reports of both regulating lipolysis and FFA release from adipose tissue
defective and intact respiratory activity (32, 206, 233). In (247), primary improvements in adipose tissue with exercise
contrast, exercise results in numerous structural and func- are via alterations in cytokine production. Chronic exercise
tional adaptations in mitochondria. These adaptations are training decreases adipose tissue inflammation, primar-
best characterized in skeletal muscle, where exercise in ily through decreased TNFα production (146, 223, 282,
patients with and without diabetes increases mitochondrial 327). Most notably, exercise has been shown to increase
number, size, oxidative capacity, electron transfer, and DNA adiponectin release and decrease leptin production in patients
(203, 303, 304). While determining whether the changes in with diabetes (115, 151, 168). Thus, exercise is capable of
mitochondrial function are independent of the increase in suppressing unfavorable adipose cytokine production while
mitochondrial content following aerobic and resistance train- stimulating secretion of favorable cytokines, all of which
ing was originally debated (110, 123, 124), it was recently contribute to adipose-related metabolic improvements.

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Comprehensive Physiology Exercise and Type 2 Diabetes

Exercise and cardiorespiratory fitness in type 2 levels, including IL-6, IL-1β, and TNFα, numerous studies
diabetes show that long-term adaptations to exercise indicate an
overall decrease in inflammatory signaling (87, 88, 226, 282,
Insulin can promote myocardial regeneration directly (329) or 318). Importantly, physical activity status is the best predictor
indirectly via attenuation of systemic TNFα production (93). of inflammatory biomarker levels, specifically TNFα and
In view of the fact that diabetes is associated with decreases IL-6, even compared to other factors such as age (202, 285).
in insulin secretion, it is often associated with cardiac and In patients with diabetes, exercise training has been shown to
endothelial dysfunction (60), and evidence suggests a direct induce decreases in systemic inflammation that correspond
association with diastolic dysfunction that leads to cardio- with improvements in glucose regulation (280). Rodent
vascular disease and diminished cardiorespiratory function studies further support long-term exercise training as an anti-
across the glucose tolerance spectrum (314). Since vascular inflammatory regulator, as indicated by decreased cytokine
endothelial function is highly dependent on ambient hyper- production in skeletal muscle, heart, and liver tissues after
glycemia, hyperinsulinemia, and insulin resistance (190), prolonged exercise intervention in animals with diet-induced
multiple exercise models have been proposed to promote vas- obesity (141). Altogether, these findings demonstrate the
cular health in patients with diabetes (174, 297). Short-term positive impacts of exercise on systemic inflammation, which
exercise training rescued high-fat diet-induced loss of insulin- further extends to improvements in glycemic control and
stimulated glucose uptake in the myocardium and normalized insulin signaling in diabetes.
associated chemokine and cytokine levels in the heart (141),
and consistent long-term aerobic exercise has been shown to
enhance endothelial function (302). More recently, 3 months Exercise and diabetic neuropathies
of combined aerobic and resistance training in patients with Small and large nerve fibers play a role in tactile, vibration,
diabetes improved flow-mediated endothelium-dependent pain, and proprioceptive sensitivity (31). Diabetes can lead to
vasodilation and reduced cardiovascular events for 2 years impaired sensory function in these nerves, as hyperglycemia
compared to sedentary controls (222). Furthermore, regular plays a key role in the activation of biochemical pathways
exercise is known to improve cardiorespiratory fitness, thus that, together with impaired nerve perfusion, contribute to
contributing to improved cardiovascular health, and these the development of diabetic neuropathies (237, 337). Diag-
improvements have been linked to improvements in diastolic nosable neuropathy occurs in nearly half of all patients with
function and prevention of heart failure in patients with diabetes (72), and nerve conduction studies demonstrate that
diabetes (105). neuropathy is present in 10% to 18% of patients at the time
of diagnosis, suggesting that peripheral nerve injury occurs
early in the disease and coincides with the progression of
Impacts of exercise on systemic inflammation in type
insulin resistance (56). Diabetic neuropathy is characterized
2 diabetes by infections, ulcerations, and tissue destruction associated
Inflammation, especially as a result of tissue damage, is with neurological abnormalities and various levels of periph-
commonly associated with diseased states (47). Tissue eral artery disease that cause progressive disability and can
inflammation may play a role in the pathogenesis of diabetes, have consequences as severe as amputation (10, 11).
particularly obesity-associated diabetes, which appears to Regulation of glycemic control is the primary strategy
be mediated by oxidative stress, lipotoxicity, ectopic lipid for the prevention and management of diabetic neuropathies
deposition, and macrophage activation, most commonly in (266); however, pharmacological treatment of neuropathies
the liver and adipose tissue (67, 225, 268, 311). Long-term remains a challenge, highlighting the need for other treatment
immune system activation impairs insulin secretion and can strategies (337). Rational therapies aimed at direct control of
lead to diabetes and other comorbidities, including CVD (66, glucose have failed in preventing and treating diabetic neu-
75). Elevated levels of inflammatory markers and immune ropathy in human trials (271). In contrast, aerobic exercise
cells have been reported in humans and rodent models with training produces salutary effects simultaneously in many of
diabetes (76, 279). Furthermore, the European Prospec- the pathways that lead to neuropathy and has been shown
tive Investigation into Cancer and Nutrition (EPIC) study to improve symptoms of neuropathy and promote regrowth
reported that inflammatory cytokine levels, most notably of cutaneous small-diameter fibers in both animal models
IL-6 and TNFα, were elevated in patients with diabetes and human trials (61, 90, 126, 271). Additionally, mice were
(279). Moreover, IL-6 levels were identified as a predictor of able to regain islet function and demyelination of axons was
diabetes incidence independent of age, sex, BMI, and HbA1c prevented with exercise intervention during early stages of
(279), while inhibition of these cytokines has been shown to neuropathy (152). In addition to improving overall nerve
relieve β-cell dysfunction in human trials (75). integrity, exercise has also been shown to have positive
Exercise has chronic cytokine-lowering effects, and regular impacts on specific types of neuropathy. Diabetic retinopathy
physical activity elicits anti-inflammatory effects that account is the leading cause of visual impairment and blindness (287).
for decreased risk of chronic diseases (170, 270). Although Recent evidence suggests that while sedentary behavior is
acute responses to exercise actually include elevated cytokine associated with increased risk of retinopathy in diabetes,

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Exercise and Type 2 Diabetes Comprehensive Physiology

physical activity is effective for preventing retinopathy in autonomic dysfunction and heart rate variability measures
high-risk patients and with improving vision in patients with were worse in diabetes, and these measures were associated
mild impairments (242). Similar effects have been reported with elevated HbA1c and diabetes duration (264).
for other forms of neuropathy, including two of the most The metabolic demands of exercise require sufficient
common in diabetes, diabetic peripheral neuropathy (DPN) increases in cardiac contractility and vagal innervation of the
and cardiac autonomic neuropathy (CAN). ventricles (274). Increased exercise capacity is associated
with reduced resting heart rate and increased cardiac vagal
activity, responses that are indicative of involvement of the
Exercise and diabetic peripheral neuropathy
parasympathetic branch of the autonomic nervous system
The most common form of neuropathy in diabetes is DPN, and suggest that parasympathetic function plays a role in
which is a chronic, symmetrical, length-dependent senso- exercise performance (101). In healthy untrained individuals,
rimotor polyneuropathy where autonomic dysfunction and aerobic exercise training reduces heart rate and increases
pain develop over time (295). Peripheral artery disease and vagal activity (4). Studies investigating the effects of exercise
neuropathy frequently coexist, and consequently, over 50% on cardiac autonomic function in healthy individuals and
of diabetic foot ulcers are ischemic or neuro-ischemic (239). patients with heart failure or diabetes demonstrate that the
Peripheral artery disease and collagen cross-links contribute speed of heart rate recovery is accelerated with exercise
to limited joint mobility, muscular impairment, and foot training (23, 62, 195, 288); thus, vagal tone can be enhanced
deformities, which in turn lead to changes in mechani- with exercise. Furthermore, regular exercise offers a means
cal properties of the tissues that can cause poor balance of training cardiac vagal tone, which in turn increases
(36, 90). Sensory loss often begins at the foot and progresses exercise capacity, thus amplifying cardiac improvements.
proximally (9). These impairments propagate a cycle that Consistent exercise may also modulate cardiac vagal tone
progressively alters foot plantar pressure distribution and via the enhancement of angiotensin II suppression (37).
exacerbation of the foot condition (90). Patients with diabetes Evidence suggests that both aerobic and resistance exercise
often have deficits in their ability to maintain posture prior may improve cardiac autonomic function in diabetes (20);
to ulceration and diagnosis of DPN (258). Small fiber injury however, few studies have investigated the effects of exercise
occurs early in disease progression and leads to neuropathic on cardiac function in this patient population. A recent meta-
pain, while overt gait and foot ulcers are due to loss of large analysis reported that exercise improved cardiac autonomic
myelinated fibers that regulate touch and proprioceptive function in diabetes, but the strength of the evidence was
function, functional abnormalities of DPN that are late com- low due to the scarcity of existing studies (23), highlighting
plications and reflect irreversible axonal loss (301). Regular the need for additional research examining the impacts of
exercise addresses glycemic control and other pathologies exercise on cardiac function in patients with diabetes to
associated with DPN, including microvascular function, determine the most impactful treatment methods.
lipid oxidation, and oxidative stress (61, 163, 271). More However, it is important to emphasize that exercise is
importantly, evidence suggests that axonal regeneration can intolerable for some patients with neuropathy and may not be
occur as a result of exercise training (90), thus preventing and a suitable treatment due to reduced heart rate, blood pressure,
relieving DPN symptoms. and cardiac output in response to exercise that is associated
with autonomic dysfunction (237). Moreover, in diabetes,
CAN typically occurs in conjunction with DPN, and pain
Impacts of exercise on cardiac autonomic
associated with DPN may further limit exercise capability
neuropathy in type 2 diabetes
(94). These conditions should be carefully considered when
In diabetes, CAN is defined as impairment of autonomic prescribing or studying exercise treatment, and appropriate
control of the cardiovascular system resulting from damage precautions should be employed. Additionally, there appears
to the nerves and blood vessels innervating the heart, which to be a point of no return where recovery and regeneration
can lead to dysfunctional heart rate control and abnormal of axonal function are not possible, particularly damage to
vascular dynamics (264). Chronic hyperglycemia leads to large myelinated axons (103, 152), making early intervention
progressive autonomic neural dysfunction that first affects crucial for prevention or reversal of neuropathic development.
the vagus nerve, which largely mediates parasympathetic
activity (272). In diabetes, this is characterized by initial
increases in sympathetic tone with increased resting heart Exercise and diabetic nephropathy
rate, while sympathetic denervation soon follows (14). CAN Diabetic nephropathy is a common long-term complication
is a complication that increases risk of all-cause mortality and the most common cause of mortality in patients with
and myocardial ischemia, a risk that is further heightened type 2 diabetes, as well as a leading cause of end-stage renal
in diabetes (199, 315). The Treatment Options for Type 2 failure globally (46, 253). Chronic dysregulation of glucose
Diabetes in Adolescents and Youth (TODAY) study, the homeostasis activates the renin-angiotensin-aldosterone sys-
largest reported cohort of participants with youth-onset T2D, tem, renal hyperfiltration, and oxidative stress, leading to renal
found that compared to participants with obesity, cardiac vascular abnormalities, glomerular lesions, and impairments

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Comprehensive Physiology Exercise and Type 2 Diabetes

in glomerular filtration, resulting in kidney failure when left diabetes can cause cerebrovascular complications and lead
untreated (46, 189). Primary treatment methods are targeted to blood-brain barrier breakdown, initiating neural cell death
at improving glucose control and blood pressure regula- and dysfunction (21).
tion through antidiabetic pharmacotherapies or angiotensin Because of its chronic anti-inflammatory capabilities
receptor blockers to alleviate microvascular stress associated and associations with improved endothelial function and
with nephropathy, although continued disease progression increased brain capillarization, regular exercise has been
requires hemodialysis treatment, and in extreme cases, kidney proposed as a method to prevent neurodegenerative disease
transplant (253). However, some first-line pharmacological development in patients with diabetes (27, 191, 289, 319).
interventions for type 2 diabetes, including metformin, are Exercise training is also hypothesized to induce neurogenesis
contraindicated as a treatment for diabetic nephropathy, as (312), making it an appealing approach for the prevention
they are not metabolized by the liver and are thus excreted of metabolically associated neuronal diseases (21). In mice
by the kidneys, increasing renal stress (240). Hence, alter- genetically predisposed to the development of Alzheimer’s
native medications or adjustments to treatment strategies are disease, treadmill exercise ameliorated declining cognitive
required for simultaneous management of type 2 diabetes and function by suppressing neuronal cell death (165). Similarly,
complications from nephropathy. in diabetic rats, treadmill exercise was shown to prevent
The association of frailty and sarcopenia with mortality diabetes-associated neurodegenerative disease development
in patients with chronic kidney disease has increased inter- (154), collectively suggesting therapeutic effects of exercise
est in exercise as a preventative and long-term treatment on neurodegenerative disease development and progression.
to aid in survivability of renal-associated complications in While the majority of the evidence for exercise as a preven-
patients with type 2 diabetes (43, 127, 136, 138). Intradialytic tion and treatment for neurodegenerative diseases is based
exercise has been shown to improve hemodialysis effective- on preclinical rodent models, there is growing evidence that
ness (35, 131, 267), and regular exercise training is associated exercise prevents neurodegeneration in aging adults with
with improved survival in patients receiving hemodialysis diabetes. Six months of aerobic training has been shown
(209, 281). Although randomized controlled trials on exercise to improve executive function and lower β-amyloid levels
training and renal outcomes in patients with type 2 diabetes in older glucose-intolerant adults, suggesting cognitive-
are lacking, studies in diabetic preclinical animal models enhancing effects of aerobic exercise in older metabolically
support exercise training as a mechanistic regulator of renal impaired adults (16). Large-scale, long-term clinical studies
health through attenuation of renal apoptotic cell death, are needed to fully describe how exercise interventions
reduction in glomerular lesions, and reduced albumin excre- contribute to enhanced cognitive function in patients with
tion (306, 320, 330), supporting the use of exercise training diabetes and specifically explore the links between cognition,
as a potential mediator of kidney health in type 2 diabetes body composition, metabolism, and inflammation (335).
and highlighting the need for further investigation of the Nevertheless, evidence suggests that exercise may medi-
impacts of exercise training on renal outcomes in diabetic ate prevention and delay progression of neurodegenerative
patients. diseases in older patients with diabetes.

Effects of exercise on the development and Changes in microbial regulation with exercise in
progression of neurodegenerative diseases in type 2 type 2 diabetes
diabetes Given the recent interest in delivering personalized medicine
Patients with diabetes are at greater risk for developing neu- and findings regarding the impact of nutrition on the function
rodegenerative diseases such as Alzheimer’s and Parkinson’s of the gut and subsequent metabolic implications (51), the
or dementia (208, 250). Importantly, impaired glucose reg- effects and interactions of exercise on the gut microbiome
ulation via insulin resistance is a pathological characteristic are of growing interest. Diabetes is associated with distinct
that has been linked to increased risk of cognitive impairment microbial dysbiosis characterized by decreased butyrate-
and dementia (293). Obesity leads to neuroinflammatory producing bacteria, as well as increased pathogens and
molecular changes, specifically in the hypothalamus, thus microbes of oxidative stress resistance, compared to individu-
impairing neuroendocrine and autonomic regulation of glu- als without diabetes (241). While still a largely underexplored
cose homeostasis and insulin secretion (109). Hypothalamic field, preliminary studies show that exercise mediates alter-
inflammation links aging and diabetes to neurodegenerative ations in gut microbiota composition and function. Exercise
diseases (22, 177), and causal relationships between diabetes has been shown to improve gut microbiota to a greater extent
and neurodegenerative diseases have been demonstrated in than caloric restriction in rats with diet-induced obesity,
rodent models, as the development of Parkinson’s disease can independent of weight loss (324). In rats with early-onset
be promoted by excessive energy intake, and brain-insulin obesity, exercise similarly counteracted high-fat diet-induced
signaling changes and mitochondrial dysfunction can lead gut microbial imbalances and mediated intestinal barrier
to Huntington’s disease (33, 249, 262). Furthermore, inflam- preservation (38). Furthermore, seven days of vigorous aer-
matory, oxidative, and metabolic changes associated with obic exercise normalized GLP1 expression and responses

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Exercise and Type 2 Diabetes Comprehensive Physiology

in patients with obesity and NAFLD (169), suggesting that metabolites mediating tissue crosstalk, specifically skeletal
exercise positively modulates gut-hormone regulation and muscle-initiated crosstalk (50). In conjunction with the pre-
may have implications for patients with diabetes. While viously reported impacts of exercise training on metabolomic
exploring the gut microbiota in the context of disease is still outcomes, these findings expand our understanding. How-
an emerging area of research, the few studies investigating the ever, they underscore the paramount importance of future
impacts of exercise on improving gut health in patients with larger clinical and translational trials that could characterize
diabetes show favorable results for using exercise to treat molecular determinants of the impacts of exercise in diabetes
microbial dysbiosis. In patients with diabetes, exercise has and other metabolic diseases (216).
been shown to reduce intestinal inflammatory markers, leaky
gut, and endotoxemia, thus improving overall gut microbial
symbiosis (210, 230); however, additional research is needed Genomic impacts of exercise on type 2 diabetes
to better understand the effects and mechanisms whereby Although genomic findings typically indicate disease risk and
exercise induces improvements in gut health. susceptibility rather than the cause, multiple genome-wide
association studies have identified and implicated the role
of various loci associated with diabetes. The Meta-Analysis
Impacts of exercise on metabolic profiles of patients of Glucose and Insulin Related Traits Consortium (MAGIC)
with type 2 diabetes study on genome-wide associations of glucose, insulin,
The effect of exercise on metabolomics has implications for β-cell function, and HOMA-IR in patients with diabetes
preventing metabolic-related disease outcomes, as exercise indicates that genes regulating glycemic traits can identify
training has been shown to induce changes in metabolite diabetes risk, specifically loci that modestly elevate fasting
signatures related to mitochondrial remodeling and improved glucose (71). Likewise, there is evidence that the phenotypic
cardiometabolic fitness in exercise-trained patients at risk responses to regular exercise in diabetes are heritable, and
for metabolic diseases compared to sedentary controls (133). the heterogeneity in metabolic responses to exercise training
Aerobic exercise has also been shown to alter the metabolome is partly explained by individual genetic structure, such as
of rats, and this occurs in a tissue-specific manner, explicitly differences in peroxisome proliferator-activated receptor
by increasing oxidative metabolism, acyl-carnitine metabo- gamma (PPARγ) isoforms or skeletal muscle glycogen syn-
lites, and tricarboxylic acid (TCA) cycle intermediates in the thase genes (106). Combined transcriptomic and metabolomic
liver and skeletal muscle (283). Additionally, both serum- analysis revealed that diabetes was associated with upreg-
and tissue-specific metabolomics may provide a unique ulation of glucose degradation and differential amino acid
opportunity to determine sensitive metabolite signatures of metabolism after exercise in comparison to healthy controls.
exercise and potentially identify metabolic responders and Furthermore, acute responses to exercise in patients with
nonresponders. Results of the Trainability and Metabolomics diabetes have been shown to induce compensatory regula-
(TIMES) study, which investigated the impact of continuous tion of amino acid biosynthesis genes (112). Thus, specific
or HIIT aerobic exercise in healthy, previously sedentary, exercise-regulated gene expression in diabetes may induce
young individuals for 8 weeks, identified potential character- alterations in glucose and amino acid metabolism. This is a
istics of exercise responses (42). High metabolic responders growing area of research, and the role of SNPs, mi-RNAs,
to exercise showed significant metabolomic differences lncRNAs, and other variants in the context of exercise training
at baseline compared to lower responders, specifically and diabetes are under active investigation.
higher concentrations of 3-hydroxybutyrate, glycerol, acetyl-
carnitine, alanine, proline, and pyruvate and lower levels of
isobutyrate, glycolate, lysine, and phenylalanine, collectively Exercise as an Adjunct Therapy for Type
suggesting that baseline amino acid metabolites may be
indicative of exercise training response potential (42).
2 Diabetes
More recent investigations have focused on the effects of While exercise training remains an effective treatment strat-
exercise on metabolomics in patients with diabetes and indi- egy and is still used as a primary intervention for diabetes,
cate alterations in lipid and amino acid metabolism (19, 104, medications such as metformin have become more com-
291). Studies show that there are significant metabolite dif- monly prescribed as first-line therapy. Moreover, exercise
ferences between patients with diabetes and normoglycemic is now suggested as an adjuvant therapy along with other
individuals, specifically in skeletal muscle (19). Interestingly, lifestyle interventions, medications, or surgical interventions.
these changes may begin to develop in independent tissues Thus, understanding the role of other treatment methods
prior to clinical diagnosis (316). Exercise interventions and the interactions with exercise is paramount to most
altered the metabolic profiles of patients across the glucose safely and effectively treat the disease. With the growing
tolerance spectrum, particularly ceramides, acylcarnitines, number of pharmacotherapies available and the increasing
and lipid profiles, with larger improvements in individuals prevalence and availability of various surgical techniques for
with glucose intolerance (121, 291). Furthermore, exercise patients with obesity and diabetes (176, 255), investigating
training in patients with diabetes led to improvements in the impacts of combined therapeutic methods is necessary for

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Comprehensive Physiology Exercise and Type 2 Diabetes

understanding the additive or deleterious effects of multiple patients with prediabetes, when compared to lifestyle inter-
treatments combined. ventions, exercise is more efficacious in reducing long-term
incidence (215, 296). Because both metformin and exercise
activate AMPK, the combined effects of the two treatment
Efficacy of combined lifestyle interventions for the methods are expected to be additive. Surprisingly, studies
treatment of type 2 diabetes investigating these treatments in combination have reported
Combined lifestyle interventions are commonly recom- contradictory results. Acutely, combined exercise training
mended for preventing diabetes, typically via the inclusion and metformin were shown to lower postprandial glucose
of exercise and dietary modifications (256). Long-term com- more effectively than either therapy alone (79), and exercise
bination of diet and exercise for 6 years conferred lasting with metformin has been shown to enhance GLP1 and GIP
metabolic benefits for up to 23 years in terms of preventing secretion (80). Contrarily, other studies report that exercise
diabetes incidence (181). Numerous studies have examined counteracted metformin-induced improvements in glycemic
the effects of various dietary interventions in combination responses to a mixed meal (30, 214), while metformin
with consistent exercise training, showing the importance reduced exercise-associated improvements in insulin sensi-
of combined lifestyle interventions for preventing disease tivity, VO2max , and skeletal muscle mitochondrial respiration
onset and maximizing improvements in disease symptoms. when combined with aerobic exercise training for 12 weeks
Unsurprisingly, exercise and caloric restriction have additive (164). Additionally, while 12 weeks of exercise training
impacts on inducing weight loss and improving insulin increased insulin sensitivity, metformin in combination with
resistance. Caloric restriction of approximately 500 kcal/day exercise blunted this effect (192). Aerobic training alone
combined with moderate-intensity exercise has been reported was the most effective for managing diabetes and preventing
to achieve greater weight loss and larger improvements in NAFLD in rats, while combining metformin and exercise
adipose insulin resistance and protection from lipid-induced negated improvements in exercise-restored complete mito-
hepatic insulin resistance than exercise alone (114). Addi- chondrial palmitate oxidation (184). Therefore, while both
tionally, exercise combined specifically with carbohydrate exercise and metformin can mediate prevention and treatment
restriction, induced greater improvements in glycemic control of diabetes, collectively there is not a significant additive
and endothelial function than just dietary intervention (91). benefit of combined metformin and exercise interventions.
There is also evidence that metabolic benefits of exercise can Future research should consider examination of the possible
be enhanced by altering the quality of carbohydrates rather mechanisms via which each may attenuate the effects of the
than solely restricting them, as diets with a low glycemic other as well as the impact of dosage and timing of each
index combined with aerobic exercise have been shown to treatment when combined.
have synergistic metabolic effects in terms of postprandial Liraglutide, a GLP1 analog, is another medication com-
hyperinsulinemia, incretin responses, and systemic anti- monly used for treating diabetes. It primarily lowers blood
inflammatory effects in obese patients with prediabetes glucose but has also been shown to lower blood pressure,
(150, 275). Collectively, dietary interventions combined with body weight, and incidence of adverse cardiovascular events
exercise training induce greater improvements for patients (196, 217). Aerobic and resistance exercise in combination
with diabetes than either lifestyle intervention alone, high- with liraglutide decreased HbA1c , fasting plasma glucose,
lighting the importance of both diet and exercise in metabolic blood pressure, and body weight in patients with obesity
function and symptom relief. and diabetes to a greater extent than either treatment alone
(204). Furthermore, combined therapies induced the greatest
improvements in insulin sensitivity and GLP1 production
Combination of exercise and pharmacotherapies for (204), indicating that liraglutide is a more favorable option
type 2 diabetes treatment when combined with exercise compared to metformin.
Recent pharmacological advances have led to new medica- Although additional pharmacotherapies exist, their interac-
tions for diabetes, making them the primary intervention for tions with exercise are largely unstudied and thus remain
treatment and even prevention. As the number of available unknown. Therefore, future research should investigate mech-
medications continues to grow, understanding their interac- anistic interactions between exercise therapy and medication
tions with commonly recommended lifestyle interventions, on glycemic control and secondary outcomes to determine
particularly exercise, is crucial to understand the potential of the best treatment combinations for diabetes.
medications to treat the disease and how to maximize their
effects for symptom relief.
Metformin is an established and widely used medication
Exercise after bariatric surgery in patients with
with proven effectiveness in diabetes prevention and treat- type 2 diabetes
ment (309). Metformin lowers blood glucose by decreasing Bariatric surgery is a highly effective treatment for patients
hepatic glucose production and increasing glucose disposal in with obesity and diabetes and has been shown to have substan-
skeletal muscle through activation of AMPK (134, 156, 213, tially greater improvements compared to intensive medical
336). While metformin is an effective preventive agent for therapy at 1-, 3-, and 5 years postsurgery (157, 259–261).

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Exercise and Type 2 Diabetes Comprehensive Physiology

Bariatric surgery combined with medical therapy is also with other diseases. However, because diabetes is associated
more effective than either intervention alone at decreasing with a large range of comorbidities, future research should
and reversing hyperglycemia and at improving secondary focus on the appropriate exercise doses and intensities nec-
outcomes of diabetes (55, 260, 323), indicating favorable essary to safely implement exercise interventions and elicit
effects of surgery when combined with other treatment the greatest metabolic improvements in combination with
methods. Exercise has also been validated as a feasible and other health conditions. Nevertheless, exercise is feasible for
effective adjunct therapy for long-term health maintenance most pregnant women, elderly individuals, and patients with
in bariatric surgery patients (53). Moderate-intensity exercise additional comorbid diseases. Although each case should
after bariatric surgery facilitates continued improvements in be considered individually, especially in these populations,
postprandial glucose regulation and insulin responses while exercise can induce favorable health outcomes for patients
also inducing greater weight loss than surgery alone (265). with diabetes and special health considerations.
Furthermore, combined aerobic and resistance training after
bariatric surgery promotes sustained endothelial improve-
ments and decreased inflammatory markers postsurgery, as
well as mitigates losses in bone density induced by bariatric Conclusions and Future Research
surgery (63, 212). Additional benefits are seen in skeletal Exercise has been extensively studied as a therapeutic inter-
muscle mitochondria, with improvements in mitochondrial vention for diabetes and has been validated as a treatment
respiration and enzymatic activity independent of changes in not only for glycemic control but also for numerous diabetes-
mitochondrial density (54). Therefore, exercise is not only associated comorbidities. While the mechanisms through
feasible in patients after bariatric surgery, but it is benefi- which exercise elicits improvements in glucose uptake and
cial for the long-term maintenance of health improvements insulin effectiveness are well-studied, how exercise ame-
initiated by surgical intervention. liorates secondary negative health outcomes is less defined.
Thus, future studies should investigate the crosstalk between
organs during and postexercise to fully characterize the
Population-Specific Considerations for impacts of exercise on organ-specific and systemic metabolic
improvements. Additionally, attention should be focused on
Exercise Prescription in Patients with genetic variations in exercise responses in populations with
Type 2 Diabetes related chronic diseases, particularly pertaining to racial and
ethnic differences and associated exercise outcomes. Further-
While exercise is generally beneficial for patients with more, links between genetic variation, the gut microbiome,
diabetes, there are sub-populations that warrant special con- and exercise-associated alterations should be considered.
sideration, as exercise may increase risk of adverse health Finally, with the increasing prevalence of exercise prescrip-
events under certain circumstances. Additional attention tion as an adjuvant therapy, interactions between exercise
should be given when evaluating the safety, feasibility, and and the growing number of pharmaceutical and nutraceutical
effectiveness of exercise interventions in these populations, treatments should be evaluated to determine their effective-
specifically pregnant women, elderly patients, and individ- ness and safety for diabetes treatment and management.
uals with other comorbid diseases. Although studies on
exercise in pregnant women with diabetes are scarce, low-
to-moderate intensity exercise during pregnancy has been References
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