Effect of Calorie Restriction and Exercise On Type 2 Diabetes
Effect of Calorie Restriction and Exercise On Type 2 Diabetes
Effect of Calorie Restriction and Exercise On Type 2 Diabetes
Corresponding author: Lily Stojanovska, Department of Nutrition and Health, College of Medicine and Health
Sciences, United Arab Emirates University, PO Box 15551, Al Ain, United Arab Emirates. Email:lily.stojanovaska@
uaeu.ac.ae Phone: +971525308064
ABSTRACT
Type-2 diabetes (T2D) is a chronic condition, generally regarded as an irreversible, that is among the top
10 causes of death globally. The hallmark of T2D is hyperglycemia, which results from disturbances in
insulin sensitivity, insulin secretion, β-cell dysfunction and insulin resistance. Several clinical and lifestyle
factors are involved in the progression of T2D, such as obesity and physical inactivity. A high-calorie
diet is the main contributor to the development of obesity, which results in T2D, as obesity or increased
intra-abdominal adipose tissue is related to insulin resistance. Technological advances have contributed to
individuals having a more sedentary lifestyle, leading to obesity and T2D. T2D can be treated with lifestyle
interventions, such as diet and exercise. Herein, we highlight the positive impact of a very low-calorie diet
(VLCD) and lifestyle modalities in the treatment and prevention of T2D. An inclusion of VLCD 400-800
kcal/day for 8 weeks and ≥ 150 minutes exercise 5 times a week as lifestyle interventions can decrease
glucose levels to normal, reduce HbA1c and improve insulin resistance and sensitivity. Therefore, a
potential mechanism in maintaining glucose homeostasis and remission of T2D by VLCD and exercise
reduces body weight.
Keywords: Hyperglycemia, very low-calorie diet, insulin sensitivity, insulin resistance, type 2 diabetes
INTRODUCTION
Type-2 Diabetes (T2D) is a complex meta- T2D, which is forecasted to increase to 693 mil-
bolic disorder characterized by hyperglycemia due lion by 2045 [3]. This increasing trend in diabetes
to an impairment in macronutrient metabolism. incidence is a significant economical burden, and
T2D is associated with a high risk of micro- and currently, about US $727 billion are being spent an-
macrovascular co-morbid disease [1]. The first nually on those suffering from T2D equating to one
known reference to T2D comes in Egyptian manu- in every eight dollars spent on healthcare [3]. T2D
scripts from 3000 years ago [2], and in the modern was first considered as one of the central compo-
era is amongst the top 10 causes of death world- nents of metabolic syndrome. However, it is now
wide. Globally, 425 million people are affected by recognized as a complex endocrine and metabolic
110 Hira Shakoor et al.
β-cells cannot maintain insulin production, leading decrease in the uptake and utilization of glucose
to dysfunction [10]. Additionally, insulin is a pow- results in hyperglycemia 21. Additionally, obesity
erful inhibitor of lipolysis; even mild elevations of and intra-abdominal adipose tissue are also related
insulin in the plasma cause a remarkable reduction to insulin resistance, with evidence suggesting that
in free fatty acid levels [11]. in T2D it increases in parallel with adiposity [19].
When glucose homeostasis is disrupted, the Adipose tissue is sequestered in different locations
risk of T2D increases. The pathophysiology of throughout the body, with varied physiological im-
T2D centres on two main factors: progressive pe- pacts, with the primary two forms being subcuta-
ripheral resistance to insulin and pancreatic β-cell neous fat under the skin, and visceral fat surround-
dysfunction with their eventual failure. ing the abdominal organs. Subcutaneous fat is
considered to be less active, with lower adipokine
secretion and less macrophage infiltration [20].
Insulin resistance Visceral adipose tissue is a highly active secretory
Chronic hyperglycemia due to factors such organ, releasing adipokines (such as adiponectin,
as poor diet and obesity leads to ongoing insulin leptin, interleukin [IL-6] and tumor necrosis fac-
release, and eventually the tissues lose responsivity tor-α) directly into the portal circulation affecting
to the hormone. Resistance to insulin action leads to hepatic glucose and lipid metabolism. High levels
the impairment of insulin-mediated glucose uptake of adipokines induce a pro-inflammatory and oxi-
in peripheral tissues (particularly the muscle and dative state, further reducing insulin sensitivity and
fat); impairment of triglyceride uptake by the adi- exacerbating insulin resistance [21]. Together, in-
pose tissue and incomplete suppression of hepatic sulin resistance and β-cell dysfunction eventually
glucose output. To maintain glucose homeostasis lead to T2D (Fig. 2).
in these conditions, β-cells secrete more insulin,
leading to hyperinsulinemia [16]. Chronic hyper-
insulinemia causes a reduction in the sensitivity of Pancreatic β-cells
insulin, known as resistance. The main outcome of In T2D, the early stages of β-cell dysfunc-
insulin resistance is to reduce glucose uptake and tion are characterized by impairment of the secre-
utilization by most body cells, with the exception of tion of insulin and ultimately leads to the onset of
neuronal and endothelial cells. Consequently, this glucose intolerance [13]. In the first phase of the
OBESITY AS A RISK FACTOR FOR ly focus on reducing the intake of dietary fats,
TYPE 2 DIABETES particularly saturated and trans, cholesterol,
refined grains, sodium, and added sugar [39].
Physical activity and a balanced diet decrease
intra-abdominal fat, and reduce the impact of its
Obesity results from a chronic imbalance metabolic effects [40] thereby improving insulin
between energy intake and expenditure, with sensitivity and reducing the progression of T2D.
multifactorial contributions from genetic, epi- Studies have shown that a hypocaloric diet reduc-
genetic, physiological, behavioral, socio-cultural es body mass, BMI, body fat percentage, waist
and environmental factors [31]. Obesity is relat- to hip ratio, and leptin production [41]. A study
ed to a wide range of adverse effects on health, of 60 obese women who ate a very low-calorie
including increased risk of disease, disability and diet that included four phases (Intensive: 450–
death. Obesity has been recognized as a medical 680 kcal, transition: 800–880 kcal, maintenance:
disorder since the height of ancient Greece, and 1000–1400 kcal, stabilization: 1200 kcal). This
the Hindu physician Sushrut (500-400BC) iden- was delivered alongside an exercise interven-
tified that obesity is linked with other diseases tion of 60 minutes of moderate exercise, 20–30
including T2D [32]. Obesity is involved in an in- minutes of aerobic training, followed by 20–30
creased risk of various diseases, including meta- minutes of resistance exercise. They found an
bolic syndrome, nonalcoholic fatty liver, autoim- improvement in body composition, quality of
mune disorders, gout, osteoarthritis, obstructive life and cardiovascular risk factors [42]. Another
sleep apnea and cancer [33]. cohort of 191 obese, nondiabetic patients were
Obesity causes alterations to both the provided with 800-1000 kcal/day for 8 weeks.
metabolic and endocrine functions of adipose Transcriptome profiling of participant showed
tissue [34]. Increased macrophage accumulation improvements in genes related to weight, lipid
in adipose tissue causes metabolic complica- profile and glucose level [43].
tions of obesity including insulin resistance and
T2D [35]. Obesity leads to high levels of fatty
acids and hormones, low lipid turn-over and MANAGING TYPE 2 DIABETES
an increase in inflammatory macrophages that
cause activation of pro-inflammatory cytokines
(TNF-α, IL-6) [36]. This pro-inflammatory mi- Calorie restriction and weight reduction
lieu contributes to insulin resistance, T2D, car- Dietary interventions that provide ade-
diovascular disease, and other co-morbid disor- quate nutrition but are low in energy are known
ders [34], therefore, obesity is a known risk fac- as calorie restriction (CR). As there are a num-
tor that causes the development of T2D. ber of intrinsic links to calorie intake, glucose
Obesity is thought to contribute to approx- homeostasis and obesity, calorie restriction aids
imately 70% of diabetes cases [37]. In the last in the prevention and management of T2D. Evi-
decade, dietary patterns have shifted towards dence has shown that calorie restriction in obese
unhealthy food (junk and fast foods) worldwide individuals increases insulin sensitivity and de-
[38]. However, this is contrary to modern nutri- creases acute insulin response to glucose [44].
tional science, which emphasizes a varied diet In fact, calorie restriction improves insulin sen-
rich in fresh food. It is known that poor diet has a sitivity by as much as 40%, as well as assisting
widespread impact on cardiometabolic risk fac- in improved β-cell responsiveness of to glucose
tors that not only include obesity and dyslipid- [45]. Very low calorie diet (VLCD) treatment
emia but also blood pressure, glucose-insulin ho- for weight reduction consist of four phases: (1)
meostasis, lipoprotein concentrations and func- initial phase: patients consume a balanced LCD
tion, oxidative stress, inflammation, endothelial of 1200 to 1500 kcal daily for 1 to 4 weeks;
health, hepatic function, adipocyte metabolism, (2) modified fast phase: consumption of VLCD
cardiac function, metabolic expenditure, path- only; (3) refeeding phase: reintroducing solid
ways of weight regulation, visceral adiposity, food; and (4) stabilization/ maintenance phase:
and the microbiome [39]. Therefore, a healthy which focuses on nutritional education and be-
diet and active lifestyle is suggested to decrease havior modification that help to sustain weight
the risk of life-threatening disease. For greater loss [1]. VLCD treatment can results in achiev-
health benefits, general dietary guidelines main-
EFFECT OF CALORIE RESTRICTION AND EXERCISE ON TYPE 2 DIABETES 115
American Diabetes
ET, RT, CT ≥5 ≥ 150 Moderate intensity
Association (ADA)
European Association
Moderate to
for the Study of ET, RT, CT – ≥ 150
moderate intensive
Diabetes (EASD)
15–60 min/
Diabetes UK ET 3–5 Moderate
session
more than 150 min/week was effective for car- Combination of very-low-calorie diet and
diovascular health and improved T2D outcomes exercise in improving the biomarkers of type-2
[62]. Therefore, it is recommended to have 150 diabetes
min/week of moderate activity or 75 min/week Insulin resistance is related to the etiolo-
of vigorous activity. gy of T2D in both aging and obesity. However,
b) Strength training is an effective form the exact causes for the development of insu-
of exercise for building bones, muscle strength, lin resistance are still unclear but it is thought
burning fat and increasing general metabolism. that overnutrition, overweight and obesity are
Evidence shows that physical activity during the major contributing factors [70]. Sedentary
menopause prevents weight gain and reduces the lifestyle, and alterations in glucose metabo-
risk of heart disease, T2D and cancer [63,64]. lism due to aging and mitochondrial function
Aerobic exercise has been reported to result in are also believed to cause insulin resistance
a greater reduction in HbA1c when compared to [71]. Combination of both calorie restriction
resistance training. However, combined resis- and exercise have been shown to significantly
tance and aerobic exercise training was signifi- decrease insulin levels in the plasma and im-
cantly better than only aerobic exercise. Simi- prove insulin sensitivity in middle-aged obese
larly, some long term endurance training inter- and elderly overweight individuals [72]. The
vention studies showed a significant reduction in insulin-dependent glucose transporters are as-
HbA1c, which indicates that endurance training sociated with specific classes of skeletal mus-
is associated with reducing T2D risk [65,66]. cle oxidative metabolism. Skeletal muscle is of
In a systematic review and meta-analysis, two types: low oxidative skeletal muscle (type
it was shown that 3,600 Metabolic Equivalent 1 slow-twitch), the main fuel source are tri-
(MET) minutes/week reduced the risk of T2D glycerides, fatigue slowly and use aerobic res-
by 19% [67]. Another study of 98 participants, piration; fast oxidative skeletal muscle (type 2
receiving lifestyle intervention of 5-6 aerobic fast-twitch), in which the main fuel source is
and combined aerobic and strength training ses- glycogen, break down ATP quickly, contraction
sions for 30‐60 minutes a week for 12 months force is greater and while also using aerobic
found remission of diabetes in 23% of partici- respiration. Low oxidative type skeletal muscle
pants [68]. Similarly, 98 participants with T2D tissue has less glucose transporters 4 (GLUT4);
who performed 5 to 6 aerobic training sessions and hence, shows a decrease in insulin sensi-
of 30-60 minutes per week alongside 2 to 3 of tivity compared to high oxidative fibers [73].
resistance training showed reductions in HbA1c, Exercise helps increase both mitochondrial and
glycemic control and need for glucose-lowering GLUT4 content in skeletal muscle, improving
medications [69]. glucose transport and utilisation in the muscle.
EFFECT OF CALORIE RESTRICTION AND EXERCISE ON TYPE 2 DIABETES 117
Evidence shows that exercise increases mito- T2D [78]. Recent evidence has also reported that
chondrial content and electron transport chain low-calorie diet and lifestyle interventions re-
activity, whereas calorie restriction improves sulted in a significant improvement and T2D re-
insulin sensitivity in overweight older adults mission [79]. For, instance, An open-label clus-
[74]. Weight reduction secondary to calorie re- ter-randomized primary care trial, (the DiRECT
striction also improves tyrosine kinase activi- study), of 49 primary care practices in Scotland
ty, the enzyme responsible for the transfer of and the Tyneside region of England, demon-
a phosphate group from the ATP molecule to a strated the impact of a low energy diet (LED)
protein in skeletal muscle insulin receptors [75], for T2D remission. This study followed the par-
thus increasing the concentration and function ticipants for 12 months, and it was shown that
of GLUT4 receptors, however it is unable to 24% of the LED intervention group achieved 15
activate muscle glycogen synthase by insulin. kg weight loss, with nearly half (56%) achieving
Different mechanisms, such as the depletion of full remission [79]. Similarly, evidence showed
muscle glycogen, are involved in improving in- that calorie restriction combined with exercise
sulin sensitivity with calorie restriction, how- improved blood pressure, glucose level, lipid
ever the undelying mechanisms require further profile, inflammatory cytokines, reduce insulin
investigation [46]. Thus, taken together the ev- resistance, HbA1c, circulating level of leptin,
idence suggests that the combination of VLCD weight and waist circumference [80,81].
and physical activity results in weight loss and
a decrease in T2D risk. A systematic review of VLCD treatment Safety and Precautions
studies showed that aerobic activity and diet
combination resulted in greater reductions in VLCD therapy is safe for BMI >30 kg/
weight and fasting glucose level [76]. Likewise, m2 along with regular medical supervision but
the long-term effect of exercise and VLCD for for overweight individuals with BMI of 27-30
16 weeks in twenty-seven obese, insulin-depen- kg/m2, VLCD should only reserved to those
dent T2D participants was observed. Patients who have any weight-related medical problems
followed a combination of VLCD, consisting of [94, 96]. BMI ≥ 30 kg/m2 is a risk factor for
450 kcal/day, with a weekly exercise program cardiovascular morbidity and mortality, there-
of 30 min aerobic exercise for four months at fore substantial weight reduction is necessary
70% of maximum heart rate. Bodyweight and to improve quality of life [100]. Generally, Na-
the glucoregulatory parameters significant- tional Institute of Health (NIH) recommends
ly improved after the four-month intervention to reduce energy intake by 500 kcal/day to
period compared to the baseline value. Body those who have class I obesity [101]. Individ-
weight (kg) in this group decreased from 114 uals with class II and class III obesity should
± 5 to 86 ± 4 and HbA1c (%) from 7.8 ± 0.4 to restrict to 500–1000 kcal/day reduction. By re-
6.3 ± 0.4 [77]. Studies that report a reduction ducing 500 kcal/day energy intake, a person can
in the risk of T2D through the combination of a achieve 0.5 kg/week weight loss [102].
low calorie diet and physical activity have been However, VLCD treatment is not advis-
summarized in Table 2. able for childern and adolescents. VLCD can
T2D and excess adiposity are linked with effect normal body growth, protein intake and
one another. Recent evidence shows that weight increase nitrogen loss [103,104]. Also VLCD
reduction through medical interventions or bar- terapy is not considered safe for adults older
iatric surgery can cause remission in T2D in than 50 years. Older people are at higher risk
young people and in those with recent onset of of negative nitrogen balance with weight loss
disease [78]. The Diabetes Intervention Accen- as they have already depleted lean body mass
tuating Diet and Enhancing Metabolism (DIA- and low immune response [105]. Similarly,
DEM-I) study is a current, non-blinded, prag- VLCD is not appropriate for pregnant and lac-
matic, randomized, controlled, parallel-group tating women as they have increased nutritional
trial. It includes 138 subjects, younger adults requirements [106]. Furthermore, other people
with T2D, in the early stage of diabetes (≤ 3 year that should be excluded from VLCD treatment
duration) who have undergone intensive lifestyle are those suffering from cardiac disease, he-
intervention changes (i.e., 800 kcal/day intake patic disease, renal disease, infectious disease,
and 150 min/week exercise for 12 weeks) and psychiatric disease (bulimia nervosa or anorex-
results are hoped to identify a path to reversal of
118 Hira Shakoor et al.
Table 2. Studies showing the effect of very low calorie diet, low calorie diet and exercise on type-2 diabetes
Characteristics of
Diet and lifestyle modification Duration Primary outcomes Results
participants
11 participants with type 2 600 kcal/day and habitual level of Normalization of both beta cell Normalized Fasting plasma glucose and
8 weeks
diabetes physical activity function improve hepatic insulin sensitivity [99]
800-1000 kcal/day
70 participants with 12 week aerobic interval training 8-10 Lower, total cholesterol, triglycerides,
Weight and central body fat loss
coronary artery disease 3 times/week followed by 40 weeks and inflammation [84]
weeks AIT 2 times a week
383 obese but non diabetic Reduced weight and improve Improve long term metabolic outcomes
800-100kcal/day 8 weeks
patients glycemic control and prevent T2D [88]
Reduce fat free mass, hip Following calorie restricted diet cause
2224 individuals 810 kcal/day 8 weeks circumference, pulse pressure, and normal glycemia in 35% of participants
insulin resistance. [90]
Characteristics of Results
Alternate day calorie restriction Habitual diet days Duration
participants
35 overweight or obese
but healthy adults into 4 ADCR and exercise induce beneficial
VLCD (400–500 kcal)
groups: Alternate days Received ad libitum changes in body weight, body
Exercise session: 1) 5 min warm up; 2) 40
calorie restriction(ADCR) on the remaining 4 8 weeks composition, glucose, insulin,
minutes resistance training; 3) 20 minutes
(n=13), exercise (n=10), days of the week insulin resistance and triglyceride in
aerobic exercise; 4) 5 minutes cool-down
exercise plus ADCR (n= overweight and obese adults [93].
12), and control (n = 10)
VLCD= Very Low Calorie Diet, LCD=Low Calorie Diet, ADCR= Alternate Day Calorie Restriction
EFFECT OF CALORIE RESTRICTION AND EXERCISE ON TYPE 2 DIABETES 119
ia nervosa) and type 1 diabetes because of se- ly, Astrup and Rossner illustrated that the larger
vere ketosis or hypoglycemia [94]. initial weight loss induced by VLCD is related
The VLCD is known to reduce weight to greater long‐term weight reduction [115], Al-
while preserve lean body mass, achieved by pro- though, long term weight loss with VLCD can be
viding greater amount of dietary protein 0.8 to obtained when combined with behavioral thera-
1.5 g protein/kg ideal body weight [107]. Pro- py and regular exercise. Considerably, exercise
tein can be provided in form of milk, soy, or will not increase the weight reduction, but it is
egg‐based powder (mixed with water). Vitamins helpful in maintaining weight loss [116]. Be-
and mineral supplements should be given to ful- havioral therapy (food diaries, shopping strate-
fill body needs [96,108]. To maintain electrolyte gies, dietary preference) and exercise can help to
balance, 3 to 5 g of sodium chloride, and 3 g of maintain weight loss for 1- 3 years after VLCD.
potassium will be given and patients should be However, VLDL diets results in increasing psy-
asked to drink 1.5 to 2 L of noncaloric fluid per chological stress and hormone level such as cor-
day[109]. Maintaining proper hydration is very tisol that can eventually induce negative effects
important during VLCD treatment to prevent or- on insulin resistance and lower dietary success
thostatic hypotension [110]. [117]. Therefore, psychological counselling is
Patients receiving VLCD should be mon- very important for patients receiving VLCD.
itored during first 2 weeks of rapid weight loss Consequently, total duration VLCD intervention
as the side effects from VLCD therapy are com- consist of 4-6 months that includes introduction
mon during the first 2 weeks of treatment [111]. of VLCD for 8 weeks, refeeding and stability
It is difficult to maintain weight loss in a long phase, is helpful to reduce weight without any
term after VLCD treatment. Maintenance of further complications. After VLCD treatment
weight loss can be achieved by active follow (4-6 months), patients should gradually intro-
up with behavioral therapy, nutrition education duce to LCD along with behavioral modification
and exercise [108]. Unsupervised VLCD can and exercise to sustain body weight.
results in serious complications including death
of patient [108]. Evidence showed that VLCD CONCLUSION
for longer duration can even lead to cardiac
complication and hence death. No death rate
was observed when VLCD has been taken for 8
weeks or less [112]. The number of cases of T2D is increas-
ing rapidly worldwide and contributes to
enormous social and personal suffering and
Weight reduction maintenance with VLCD economic burden. Patients present with hy-
VLCD is known to be superior treatment as perglycemia due to the progressive deterio-
compared to LCD to achieve short term weight ration of glucose metabolism over the years.
loss but achieving long term weight loss main- High-calorie diets and physical inactivity are
tenance is difficult. The National Heart, Lung, major contributors to the causes and initiation
and Blood Institute (NHLBI) expert panel rec- of T2D. There is a strong evidence that phys-
ommended LCD (1000 to 1500 kcal/day) over ical activity and dietary modalities reduce the
VLCD. The panel’s decision was based on data risk of morbidity and mortality in individuals
from randomized trials that reported no differ- with T2D. Strategies that deal with this global
ences in long‐term weight losses between VL- problem of increased rates of T2D and its com-
CDs and LCDs; in fact, greater weight regain plications should focus on physical activity
was observed after VLCD treatment [113]. How- and how to reverse the condition at the popu-
ever, despite this expert panel’s conclusion, the lation level. Moreover, calorie restriction diets
majority of individual randomized trials report- also prove to be beneficial in the management
ed greater long‐term weight losses after VLCDs. of T2D. Therefore, future research is required
For instance, in a meta‐analysis of long‐term to include long-term lifestyle interventions
studies, demonstrated that VLCD treatment has including very low-calorie diets and exercise
been association in achieving greater long‐term and to analyzed the remission outcomes of pa-
weight loss as compared to LCD [114]. Similar- tients with T2D.
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Резиме
1
Оддел за исхрана и здравје, Колеџ за медицина и здравствени науки, Обединети Арапски
Емирати, Ал Аин, Обединети Арапски Емирати
2
Институт за здравје и спорт, Универзитет Викторија, Мелбурн, Австралија
3
Оддел за западна медицина, Медицинска школа во Мелбурн, Универзитет во Мелбурн, Сент
Албанс, Австралија
4
Оддел за клиничка исхрана и диететика, Колеџ за здравствени науки, Универзитет во Шарџа,
Шарџа, Обединети Арапски Емирати
5
Оддел Nuffield за здравјето на жените и репродуктивното здравје, Универзитет во Оксфорд,
Оксфорд, Велика Британија
Дијабетес тип 2 (T2D) е хронична состојба, општо се смета за неповратна и е меѓу првите
10 причини за смрт на глобално ниво. Карактеристика на Т2D е хипергликемијата, што произ-
легува од нарушувања на чувствителноста на инсулин, секрецијата на инсулин, дисфункцијата
на β-клетките и инсулинска резистенција. Неколку клинички фактори и фактори на живот се
вклучени во прогресијата на Т2D, како што се дебелината и физичката неактивност. Високо-
калоричната диета најмногу придонесува за развојот на дебелината, што резултира со Т2D,
бидејќи дебелината или зголеменото интраабдоминално масно ткиво е поврзано со инсулин-
ската резистенција. Технолошкиот напредок придонесе поединци да имаат повеќе седентарен
начин на живот, што доведува до дебелина и Т2D. Т2D може да се третира со интервенции во
животниот стил, како што се диета и вежбање. Овде го потенцираме позитивното влијание на
многу нискокалоричната диета (VLCD) и модалитетите на животниот стил во третманот и пре-
венцијата на T2D. Вклучување на VLCD 400–800 kcal/ден за време од 8 недели и ≥ 150 минути
вежбање петпати неделно – бидејќи интервенциите во животниот стил може да ги намалат ни-
воата на глукоза до нормала, да го намалат HbA1c и да ја подобрат инсулинската резистенција
и чувствителност. Затоа, потенцијалниот механизам за одржување на хомеостазата на глукозата
и ремисијата на T2D со VLCD и вежбање ја намалува телесната тежина.