Clinical Nutrition ESPEN xxx (xxxx) xxx

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Clinical Nutrition ESPEN

journal homepage: http://www.clinicalnutritionespen.com

Narrative Review

Low-carbohydrate diets: Effects on metabolism and exercise e A

comprehensive literature review
Rodrigo C.O. Macedo a, b, *, 1, Heitor O. Santos c, **, 1, Grant M. Tinsley d,
Alvaro Reischak-Oliveira b
a
University of Santa Cruz do Sul (UNISC), Santa Cruz do Sul, Brazil
b
Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
c
School of Medicine, Federal University of Uberlandia (UFU), Uberlandia, Minas Gerais, Brazil
d
Department of Kinesiology and Sport Management, Texas Tech University, Lubbock, TX, USA

a r t i c l e i n f o s u m m a r y

Article history: Background & aims: Low-carbohydrate diets (LCD) have gained substantial attention in recent years for
Received 21 April 2020 their potential in health promotion and treatment of diseases, but they remain controversial in nutrition
Accepted 30 July 2020 guidelines and exercise performance. Herein, through a literature review, we discuss the current evi-
dence base by considering management of LCD and potential coupling of these dietary regiments with
Keywords: physical exercise.
Carbohydrate restriction
Methods: We performed a comprehensive literature review with no date limits as a means of including
Glucose metabolism
seminal to current studies.
Low-carbohydrate diet
Low glycogen
Results: Reduction of CHO intake decreases muscle glycogen, yielding greater fat oxidation and associ-
Obesity ated metabolic benefits. LCD may promote fat mass loss and regulation of biochemical parameters, such
Exercise as lipid and glycemic biomarkers. The therapeutic potential of LCD towards noncommunicable diseases,
particularly obesity and its comorbidities, is therefore reasonable as a dietary candidate in this context.
Potential benefits to this approach are linked to enhancement of mitochondrial gene expression and
mitochondrial biogenesis. As such, LCD may be a feasible tool in a ‘periodized nutrition’ for athletes and
within clinical scenarios. Long-term observational follow-up studies have demonstrated increased
mortality and cardiovascular implications of LCD. However, harmful associations may depend on the food
source (e.g., animal-based vs. plant-based foods).
Conclusion: LCD may decrease body mass, waist circumference, and improve fat and carbohydrate
metabolism. When combined with exercise, LCD seems to be an effective strategy in regulating metabolic
factors of cardiovascular diseases. Conversely, LCD may be associated with higher mortality and meta-
bolic dysregulations if it contains large amounts of animal-based foods, particularly saturated fat.
© 2020 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights
reserved.

1. Introduction prevalence of overweight and obesity in individuals >18 years was

39% and 13%, respectively [1].
In recent years, there has been an increased incidence of in- Obesity can be defined as a chronic noncommunicable disease,
dividuals with obesity worldwide. Between the years 1980 and which is characterized by a body mass index (BMI) greater or equal
2013, it was estimated that the number of those with overweight to 30 kg/m2, whereby the body fat mass is a considerable contrib-
and obesity increased from 857 million to 2.1 billion [1]. In 2016, utor [2,3]. Increased adipose tissue causes significant metabolic
the World Health Organization estimated that the global dysfunction, resulting higher risk of comorbidities such as type 2
diabetes (T2DM), cardiovascular disease, high blood pressure, hy-
percholesterolemia, hypertriglyceridemia, arthritis, asthma and
* Corresponding author. University of Santa Cruz do Sul (UNISC), Brazil. cancers [3e6] and even mortality [5,7]. In 2015, high BMI
** Corresponding author. Federal University of Uberlandia (UFU), Uberlandia, contributed to 4 million deaths and represented 7.1% of the deaths
Minas Gerais, Brazil.
from any cause [8,9]. For this reason, obesity represents one of the
E-mail addresses: nutricionistarodrigomacedo@gmail.com (R.C.O. Macedo),
heitoroliveirasantos@gmail.com (H.O. Santos). major public health problems in several developed and developing
1
Shared first authorship. countries [10,11].

https://doi.org/10.1016/j.clnesp.2020.07.022
2405-4577/© 2020 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.

Please cite this article as: Macedo RCO et al., Low-carbohydrate diets: Effects on metabolism and exercise e A comprehensive literature review,
Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.07.022
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Comorbidities caused by obesity may be attenuated or prevented levels, yielding increased glucagon production [29]. These changes
as a result of weight loss and decreased visceral fat [12]. Therefore, lead to a catabolic state in which intense gluconeogenesis is similar
the prophylaxis and treatment of obesity and its comorbidities to fasting [30]. Approximately 200 g of glucose daily are synthe-
should be based on lifestyle changes, notably the inclusion of exer- sized from liver and kidneys even without CHO consumption [21].
cise and health-promoting eating habits [13,14]. Thus, several types The glucose production from amino acids, glycerol and lactate is
of dietary approaches to this public health problem have been rec- adequate for the demand of glucose-dependent tissues and cells
ommended. One polarizing approach that has gained substantial such as erythrocytes and neurons (Fig. 1). Through a LCD protocol,
popularity over the past several decades is the low-carbohydrate diet glucose demand and skeletal muscle proteolysis are reduced, once
(LCD) [15]. LCDs represent a multi-billion-dollar industry, with pronounced fatty acid mobilization from the adipocytes (i.e. lipol-
widespread availability of low-carbohydrate food products and ysis) and elevated ketone bodies production increase their contri-
millions of LCD book copies sold worldwide. Books and media often butions to the body's energy requirements [21,26,31]. Therefore,
argue that LCD may improve lipid metabolism, resulting in rapid there is evidence that LCD may maintain the lean mass while
weight loss without adverse effects [16,17]. inducing body mass loss [27].
In addition to nutrition, exercise has established benefits to hu- Hormonal shifts are a metabolic concern that can affect body
man health and is another fundamental factor for body mass composition, and thyroid hormones have garnered particular
reduction, thus supporting obesity treatment [13,14,18]. On the other attention in the context of LCD. Some studies have shown that CHO
hand, scientific literature is still controversial regarding the safety, restriction may decrease triiodothyronine (T3) concentrations even
and acute and chronic adaptations due to the association of LCD and in isocaloric interventions [32,33]. Concerning biochemical path-
exercise [19e22]. Therefore, the aim of this review was to compre- ways, in rats the type-1 deiodinase activity, an enzyme that facili-
hensively explore the effect of LCD on metabolism and exercise. tates peripheral thyroxine (T4) to T3 conversion, is insulin and
glucose-dependent, thereby corroborating with a detrimental ef-
2. Materials and methods fect of LCD to thyroid health [32]. In humans, Volek et al. found
hormonal improvement with LCD through increased values of total
We used the electronic databases Pubmed, (MEDLINE), Scopus, and free serum T4 when compared to a low-fat diet (LFD) during 6
Cochrane and Google scholar. The terms (and entry terms) com- weeks of LCD intervention [27]. Furthermore, LCD did not decrease
bined “low-carbohydrate diet”, “very-low-calorie diet”, “ketogenic resting metabolic rate and thyroid-stimulating hormone (TSH)
diet”, “low glycogen”, “carbohydrate restriction”, “cardiometabolic levels when compared with isocaloric diets [27]. It must also be
markers”, “cardiometabolic biomarkers”, “physical exercise”, “ex- noted that across several clinical trials of 1e2 years of LCD there
ercise performance” were searched from the date of inception until were no occurrences of hypothyroidism [34e38]. Therefore, despite
December 2019. Eligibility criteria included full-text articles, writ- some alterations in thyroid hormones during LCD, these may not
ten in English, and human studies. We excluded in vitro studies. correspond to clinically meaningful changes. LCD-induced effects
References of the retrieved papers were also screened. Abstracts, on thyroid hormones are distinct from those observed during se-
case reports and editorials were not withheld. vere hypocaloric diets and complete starvation [32]. As opposed to
severe hypocaloric diets causing massive weight loss, an adequate
3. Results and discussion LCD (i.e. with sufficient micronutrient intake and without extreme
caloric restriction) may not dysregulate the thyroid hormones
3.1. Definition [39e41].

In addition to the controversy regarding applicability and safety 3.3. Cardiometabolic effects
of LCD, the actual definition of a “low carbohydrate diet” is still
discussed. Some term any diet containing a proportion of carbo- Exercise and diet are essential components of short- and long-
hydrate (CHO) lower than federal recommendations a LCD. For term obesity treatment [42] because they promote greater body
example, due to the Acceptable Macronutrient Distribution Range fat loss compared to either intervention in isolation [43,44]. High
(AMDR) of 45e65% of energy from carbohydrate in the United fat meals, especially those containing saturated fat, may increase
States [23], diets containing <45% are often termed LCD. Diets serum triglycerides (TG) concentrations and are associated with
composed of less than 40e50 g/d of CHO are named as very-low- obesity and insulin resistance. Hypertriglyceridemia or elevated
carbohydrate diet (VLCD) or ketogenic diets if they elicit a suffi- postprandial levels of triglyceride-rich lipoproteins induces endo-
cient elevation in blood ketone concentrations, whereas a non- thelial dysfunction through increased oxidative stress and is an
ketogenic, low-carbohydrate diet contains relatively low CHO independent risk for cardiovascular diseases [45,46]. Throughout
content, often ~60e150 g/d, that does not elicit the pronounced the past, the low-fat diet (LFD) played a central role on the nutri-
elevation in blood ketones. Diets with low CHO are associated with tional management for obesity and its comorbidities [47]. However,
increased endogenous production of ketone bodies (acetoacetate, there has also been sustained interest in LCD for obesity treatment
acetone and b-hydroxybutyrate), which together with fatty acids and prevention. Additionally, some contend that the influence of
are crucial metabolic fuels in a low-CHO state [20,21]. Generally, a sugar industry on international nutrition policies and guidelines
moderate CHO diet consists of 45e55% intake of energy from CHO since the 1960s further calls into question the development of
[24], which is relatively aligned with the AMDR of 45e65%. This is traditional LFD recommendations [48]. Thus, continued discussion
also similar to typical intakes observed in North America and of potential clinical benefits and side effects of the LCD are essential
Europe, although it can be considered a LCD in other regions, such to expand the insights into practitioners and scientists [49].
as Asia [24,25]. High CHO diets in turn contain >65e70% intake of Even without intentional energy restriction, LCD may be more
energy from CHO [23,24]. effective in reducing body mass in obese patients than a LFD [50].
Brehm et al. examined two types of diets in 53 obese women [50].
3.2. Metabolism under carbohydrate restriction One group was instructed to restrict dietary fat and energy intake,
and the second was only instructed to restrict CHO (20e60 g/d), but
One of the major physiological effects of LCD is hormonal ad- not energy. After 6 months of intervention, there was a significant
aptations [26e28]. There is a notable reduction of serum insulin decrease of body mass and fat mass in the VLCD group, but not in

Please cite this article as: Macedo RCO et al., Low-carbohydrate diets: Effects on metabolism and exercise e A comprehensive literature review,
Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.07.022
 R.C.O. Macedo et al. / Clinical Nutrition ESPEN xxx (xxxx) xxx 3

Fig. 1. Energy substrates during a low-carbohydrate-diet (LCD). Under LCD the body is conditioned to predominantly produce glucose from amino acids, glycerol and lactate, in a
process known as gluconeogenesis. This metabolic system supplies glucose-dependent tissues and cells (e.g. erythrocytes and neurons), allowing ATP production to carry out the
cellular actions necessary for human life. ATP, adenosine triphosphate.

LFD. However, there were no differences between groups regarding was animal-based, whereas the vegetable-based LCD was associ-
values of high-density lipoprotein cholesterol (HDL-c), low-density ated with lower all-cause and cardiovascular disease mortality
lipoprotein cholesterol (LDL-c), TG, blood pressure, and serum rates [53]. Similarly, Seidelmann et al. demonstrated through a
glucose and insulin. median follow-up of 25 years that LCD based on animal-derived
Foster et al. conducted a study with 63 subjects (43 women and protein and fat sources were associated with higher mortality,
20 men) and divided them into 2 groups e LFD or VLCD e for 12 while LCD based on plant-derived protein and fat intake were
months [35]. In the VLCD group, there were reductions in body associated with lower mortality [24]. Likewise, high percentages of
mass, diastolic blood pressure, TG and glycemic curve, along with CHO were associated with increased mortality. The minimal risk
increases in HDL levels and insulin sensitivity. The authors was observed at moderate (50e55%) CHO intake [24], a level that
concluded that, although noticeable benefits were observed, the corresponds to the approximate mid-point of the AMDR of 45e65%.
safety and efficacy of VLCD are not fully supported. Subsequently, Despite the consistent representation in the epidemiological sce-
Foster et al. found improvement in some risk factors for coronary nario, these follow-up studies not infer the “cause-and-effect”
heart disease due to LCD intervention [51]. They performed a study relationship between LCD and clinical outcomes. Therefore, clinical
in 307 obese adults (208 women and 99 men) with BMI between 30 trials are essential to underpin the interplay between the dietary
and 40 kg/m2 and randomized them into VLCD or LFD groups for 24 factors and clinical outcomes through potential mechanisms.
months. Significant results were observed between the 3rd and Bearing this in mind, cardiometabolic-related markers and
12th month of intervention. The VLCD group achieved greater re- anthropometric characteristics addressed by meta-analyses of
ductions of body mass, diastolic blood pressure, TG, VLDL, LDL-c randomized clinical trials are summarized in Table 1.
values in the first 6 months, compared to LFD. However, weight A number of meta-analyses show favorable effects of LCD on
loss, TG and LDL-c levels did not differ between groups at 12 and 24 weight loss [20,54,56,58,60e62], while others show comparable
months of intervention. effects between LCD and LFD or balanced diets [55,57,59]. Likewise,
Similar to the study above with regard to number of patients when viewed in general, these studies corroborate with similar
and duration, Shai et al. randomized 322 class I obese individuals effects of both LCD and LFD on cardiometabolic markers (e.g. gly-
into three groups of intervention during 24 months: 1) LFD with cemic and lipid indices). In addition to the pooled results from
energy restriction; 2) Mediterranean diet with energy restriction; meta-analyses, most recently Hyde et al. demonstrated that LCD
and 3) VLCD without energy restriction [38]. Mediterranean diet was more effective in reversing metabolic syndrome regardless of
and VLCD were the most effective for reducing body mass and whole-body or fat mass in individuals with obesity and a diagnosis
exhibited clinical safety equal to LFD. Besides that, VLCD group had of metabolic syndrome [63]. Despite a small sample (n ¼ 16), this
the greatest reduction of body mass, TG and high-sensitivity C- study should be highlighted due to the novelty and attractive
reactive protein, and increase in HDL-c and adiponectin values, control and metabolic measures, which may amplify the meta-
even without energy restriction. analysis findings.
In a 20-year follow-up period, investigations from the Nurses' The researches detected decrease of plasma TG and increase of
Health Study (NHS) encompassing more than 85,000 women did HDL-c concentrations, while modulating LDL subclass phenotype in
not find increased risk of coronary artery disease [19] and T2DM a positive manner by which increased LDL size and decreases the
[52] with the LCD. In contrast, using the NHS database plus another small dense LDL particles independent of LDL-c concentration [63].
follow-up study involving about 45,000 men, LCD was associated The authors analyzed obese subjects with metabolic syndrome on
with higher all-cause mortality in both men and women when it three phases of 4-week weight-maintenance isocaloric diets: low,

Please cite this article as: Macedo RCO et al., Low-carbohydrate diets: Effects on metabolism and exercise e A comprehensive literature review,
Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.07.022
4 R.C.O. Macedo et al. / Clinical Nutrition ESPEN xxx (xxxx) xxx

Table 1
Effects of low-carbohydrate diets on cardiometabolic markers and anthropometric characteristics through meta analyses of randomized clinical trials.

Author (year) Population/ n Low carbohydrate Comparator, % kcal Energy restriction

condition (LC), % kcal

Bueno (2013) [54] BMI > 27.5 kg/m2 1415 VLCD LFD Both
CHO: <50 g/d or FAT < 30%
10%
Naude (2014) [55] Overweight and 3209 LC, high protein Balanced diet Only in balanced diet
obese, diabetes, diet (FAT 25e35%) CHO: 45e65%
glucose intolerance LC, high fat diet PTN: 10e20%
or insulin (unrestricted fat FAT: 25e35%
resistance, and protein)
cardiovascular
conditions
BMI > 25 kg/m2
Nordmann (2006) BMI > 25 kg/m2 447 LCD LFD Only in LCD
[56] CHO: < 60 g/d FAT < 30%
Johnston (2014) BMI > 25 kg/m2 7286 LCD Moderate diet Subanalysis of energy restriction
[57] CHO: 40% CHO: 55e60% by meta-regression
PTN: ~30% PTN: ~15%
FAT: 30e55% FAT: 21e30%
LFD
CHO: ~60%
PTN: ~10e15%
FAT: 20%
Mansoor (2016) Severely obese, 1369 LCD, atkins diet Conventional LFD (no Not clear
[58] previously healthy First phase: 20e40 clear definition of
BMI > 35 kg/m2 g/d or <20% macronutrients)
Hession (2009) [20] BMI  28 kg/m2 1222 LC/HP LFD Both, but necessary in LCD
CHO: <40 g/d FAT: <30%
Irrespective of 600 kcal deficit
energy content
Hu (2012) [59] Reported metabolic 2788 LCD LFD Not clear
risk factors CHO: 45% FAT  30%
Santos (2012) [60] Overweight and 1141 LCD baseline (no LCD after treatment (no Not clear
obese (no clear clear definition of clear definition of
definition) macronutrients) macronutrients)
Sackner-Bernstein Overweight and 1797 LCD LFD Not clear
(2015) [61] obese, with no CHO: <120 g/d FAT: <30%
comorbities but
with dyslipidemia
(no clear definition)
Hashimoto (2016) Overweight and 1805 Moderate LCD Control diet (no clear Not clear
[62] obese (no clear CHO: ~40% definition of
definition) VLCD macronutrients)
CHO: ~50 g/day or
10%

Author (year) Length of follow-up AMSTAR2 Conflict of Results

(months) interests

Bueno (2013) [54] >12 High None Individuals assigned to a energy-restricted, VLCD, achieved greater
reductions in body weight, TG and DBP, and a greater increase in HDL-c
and LDL-c, compared to a LFD after 12 months or more.
Naude (2014) [55] >3 High None Weight loss was demonstrated in both LCD and balanced diets. There
was little or no difference in changes in cardiovascular and diabetes risk
between diets up to 2 years of follow-up.
Nordmann (2006) >6 Moderate An author's salary is LCD, without energy restriction, was more effective in inducing weight
[56] funded in part by loss after 6 months, but not after 12 months. TC and LDL-c decreased
Robert Atkins more in LFD, however HDL-c and TG were more favorably to LCD.
Foundation
Johnston (2014) >3 Moderate None Both LCD and LFD were associated with a greater weight loss compared
[57] with no diet.
Mansoor (2016) >6 Moderate None LCD showed greater weight loss and TG reductions, and a significant
[58] increase in HDL-c and LDL-c, compared to a LFD.
Hession (2009) [20] >6 Low None Weight loss was greater in LC/HP at 6 and 12 months compared to LFD.
There was a greater increase in TC, LDL-c and HDL-c in LC/HP diet and a
decrease in TG and SBP.
Hu (2012) [59] >6 Low None Both diets were effective at reducing body weight, waist circumference,
blood pressure, TC, total to HDL-c ratio, LDL-c, TG, blood glucose and
serum insulin. LCD showed greater increase in HDL-c and decrease TG,
but less reduction in TC and LDL-c, compared to LFD.
Santos (2012) [60] >3 Low None Compared to baseline, LCD was associated with significant reduction in
body weight, BMI, abdominal circumference, SBP, DBP, TG, fasting
glucose and insulin, glycated hemoglobin, plasma CRP, as well as an
increase in HDL-c and LDL-c levels.

Please cite this article as: Macedo RCO et al., Low-carbohydrate diets: Effects on metabolism and exercise e A comprehensive literature review,
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Table 1 (continued )

Author (year) Length of follow-up AMSTAR2 Conflict of Results

(months) interests

Sackner-Bernstein >2 Low Study was LCD was associated with a modest but greater improvement in weight
(2015) [61] supported by loss and ASCVD risk reduction up to 2 years, compared to LFD.
Atkins Nutritionals
Hashimoto (2016) <2 (based on Low Some authors Decrease of body weight and body fat massa were higher in LCD than in
[62] included trials) declared they control diet.
received grants,
honoraria and
research supportb

ASCVD: atherosclerotic cardiovascular disease; BMI: body mass index; CHO: carbohydrate; CRP: C-Reactive Protein; DPB: diastolic blood pressure; HDL-c: high-density
lipoprotein cholesterol; HP: high protein; LCD: low-carbohydrate diet; LDL-c: high-density lipoprotein cholesterol; LFD: low-fat diet; PTN: protein; RCT: randomized
controlled trial; SBP: systolic blood pressure; TC: total cholesterol; TG: triglycerides; VLCD: very low carbohydrate diet.
a
Authors assumed differences in kg, but standardized mean difference was used in meta-analysis of body weight and body fat mass.
b
AstraZeneca plc., Astellas Pharma Inc., Nippon Boehringer Ingelheim Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K., Kyowa Hakko Kirin Company Ltd., Kissei
Pharmaceutical Co., Ltd., MSD K.K., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Pharma Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Sanofi K.K., Ono Pharmaceutical
Co., Ltd. and Takeda Pharmaceutical Co., Ltd.

moderate, and high in CHO. All foods were prepared, weighed, and [72e74]. This expression derived from the argument that insuffi-
provided to participants. Despite containing 2.5 times more satu- cient concentrations of oxaloacetate due to a low contribution of
rated fat than the high-CHO diet (100 vs. 40 g/d), the accumulation CHO (glycogen and glucose) would inhibit Acetyl-CoA oxidation in
of plasma total saturated fat was reduced in the LCD condition. This the citric acid cycle (Krebs Cycle - KC), resulting in impaired energy
novel finding showed, in a context of LCD, intake of saturated fat production from fatty acid oxidation. This statement is incorrect,
might not be a determinant factor in dysregulating lipid meta- since some amino acids contribute to oxaloacetate production or
bolism. Moreover, it should be emphasized that the LCD condition other precursors in KC (anaplerotic metabolism), such as aspara-
produced reduced saturated fat content in isolated TG from plasma, gine, aspartate, glutamate, isoleucine, leucine and valine [26,75].
whereas the high CHO diet produced greater incorporation of Additionally, a net negative fat balance can be achieved even with
saturated fat into isolated TG. Therefore, it could be inferred that minimal to no dietary carbohydrate (e.g., intermittent fasting and
the primary factor determining the concentration of saturated fat in ketogenic diets).
the blood is the de novo lipogenesis. Overall, exercise fatigue coincides with decreased muscle
Another noteworthy point in the study of Hyde et al. is that full- glycogen concentrations [76]. The reduction of muscle and liver
fat cheese was the main source of saturated fat [63]. Consumption glycogen content is a documented effect of LCD in rodents and
of cheese may affect lipids and lipoproteins differently than other humans [77e79], promoting a metabolic adaptation in order to
food sources of saturated fat. For instance, in a systematic review enhance fat or protein oxidation, thereby providing carbon skele-
with meta-analysis of randomized controlled trials, consumption of tons in the KC. Elevated plasma fatty acid concentrations are
hard cheese lowered LDL-c and HDL-c concentrations when associated with pyruvate dehydrogenase kinase (PDHK) expres-
compared with consumption of butter [64]. Mechanistically, cal- sion, resulting in inhibition of pyruvate dehydrogenase (PDH) and
cium, specific types of saturated fatty acids, and the food matrix decreased CHO oxidation in muscle tissue [79,80]. However, in
from cheese intake are favorable dietary elements in modulating individuals adhering to a LCD, inhibition of PDH can be reversed
lipid metabolism [64]. due to increased pyruvate concentration induced by aerobic exer-
Furthermore, in the study by Hyde et al. there was low intake of cise [81]. Although CHO metabolism is reduced at rest, exercise-
fiber (14 g/d) during the LCD intervention. Chronically, low fiber induced pyruvate concentration in the muscular tissue counter-
intake is associated with increased risk for noncommunicable dis- acts the inhibition of PDH [81] by which it partially maintains
eases [65]. Thus a rational approach of fiber intake should be physical performance [82,83].
considered in order to promote overall health status with LCD. Taken together, there is still controversy regarding the LCD ef-
Avocado, cocoa powder, nuts, and flax seeds are low-carb foodstuffs fects on exercise performance and physiological responses in
that are also sources of fibers. More importantly, these are food different populations [84e86]. To the best of our knowledge,
items with well-established cardiovascular benefits [66e70]. Apart studies by Phinney et al. in obese patients [87] and athletes [88]
from fiber, avocado is a source of monounsaturated fatty acids, were the first to evaluate this combination. In these early studies,
cocoa and nuts are known to be sources of polyphenols and mag- both obese and athletic subjects were able to sustain exercise or
nesium, and flax seeds are rich in alpha-linolenic acid [71]. level of training and performance even on LCD [87,88]. Brinkworth
Collectively, these substances likely contribute to the favorable et al. compared the effects of the LCD with a high CHO diet on
cardiovascular effects of these example foodstuffs. muscle strength, aerobic capacity and metabolic adaptations in
Lastly, an important limitation of LCD studies should be noted, obese and sedentary individuals during 8 weeks [18]. There were
which is the lack of information pertaining to the types of CHO no differences in most of the variables between groups. However,
provided in the intervention diets. Accordingly, LCD retrospective there were greater loss of body mass and fat oxidation in the LCD
cohorts and meta-analysis have primarily detailed the effect of total group. The authors showed CHO restriction did not interfere with
amount of CHO in the diet or the type of proteins and fats (animals the functional/physical capacity of obese patients. In other studies,
vs. vegetables) on the analyzed outcomes rather than more the combination of VLCD and strength training in obese and
nuanced examinations of carbohydrate type. sedentary women reduced body fat, insulin levels and waist
circumference, and increased muscle strength [89,90].
3.4. Effects of LCD on exercise The VLCD may also not interfere in physical performance of
resistance-trained men. Twenty-five men were randomized to an
Since 1935, a famous biochemistry phrase appeared in several isoenergetic, Westernized diet or VLCD. After 10 weeks of dietary
articles and book chapters: “fat burns in a carbohydrate flame” intervention and resistance training, both groups increased the

Please cite this article as: Macedo RCO et al., Low-carbohydrate diets: Effects on metabolism and exercise e A comprehensive literature review,
Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.07.022
6 R.C.O. Macedo et al. / Clinical Nutrition ESPEN xxx (xxxx) xxx

load of 1 repetition maximum in squatting and bench press, the training to be promising with regards to the transcription of genes
power in the cycle ergometer through the Wingate Test (one of the involved in exercise adaptations [104e107], especially of mito-
most common tests to evaluate anerobic cycling performance) and chondrial metabolism (Fig. 2).
the muscle thickness of the thigh analyzed by ultrasonography [91]. Despite the theoretical rationale for training in a low-glycogen
Ultimately, current evidence suggests that signaling of the state, it is noteworthy that glycogen depletion in both skeletal
mammalian target of rapamycin complex 1 (mTORC1), a key muscle and liver is a pivotal cause of fatigue in both endurance and
mediator of protein synthesis, is unaffected by CHO restriction or high-intensity (intermittent) training [108e110]. In this sense,
low muscular glycogen concentrations under resistance training muscle glycogen is susceptible to fall to values approaching zero
practice [92]. during physical exercises, especially when coupled with LCD
[111,112]. When viewed as a whole, a LCD is conceivable in a model
3.5. Carbohydrate availability and training adaptations of ‘periodized nutrition’ for athletes having usefulness in training
sessions as a mediator on mitochondrial genes [113]. Regarding
Hansen et al. used the expression: “train low, compete high” competitive situations, the glycogen storage is crucial to promote
when they found greater adaptive muscular responses by training both performance and recovery, thus being required to ensure the
with reduced levels of muscle glycogen [93]. The researchers sub- daily CHO intake before, during and after competitions [108]. The
mitted healthy individuals to training with low vs. high muscle context in which these strategies are considered may ultimately
glycogen for 10 weeks. For this purpose, they analyzed the muscle dictate their utility, as needs and priorities vary between elite
glycogen content from biopsies obtained from the vastus lateralis of athletes, health conscious members of the general public, previ-
both legs before and after 10 weeks of training based on knee ex- ously sedentary individuals, and clinical populations.
tensions. The training was composed of two specific days repeated
for the 10 weeks. On day 1, both legs in LOW and HIGH protocols 3.6. LCD and glycogen overcompensation: acute and chronic
were trained for 1 h followed by 2 h of rest at a fasting state, with physiological effect
1 h of additional training for one leg in the LOW protocol. On day 2,
only one leg in HIGH protocol was trained for 1 h. In this context, Approximately 1 kg of body water is lost after 1 week of a
LOW protocol yielded low concentration of muscle glycogen, combination of VLCD and resistance training, while there is an in-
whereas in the HIGH protocol the same subjects had a higher crease of approximately 3 kg of body weight in subsequent CHO
concentration of muscle glycogen with equal intensity of training. reloading due to increase of intramuscular glycogen through
Noteworthy findings were that the LOW protocol showed a longer supercompensation [91,114]. Glycogen depletion and super-
time to exhaustion, induced a thrifty muscle glycogen effect and compensation strategies are used in combat sports and body-
increased citrate synthase activity. Additionally, this was in the building due to utilization of weight classes [115,116]. Despite
context of all volunteers consuming a controlled, high-CHO diet controversy surrounding the practice, acute LCD prior to “weigh
(70% of energy intake). ins” is commonly used for decreasing body weight of combat
A growing body of evidence has demonstrated an important role sports' athletes, in which the main contribution is water loss rather
of manipulation of CHO availability on exercise adaptations [94]. In than skeletal muscle mass [115]. After weighing, glycogen super-
this regard, some authors performed similar studies (glycogen- compensation is crucial for combat athletes' performance, which is
depletion exercise protocol) where individuals were randomized in heavily reliant on glycolytic pathways [79]. Moreover, in addition to
2 groups: LCD vs. HCD. Glycogen-depleted aerobic exercise with greater acute control of body weight, LCD in the bodybuilding is a
LCD increased peroxisome proliferator-activated receptor gamma frequent strategy employed for esthetic improvement [82].
coactivator 1-alpha (PGC1a), cyclooxygenase (COX) I and IV, mito-
chondrial transcription factor A (TFAM) and pyruvate dehydroge- 3.7. Does LCD cause hypoglycemia during physical exercise?
nase lipoamide kinase isozyme 4 (PDK-4) expression, and an
enhanced p53 phosphorylation [94e96]. Some warn against LCD during physical exercise due to the
Another way to alter CHO availability and may promote adaptive potential for hypoglycemia, but this concern is unsubstantiated in
responses to exercise is performing in the fasted stated [97]. healthy athletes. Volek et al. provided fundamental scientific sup-
Compared to fed stated, exercising while fasting induces acute port through a research encompassing ultra-marathon athletes
higher fat oxidation [98], type 1 intramyocellular triacylglycerol (>50 km) [118]. Twenty male ultramarathon athletes were divided
breakdown [99], chronic greater increase on citrate synthase (CS) into two groups: VLCD and HCD for about 20 months. In a 3 h run
and b-hydroxyacyl coenzyme A dehydrogenase (b-HAD) activity test on treadmill at 65% of VO2max, the glycemia between VLCD and
[100], muscle glycogen content and VO2peak [101], with no differ- HDC group did not differ. The sample is seemingly small, but the
ence on aerobic capacity but decreased time to exhaustion during participants were among 10% of the finalists of an ultra-marathon
anaerobic exercise [102]. These adaptations could potentially competition, or were triathlon or ironman athletes equivalent to
reduce insulin resistance and improve functional capacity of over- 113 km of course. However, even in the absence of exercise-induced
weight/obese and sedentary people [98]. hypoglycemia during a LCD intervention, it is important to note
Van Proeyen et al. showed that healthy male volunteers sub- that CHO supplementation either before or during races (i.e. in the
mitted to chronic training in fasted morning state were more form of food or sports drinks before endurance races and in the
effective to improve whole-body glucose tolerance during a period form of liquids or gels during races) improves endurance perfor-
of hyper-caloric fat-rich diet, than in fed state [103]. Chronic mance and is widely considered an evidence-based practice for
training in fasted state induced beneficial adaptations in skeletal these athletes [119,120].
muscle, triggering peripheral insulin sensitivity by increase of Overall, caution should be taken to cogitate LCD in the man-
GLUT4 protein content and AMP-activated protein kinase a phos- agement of type 1 diabetes mellitus (T1DM), since T1DM depends
phorylation. Moreover, they detected up-regulation of fatty acid of insulin therapy. In particular, attention is imperative in pre-
translocase/CD36 and carnitine palmitoyltransferase 1 mRNA exercise period [121,122]. On the other hand, LCD may be effec-
levels, thus having action in mitochondrial metabolism [103]. As tive treatment to T2DM patients [123]. According to Feinman et al.,
such, several investigations and research syntheses have consid- LCD is the first approach to treating to T2DM and represents an
ered the dietary manipulations of fasting, LCD or low glycogen effective adjunct to pharmacology in T1DM for improving glycemic

Please cite this article as: Macedo RCO et al., Low-carbohydrate diets: Effects on metabolism and exercise e A comprehensive literature review,
Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.07.022
 R.C.O. Macedo et al. / Clinical Nutrition ESPEN xxx (xxxx) xxx 7

Fig. 2. LCD and/or fasting associated with caloric restriction and physical exercise. The cellular energy is modulated by carbohydrate restriction in conjunction with musculoskeletal
contraction, thereby falling ATP and rising AMP status. As a sensor of this cellular status, AMPK regulates PGC-1a which in turn translocate GLUT4 to the musculoskeletal membrane
and promotes gene transcription in mitochondria. This context leads to decrease of serum glucose and mitochondrial biogenesis. ATP, adenosine triphosphate; AMP, adenosine
monophosphate; AMPK, 50 adenosine monophosphate-activated protein kinase; GLUT4, glucose transporter type 4; NADþ, oxidized form of nicotinamide adenine dinucleotide;
NADH, reduced form of nicotinamide adenine dinucleotide; NRF-1, nuclear respiratory factor 1; NRF-2, nuclear respiratory factor 2; PGC-1a, peroxisome proliferator-activated
receptor gamma coactivator 1-alpha; SIRTs, sirtuins; TFAM, mitochondrial transcription factor A (TFAM); UCPs, uncoupling proteins.

Table 2
Low-carbohydrate foodstuffs and particular nutrients required in the management of LCD.

Foodstuff [food code] Kcal Total fats (g) CHO (g) Total fibers (g) Calcium (mg) Magnesium (mg) Potassium (mg)

Avocado (100 g) [63105010] 160 14.7 8.5 6.7 12 29 485

Almonds (1 oz) [42101000] 164 14.2 6.1 3.5 76 77 208
Asparagus, cooked (100 g) [75202013] 19 0.7 2.5 1.6 16 10 171
Broccoli, cooked (100 g) [72103020] 33 0.52 3.1 2.8 117 27 341
Cauliflower (100 g) [75214013] 19 0.2 3.7 2.7 17 9 138
Cheese, cheddar (1 slice/21 g) [14104100] 85 7 0.7 0 149 5.7 16
Cheese, Swiss (1 slice/21 g) [14109010] 83 6.5 0.3 0 187 7 15.1
Cucumber with peel (100 g) [75111000] 12 0.2 2.2 0.7 14 12 136
Cocoa powder, unsweetened (1 tbsp, 5 g) [11830150] 12 0.74 3.2 2 7 27 82.3
Coconut meat, dried, unsweetened (1 oz) [170170] 187 18.3 6.7 4.6 7 26 154
Eggplant, cooked (100 g) [75217010] 35 0.2 8.7 2.5 6 11 123
Brown Flaxseed (2 tbsp, 21 g) [380040] 120 9 6 6 60 90 180
Lettuce, green, (1 medium leaf, 8 g) [75113000] 1.1 0 0.2 0.1 1.4 0.6 11
Pepper, sweet, cooked (1 cup, sliced 92 g) [75122100] 18 0.2 4.2 1.6 9.2 9.2 161
Sardines in oil (1 can, 92 g) [26139180] 191 10.5 0 0 351 35.9 365
Strawberries (100 g) [63223020] 32 0.3 7.7 2.0 16 13 153
Tomato, red, raw (1 thick/large slice 27 g) [74101000] 5 0.1 0.3 2.7 2.7 3 64
Walnuts (1 oz) 185 18.5 3.9 1.9 28 45 125

Data based on the Food and Nutrient Database for Dietary Studies (FNDDS). Adapted from the USDA Food Composition Database [71]. CHO, carbohydrates; kcal, calories.

control while decreasing insulin dosages [124]. More importantly, cardiovascular systemdmay be affected with LCD. The potential for
they support that LCD is a feasible strategy to reduce high blood reduced ingestion of these minerals with some LCD could possibly
glucose regardless of weight loss and, subsequently, may lead to the lead to depletion within body compartments, e.g. in blood and
reduction or even elimination of medication [124]. tissues such as skeletal muscle and bone, and could potentially
produce subsequent impairment in exercise performance and car-
3.8. A triad of macrominerals (calcium, magnesium and potassium) diovascular function [125e127].
and their management in a LCD In light of this concern, we suggest in Table 2 some foodstuffs
that would be useful in alleviating these concerns within clinical
An attendant reduction in the intake of specific minerals may implementations of LCD. Avocado is the major example of low-CHO
occur with a LCD, particularly when food groups like dairy prod- fruit with a considerable amount of potassium. Cocoa powder, as
ucts, fruits, and cereals are restricted or eliminated from the diet. well as nuts (e.g. almonds, walnuts, and pistachios), is a source of
The status of calcium, magnesium and potassiumdmacrominerals magnesium and potassium. Cheeses and sardine are examples of
with important roles in skeletal muscle function and the sources of calcium. Each of these aforementioned foods represents

Please cite this article as: Macedo RCO et al., Low-carbohydrate diets: Effects on metabolism and exercise e A comprehensive literature review,
Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.07.022
8 R.C.O. Macedo et al. / Clinical Nutrition ESPEN xxx (xxxx) xxx

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Please cite this article as: Macedo RCO et al., Low-carbohydrate diets: Effects on metabolism and exercise e A comprehensive literature review,
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