ChapterPDF Available

Abstract and Figures

The metabolic syndrome (MetS) was defined as a condition characterized by disturbed glucose and insulin metabolism, central obesity, mild dyslipidemia, and hy-pertension. These conditions are important risk factors for diabetes, cardiovascular disease, and other chronic diseases. It etiology is a complex interaction between genetic , metabolic, and dietetic factors. To overcome the epidemic values of obesity and MetS currently registered, nutritional interventions are needed and the substitution of diet components may be a good strategy. Usually, metabolic disorders that are present in MetS are associated to high consumption of fat; however, as well as fat, carbohydrates have an important influence in MetS components. Taking into account that carbohydrates may be converted to glucose or fermented, producing fatty acids or short-chain fatty acids respectively, is essential consider its influence in lipids bioavailability for the human metabolism. The impact of carbohydrates consumption on human metabolism continues to be a controversial topic and several metabolic characteristics should be considered. Thus, this chapter focuses on the role of carbohydrates in the MetS and associated complication.
Content may be subject to copyright.
Metabolic Syndrome
Chapter 1
The Role of Carbohydrates in Metabolic
Igor Otavio Minatel1,2,*, Jessica Leite Garcia3, Giusep-
pina Pace Pereira Lima1 and Camila Renata Correa3
1Department of Chemistry and Biochemistry, Institute of
Bioscience, São Paulo State University (UNESP), Botucatu,
2Faculdade Sudoeste Paulista - FSP, Avaré, São Paulo, Brazil
3Department of Pathology, São Paulo State University (UN-
ESP), Medical School, Botucatu, Brazil
*Corresponding Author: Igor Otavio Minatel, Department of
Chemistry and Biochemistry, Institute of Bioscience, UNESP,
Botucatu, 18618-689, São Paulo, Brazil, Tel/Fax: +55 14 3880-
0573; Email:
First Published July 28, 2017
Copyright: © 2017 Igor Otavio Minatel, et al.
This article is distributed under the terms of the Creative Com-
mons Attribution 4.0 International License
(, which permits
unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s)
and the source.
Metabolic Syndrome
e metabolic syndrome (MetS) was dened as a
condition characterized by disturbed glucose and insulin
metabolism, central obesity, mild dyslipidemia, and hy-
pertension. ese conditions are important risk factors
for diabetes, cardiovascular disease, and other chronic
diseases. It etiology is a complex interaction between ge-
netic, metabolic, and dietetic factors. To overcome the
epidemic values of obesity and MetS currently registered,
nutritional interventions are needed and the substitution
of diet components may be a good strategy. Usually, meta-
bolic disorders that are present in MetS are associated to
high consumption of fat; however, as well as fat, carbohy-
drates have an important inuence in MetS components.
Taking into account that carbohydrates may be converted
to glucose or fermented, producing fatty acids or short-
chain fatty acids respectively, is essential consider its inu-
ence in lipids bioavailability for the human metabolism.
e impact of carbohydrates consumption on human me-
tabolism continues to be a controversial topic and several
metabolic characteristics should be considered. us, this
chapter focuses on the role of carbohydrates in the MetS
and associated complication.
Epidemic values of obesity and MetS are currently
registered, and nutritional strategies have been proposed
to overcome these health problems. e MetS was dened
Metabolic Syndrome
as a condition characterized by disturbed glucose and in-
sulin metabolism, central obesity, mild dyslipidemia, and
hypertension [1]. ese conditions are important risk fac-
tors for diabetes, cardiovascular disease, and other chron-
ic diseases. It etiology is a complex interaction between
genetic, metabolic, and dietetic factors. Usually, the meta-
bolic disorders present in MetS are associated to high con-
sumption of fat. However, the role of carbohydrates has
been shown by reducing total and low-density lipoprotein
(LDL) cholesterol, weight loss, and improving insulin sen-
sitivity [2–6].
e European and American dietary guidelines have
established dietary reference values for the intake of car-
bohydrates, dietary bre, and fats [7, 8]. ese dietary
guidelines recommend a decrease in saturated fat to 7–
10% of the total energy intake, that represents an fat in-
take range between 20 to 35% of the total energy intake;
whereas the total carbohydrates intake, including complex
or simple molecules, should range from 45 to 60% of the
total energy intake. It is important to consider that dif-
ferent values are given for infants, young children, and
adults. However, changes in dietary patterns results in dif-
ferent responses, since the metabolic state may vary from
person-to-person. Another important situation to consid-
er is the presence of dietary bre when examining carbo-
hydrate intake and metabolic disorders. Extensive studies
have suggested that whole grains (which are rich in bers)
help to prevent chronic diseases and MetS [3, 9–11]. Nev-
ertheless, more information should be produced before
Metabolic Syndrome
change daily ingestion of fat or carbohydrates. In a study
conducted in Korean individuals, population with a high
intake of rened carbohydrates, authors showed that di-
etary carbohydrate intakes were positively related to the
prevalence of MetS [12]. In addition, elevated triglycer-
ide and blood glucose levels in combination with reduced
HDL-cholesterol levels were associated with high dietary
carbohydrate intake in men and women [12].
Simple Carbohydrates
e obesity and MetS are strongly associated to cardi-
ovascular and kidney disease, diabetes, and other chronic
diseases in industrialized societies [13]. us, prevention
or early intervention to reverse MetS would reduce the in-
cidence of this common disease [13, 14]. Mostly, the obe-
sity, dietetic imbalance and life quality may be a powerful
contributor to the development of the MetS. Our ances-
tors obtained their food from hunting and gathering, but
the transition to modern Western society lifestyle with its
tremendous technological advances in food processing
led to extensive changes in food intake and composition.
e Western-style diet, also called the meat-sweet diet is
characterized by high intakes of processed foods rich in
saturated fat, trans-fatty acids, proteins from red meat,
and sodium, as well as an excessive consumption of sim-
ple carbohydrates, such as sucrose and fructose [15]. Most
carbohydrates occur naturally in foods or can be added
articially as sweeteners, mainly in processed foods and
beverages. However, the addition of these sugars to foods
Metabolic Syndrome
has been associated to metabolic impairment in indi-
viduals by inducing weight gain, obesity, and MetS [16].
Comparing overweight and obese individuals consuming
glucose or fructose-sweetened beverages, providing 25%
of energy requirements for 10 weeks, was observed that
subjects consuming fructose-sweetened beverages exhib-
ited increased de novo lipogenesis, dyslipidemia, and cir-
culating uric acid levels and reduced fatty acid oxidation
and insulin sensitivity, while subjects consuming glucose-
sweetened beverages did not, despite comparable body
weight gain [17]. ese results clearly show that simple
carbohydrates are dierently metabolized by human or-
e rate of dietary fructose consumption, mostly in
combination with glucose, continued to rise worldwide
over the last y years [18–20]. Fructose, which is found
in fruits, became a major component of the modern diet
by robust intake of sucrose (table sugar, consisting of one
molecule of glucose and one molecule of fructose, which
are cleaved in the intestinal tract) and synthetic high fruc-
tose corn syrup (HFCS, consisting of a mixture of glucose
and fructose) that are currently added to beverages and
foods [21]. e HFCS are produced with various fructose-
to-glucose ratios, although the most commonly sugar con-
centration is 55% fructose and 45% glucose. Compared
with glucose, fructose has a lower glycemic index and does
not generate an insulin response, but has a slightly higher
sweetening power. Glucose and fructose have similar mo-
lecular structures, but its metabolism is markedly dier-
Metabolic Syndrome
ent. Fructose is rapidly absorbed by liver and converted
into glucose, glycogen, lactate, and fat. Furthermore, fruc-
tose is a potent lipogenic and adipogenic nutrient. Diets
rich in fructose have promoted an increased adipogenic
potential, on adipocyte precursor cells (APCs), that con-
sequently results in accelerated adipocyte hypertrophy
[22]. ese can be explained by the fact that hepatic me-
tabolism results in the formation of triglycerides that will
be stored in the adipocyte. In addition, a small amount of
fructose is also taken up by adipose tissue, generating tri-
glycerides as well as in the liver, potentiating the stock in
the adipocytes [22]. Unlike fructose, glucose depends on
insulin to enter the cell; aer supplying the cellular energy
requirement part of the glucose is stored as glycogen (i.e.
a limited stock), then the excess will also result in triglyc-
erides accumulation.
e accumulation of triacylglycerol in the adipocyte
and resulting hypertrophy leads to a cellular signaling re-
sponse that swi the oxidative metabolism to anaerobic
glycolysis and increases the secretion of several inamma-
tion-related adipokines (leptin, resistin, apelin, visfatin,
monocyte chemoattractant protein-1 (MCP-1), Interleu-
kin-8, Interleukin-6, Interleukin-1, Angiotensin-II, Tu-
moral Necrosis Factor-α, and Interleukin-10, among oth-
ers), which will result in cell damage. is inammatory
response, accompanied from morphological and function-
al changes, increases visceral adiposity and fat accumula-
tion, and insulin signaling impairment [23]. In addition
to the high potential of being stored in the form of triglyc-
Metabolic Syndrome
erides, fructose can follow another pathway that also re-
sults in pathological complications. Aer entering the cell
by the glucose-transporter (Glut) 2 and Glut 5 receptors,
both of which are not insulin dependent, they undergo the
action of the enzyme fructokinase and formation of uric
acid occurs, a metabolite that when generated in excess,
may be an independent risk factor for cardiovascular and
kidney disease [24], arterial hypertension, obesity, and di-
abetes [25]. us, its elevation may contribute to some co-
morbidities involving MetS. e ingestion of excess car-
bohydrates is also an oxidative stress modulating factor
that is related to the pathogenesis of the MetS. Derivatives
of glucose and fructose oxidative metabolism lead to the
formation of short chain reactive compounds or carbonyl
products, such as glyoxal (GO) and methylglyoxal (MgO),
which react with amino groups of biological molecules,
generating a large variety of adducts and crosslinks called
(AGEs - Advanced glycation end products) that stimulate
the production of inammatory cytokines and cause tis-
sue damage, especially of the kidney, an organ with a high
level of specic receptors (RAGE - Receptor for advanced
glycation end products) for these molecules (Figure1).
Excessive circulating glucose can also activate the poliol
pathway, another source of oxidative stress, in which it is
converted to sorbitol and subsequently to fructose. is
glucose-fructose conversion induces oxidative stress and
generates derivatives with higher glycation potential than
glucose itself. A cycle is formed in which fructose plays
a central role with its high potential to be converted to
Metabolic Syndrome
triglycerides that will be stored inducing inammation
and forming oxidative stress-causing derivatives that feed
Figure 1:Excess of carbohydrate intake and its metabolism lead to
the formation of short-chain reactive compounds or carbonyl prod-
ucts, such as glyoxal (GO) and methylglyoxal (MgO), which generate
a large variety of adducts and crosslinks called AGEs that stimulate
the production of inammatory cytokines via RAGE (Receptor for
advanced glycation end products).
Metabolic Syndrome
End Products of Complex Carbohydrates
e human body is unable to digest some foods com-
ponents as complex carbohydrates and dietary bers. Tak-
ing into account that carbohydrates may be converted to
glucose or fermented, producing fatty acids or short-chain
fatty acids (SCFA) respectively, is essential to evaluate its
inuence on lipids bioavailability for the human metabo-
lism. Gut microbiota is directly involved in fermentation
of these components that are incompletely hydrolysed
due to a absence of the appropriate enzymes. ese fer-
mentation products includes the SCFA (Figure 2), which
are represented by acetate, propionate, butyrate, formate,
valerate, and caproate [26]. Acetate, propionate and bu-
tyrate represents 95% from the total SCFA produced in
the human gut, and these molecules have been shown to
exert multiple benecial eects on mammalian energy
metabolism [27]. SCFA might be related to energy me-
tabolism in several tissues, such as adipose tissue, skeletal
muscle, pancreas, intestine, and liver [26, 28]. is regula-
tion is associated with the bidding of SCFA to free fatty
acids receptors (FFARs) expressed in these organs. e
FFARs belongs to G-protein coupled receptors (GPRs)
family, of which, the most studied are GPR41 (also known
as FFAR3) and GPR43 (also known as FFAR2).
Metabolic Syndrome
Figure 2: Whole grains and vegetables are rich source of complex car-
bohydrates, and these compounds are undigested or poorly digested
in stomach or by gut enzymes. Undigested carbohydrates are con-
verted by gut microbiota in short-chain fatty acids (SCFA), mainly
acetate, propionate, and butyrate. SCFA are absorbed by enterocytes,
reach the bloodstream and interact with specic organs.
e exactly tissue response induced by FFARs activa-
tion for SCFA remains unclear [28]; whereas, data from
animal studies indicate that SCFA are associated to re-
duction or reversion of MetS components as weight gain,
obesity, and insulin sensitivity. Mice fed a high-fat diet
supplemented with oral acetate, propionate and butyrate
administration shown reduced body weight and improved
insulin sensitivity [29]. In contrast, other investigators
have found that GPR43-decient mice were protected
Metabolic Syndrome
from high-fat diet induced obesity and dyslipidemia by
increasing energy expenditure [30].
Dietary bre fermentation dier signicantly in total
and individual SCFA production [31]. However, assum-
ing that 10 g of dietary bre fermentation yields about 100
mmol SCFA, individuals consuming high-bre diet may
produce ~ 400–800 mmol SCFA per day. Data sustaining
these ratio of SCFA production were observed in a human
intervention study, which a four-week supplementation
with resistant starch (30 g per day), increased postpran-
dial systemic acetate and propionate concentrations up to
280 μmol/l and 13 μmol/l, respectively [32]. e recom-
mended amount of bre ingestion per day is 25-38 grams;
whereas, the people are consuming much less than this
recommendation. Fibre intake helps the gut and human
body to prevent a ranging of diseases as heart failure, hy-
pertension [33], and intestinal disorders [34].
In a previous study, authors followed lean, overweight
and obese subjects, showing that the composition of gut
microbiota is direct associated to SCFA production and
the two major phyla related to SCFA production are Fir-
micutes and Bacteroidetes [35]. In this same study, the total
amount of SCFA was higher in the obese than in the lean
subjects. In addition, in obese and overweight subjects the
proportion of individual SCFA changed in favor of pro-
pionate and Bacteroidetes phyla, when compared to lean
subjects [35]. However, human data about gut microbiota
are inconsistent and have been shown variables bacteria
Metabolic Syndrome
Human intervention studies, using obese patients,
has demonstrated a positive eect of SCFA consumption
by preventing body weight gain [36] or reducing body
weight, body mass index, visceral fat area, waist circum-
ference, and serum triglycerides [37]. In addition, SCFA
can induce the gut-secretion of satiety hormones as chol-
ecystokinin (CCK), glucagon-like peptide (GLP)-1, pep-
tide tyrosine-tyrosine (PYY), hormones that regulates ap-
petite and satiety. On the other hand, the SCFA itself, as in
case of acetate, can cross the blood-brain barrier and sup-
press food intake by reducing appetite [38]. Furthermore,
several studies have been shown a positive eect of SCFA
in adipose tissue and the consequent release by this tissue
of leptin (satiety regulating hormone).
e eects/interactions of SCFA with body metabo-
lism is very broad, and a interesting study suggested that
these molecules can downregulate peroxisome prolifer-
ator-activated receptor-gamma (PPAR-γ) and shi the
adipose and liver tissue from lipogenesis to fatty acid ox-
idation [29]. In the same study, when SCFA at 5% were
added to high fat diet, a protection against obesity and
improved insulin sensitivity were observed. ese results
lead the authors to suggest the use of SCFA (in especial
acetate, propionate, and butyrate) as selective modulators
of PPAR-γ. Considering that insulin-sensitive organs are
responsible by energy and metabolism in human body,
and the systemic interorgan crosstalk triggered by SCFA,
these molecules are a promising eld of study intending to
prevent obesity and related diseases, such as MetS.
Metabolic Syndrome
Eects of Low-Carbohydrate Diets
Versus Low-Fat Diets on Metabolic Risk
e recommended daily intake of carbohydrates,
based on a 2.000 kcal diet, range between 225 to 300 g/day
[8]. However, minimum ingestion necessary to prevent
the loss of lean muscle tissue or avoid brain tissue glucose
starving is 100 g [39]. Carbohydrates may be divided in
groups, such as sugar, starch, and bers, according to sugar
units and chemical structures. In foods, carbohydrates are
widely used as sweeteners (to improve palatability), food
preservatives, and to improve functional properties such
as viscosity, texture, body, and browning capacity [40].
Dierent types of intervention have been used in the
tentative of prevent or reduce the physiologic markers of
MetS. Diets based on low-fat (LFD) or low-carbohydrate
(LCD) are the most common interventions, non drug-
based, methods employed. ese diets have become a
popular strategy for weight loss and weight management.
Studies have shown that people tend to remove carbohy-
drate without replacement of either fat or protein [41].
Similarly to LFD, carbohydrate-restricted diet (CRD) is
generally accompanied by weight loss [42–44].
Nowadays is still uncertain the benecial eects of
the LCD into possible prevention of MetS. Discordant re-
sults between studies have shown that replacing saturated
Metabolic Syndrome
fats from diets with carbohydrates has benecial eects
on human metabolism, but may increases blood levels of
triglycerides and reduces high-density lipoprotein (HDL)
cholesterol. However, these results can reect the incapac-
ity of the organism to lead with the increased amount of
carbohydrate ingested. When carbohydrates are fed in ex-
cess and surpass the metabolic capacity of organism oxi-
dize glucose, starts a de novo lipogenesis that culminates
in saturated fatty-acids (SFA) production. Fatty acids,
coming from dietary fat intake or endogenously synthe-
sized, are important predictors of MetS development [45].
In some experiments, the reduction of dietary carbohy-
drate results in a decreased level of lipogenic fatty acids,
despite higher saturated fat intake [46, 47]. ese results
reinforce the hypothesis that carbohydrates, as well as fat,
may induce hypercholesterolemia. In contrast, Volk et al.
showed that plasma SFA correlates poorly with dietary
saturated fat and better with carbohydrate, mainly by in-
creasing plasma levels of palmitoleic acid [48].
Low-carbohydrate diets seems as eective as LFD to
weight loss and improve other health markers, showing
that, as well as fat, carbohydrates have an important in-
uence in components of MetS. In a recent meta-analysis
comparing individuals consuming diets (6 months to 2
years of intervention) with reduced amounts of carbo-
hydrates or fat was demonstrated that LCD signicantly
decreased body weight and triacylglycerol, and increased
HDL-cholesterol, when compared to LFD. However, sub-
jects consuming LCD experienced a signicant increase
Metabolic Syndrome
in low-density lipoprotein (LDL) cholesterol compared
with their counterparts consuming an LFD [49]. Consid-
ering these results is possible suggest that benecial eects
of LCD may be dierent among individuals and must be
carefully weighted. In general, LFD and LCD have im-
proved body composition, HDL cholesterol level, triglyc-
eride level, total cholesterol; therefore, reducing the risk of
chronic diseases.
Volek et al. (2009) showed that CRD improve a wide
spectrum of lipid markers of cardiovascular disease risk,
including eects on LDL cholesterol particle size. In addi-
tion, the CRD resulted in a decrease in plasma saturated
fatty acids (SFAs) despite higher dietary saturated intake,
and resulted in a signicant decrease in retinol binding
protein 4 (RBP4) [44]. RBP4 is a adipokine that has been
associated to adiposity, insulin resistance, and type 2 dia-
betes [50, 51]. ese ndings lead the authors to suggest
that there are many options for treating obesity or the indi-
vidual components of MetS, but carbohydrate restriction
has the ability to target the range of markers with a single
intervention [44]. In another report, the introduction of
low-fat, high-carbohydrate diets in overweight subjects,
with at least three characteristics of MetS, showed that
weight gain was prevented, and modest weight loss was
achieved [52]. In this study, the high-carbohydrates di-
ets were formulated by replacing one-quarter of dietary
fat for simple or complex carbohydrates. Weight loss and
Metabolic Syndrome
cholesterol reduction were greatest in complex carbohy-
drates diets when compared to control and simple carbo-
hydrates diets [52]. Knowing that complex carbohydrates
can be fermented by human gut microbiota to produce
SCFA, we may speculate that these results are induced by
regulatory mechanisms associated to SCFA (as discussed
above in this chapter).
e direct and the indirect eects of carbohydrates
on the development of MetS should be better understood.
ere are several data supporting a direct causal role of
sugar promoting body weight gain and development of as-
sociated diseases. However, there are similar number of
data supporting an inverse role. Diet intervention has be-
came very popular nowadays, especially employing carbo-
hydrates restriction, but before change the dietary habits
individuals should consider several factor that inuences
in metabolism, such as body weight, physical status, and
the presence of metabolic disorders.
e authors gratefully acknowledge the nancial
support from the “Faculdade Sudoeste Paulista - FSP,
Fundação de Amparo a Pesquisa do Estado de São Pau-
lo - FAPESP (Project No. 2015/10626-0), and Conselho
Nacional de Desenvolvimento Cientíco e Tecnológico -
CNPq (Project No. 305177/2015-0).
Metabolic Syndrome
1. Reaven GM. Role of Insulin Resistance in Human
Disease. Diabetes. 1988; 37: 1595–1607.
2. Westman EC, Feinman RD, Mavropoulos JC, Ver-
non MC, Volek JS, et al. Low-carbohydrate Nutri-
tion and Metabolism. Am J Clin Nutr. 2007; 86:
3. Mckeown NM, Meigs JB, Liu S, Saltzman E, Wil-
son, PWF, et al. Carbohydrate Nutrition, Insulin
Resistance, and the Prevalence of the Metabolic
Syndrome in the Framingham Ospring Cohort.
Diabetes Care. 2004; 27: 538–546.
4. Rajaie S, Azadbakht L, Khazaei M, Sherbafchi M,
Esmaillzadeh A. Moderate Replacement of Car-
bohydrates by Dietary Fats Aects Features of
Metabolic Syndrome: A Randomized Crossover
Clinical Trial. Nutrition. 2014; 30: 61–68.
5. Brown MA, Storlien LH, Huang X-F, Tapsell LC,
Else, PL, et al. Dietary Fat and Carbohydrate
Composition: Metabolic Disease. In: Montma-
yeur JP, le Coutre J, editors. Fat Detection: Taste,
Texture, and Post Ingestive Eects. Boca Raton:
CRC Press/ Taylor & Francis. 2010; 643.
6. Manninen AH. Metabolic Eects of the Very-
Low-Carbohydrate Diets: Misunderstood ‘Vil-
lains’ of Human Metabolism. J Int Soc Sports
Nutr. 2004; 1: 7-11.
Metabolic Syndrome
7. European Food Safety Authority (EFSA). Dietary
Reference Values and Dietary Guidelines. https://
erence-values-and-dietary-guidelines. Acessed on
21 June 2017.
8. U.S. Department of Health and Human Services
and U.S. Department of Agriculture. 2015-2020
Dietary Guidelines for Americans. 8th Edition.
December 2015.
lines/2015/guidelines/. Acessed on 19 June 2017.
9. Nettleton JA, McKeown NM, Kanoni S, Lemai-
tre RN, Hivert MF, et al. Interactions of Dietary
Whole-Grain Intake with Fasting Glucose- and
Insulin-Related Genetic Loci in Individuals of
European Descent: A Meta-analysis of 14 Cohort
Studies. Diabetes Care. 2010; 33: 2684–2691.
10. Barclay AW, Petocz P, McMillan-Price J, Flood
VM, Prvan T, et al. Glycemic Index, Glycemic
Load, and Chronic Disease Risk: A Meta-analysis
of Observational Studies. Am J Clin Nutr. 2008;
87: 627–37.
11. Ye EQ, Chacko SA, Chou EL, Kugizaki M, Liu S.
Greater Whole-Grain Intake is Associated with
Lower Risk of Type 2 Diabetes, Cardiovascu-
lar Disease, and Weight Gain. J Nutr. 2012; 142:
12. Song S, Lee JE, Song WO, Paik H-Y, Song Y. Car-
Metabolic Syndrome
bohydrate Intake and Rened-Grain Consump-
tion are Associated with Metabolic Syndrome in
the Korean Adult Population. J Acad Nutr Diet.
2014; 114: 54–62.
13. Amiot MJ, Riva C, Vinet A. Eects of Dietary
Polyphenols on Metabolic Syndrome Features in
Humans: A Systematic Review. Obes Rev. 2016;
17: 573–586.
14. Macías-Cervantes MH, Rodríguez-Soto JM, Urib-
arri J, Diaz-Cisneros FJ, Cai W, et al. Eect of an
Advanced Glycation End Product-Restricted Diet
and Exercise on Metabolic Parameters in Adult
Overweight Men. Nutrition. 2015; 31: 446–451.
15. Malik VS, Hu FB. Fructose and Cardiometabolic
Health. J Am Coll Cardiol. 2015; 66: 1615–1624.
16. Stanhope KL. Sugar Consumption, Metabolic
Disease and Obesity: e State of the Controversy.
Crit Rev Clin Lab Sci. 2016; 53: 52–67.
17. Stanhope KL, Schwarz JM, Keim NL, Grien SC,
Bremer AA, et al. Consuming Fructose-Sweet-
ened, Not Glucose-Sweetened, Beverages Increas-
es Visceral Adiposity and Lipids and Decreases
Insulin Sensitivity in Overweight/Obese Humans.
J Clin Invest. 2009; 119: 1322–1334.
18. Park YK, Yetley EA. Intakes and Food Sources
of Fructose in the United States. Am J Clin Nutr.
1993; 58: 737S–747S.
Metabolic Syndrome
19. Vos MB, Kimmons JE, Gillespie C, Welsh J,
Blanck HM, et al. Dietary Fructose Consumption
Among US Children and Adults: e ird Na-
tional Health and Nutrition Examination Survey.
Medscape J Med. 2008; 10: 160.
20. Bray GA, Nielsen SJ, Popkin BM. Consumption of
High-Fructose Corn Syrup in Beverages May Play
a Role in the Epidemic of Obesity. Am J Clin Nutr.
2004; 79: 537–43.
21. Tappy L, Le K-A. Metabolic Eects of Fructose
and the Worldwide Increase in Obesity. Physiol
Rev. 2010; 90: 23–46.
22. Zubiría M, Alzamendi A, Moreno G, Rey M, Spin-
edi E, et al. Long-Term Fructose Intake Increases
Adipogenic Potential: Evidence of Direct Eects
of Fructose on Adipocyte Precursor Cells. Nutri-
ents 2016; 8: 198.
23. Calder PC, Ahluwalia N, Brouns F, Buetler T,
Clement K, et al. Dietary Factors and Low-Grade
Inammation in Relation to Overweight and
Obesity. Br J Nutr. 2011; 106: S5–S78.
24. Magnoni M, Berteotti M, Ceriotti F, Mallia V,
Vergani V, et al. Serum Uric Acid on Admission
Predicts In-Hospital Mortality in Patients with
Acute Coronary Syndrome. Int J Cardiol. 2017;
240: 25–29.
25. Borghi C, Rosei EA, Bardin T, Dawson J, Domin-
Metabolic Syndrome
iczak A, et al. Serum Uric Acid and the Risk of
Cardiovascular and Renal Disease. J Hypertens.
2015; 33: 1729–1741.
26. Canfora EE, Jocken JW, Blaak EE. Short-Chain
Fatty Acids in Control of Body Weight and In-
sulin Sensitivity. Nat Rev Endocrinol. 2015; 11:
27. den Besten G, van Eunen K, Groen AK, Venema
K, Reijngoud D-J, et al. e Role of Short-Chain
Fatty Acids in the Interplay Between Diet, Gut
Microbiota, and Host Energy Metabolism. J Lipid
Res. 2013; 54: 2325–2340.
28. Hara T, Kashihara D, Ichimura A, Kimura I, Tsu-
jimoto G, et al. Role of Free Fatty Acid Receptors
in the Regulation of Energy Metabolism. Biochim
Biophys Acta - Mol Cell Biol Lipids. 2014; 1841:
29. den Besten G, Bleeker A, Gerding A, van Eunen
K, Havinga R, et al. Short-Chain Fatty Acids Pro-
tect Against High-Fat Diet–Induced Obesity via
a PPARγ-Dependent Switch from Lipogenesis to
Fat Oxidation. Diabetes. 2015; 64: 2398–2408.
30. Bjursell M, Admyre T, Göransson M, Marley AE,
Smith DM, et al. Improved Glucose Control and
Reduced Body Fat Mass in Free Fatty Acid Recep-
tor 2-Decient Mice Fed a High-Fat Diet. Am J
Physiol. 2011; 211–220.
Metabolic Syndrome
31. McBurney MI, ompson LU. In Vitro Ferment-
abilities of Puried Fiber Supplements. J Food Sci.
1989; 54: 347–350.
32. Robertson MD, Bickerton AS, Dennis AL, Vidal
H, Frayn KN. Insulin-Sensitizing Eects of Die-
tary Resistant Starch and Eects on Skeletal Mus-
cle and Adipose Tissue Metabolism. Am J Clin
Nutr. 2005; 82: 559–67.
33. Marques FZ, Nelson E, Chu P-Y, Horlock D, Fie-
dler A, et al. High-Fiber Diet and Acetate Supple-
mentation Change the Gut Microbiota and Pre-
vent the Development of Hypertension and Heart
Failure in Hypertensive Mice. Circulation. 2017;
135: 964–977.
34. Sonnenburg ED, Smits SA, Tikhonov M, Higgin-
bottom SK, Wingreen NS, et al. Diet-Induced Ex-
tinctions in the Gut Microbiota Compound Over
Generations. Nature. 2016; 529: 212–215.
35. Schwiertz A, Taras D, Schäfer K, Beijer S, Bos NA,
et al. Microbiota and SCFA in Lean and Over-
weight Healthy Subjects. Obesity (Silver Spring).
2010; 18: 190–195.
36. Chambers ES, Viardot A, Psichas A, Morrison DJ,
Murphy KG, et al. Eects of Targeted Delivery of
Propionate to the Human Colon on Appetite Reg-
Metabolic Syndrome
ulation, Body Weight Maintenance and Adiposity
in Overweight Adults. Gut. 2015; 64: 1744–1754.
37. Kondo T, Kishi M, Fushimi T, Ugajin S, Kaga T.
Vinegar Intake Reduces Body Weight, Body Fat
Mass, and Serum Triglyceride Levels in Obese
Japanese Subjects. Biosci Biotechnol Biochem.
2009; 73: 1837–1843.
38. Frost G, Sleeth ML, Sahuri-Arisoylu M, Lizarbe B,
Cerdan S, et al. e Short-Chain Fatty Acid Ac-
etate Reduces Appetite via a Central Homeostatic
Mechanism. Nat Commun. 2014; 5: 3611.
39. St. Jeor ST, Howard BV, Prewitt TE, Bovee V, Baz-
zare T, et al. Dietary Protein and Weight Reduc-
tion: A Statement for Healthcare Professionals
from the Nutrition Committee of the Council
on Nutrition, Physical Activity, and Metabolism
of the American Heart Association. Circulation.
2001; 104: 1869–1874.
40. Slavin J, Carlson J. Carbohydrates. Adv Nutr An
Int Rev J. 2014; 5: 760–761.
41. Volek JS, Sharman MJ, Gómez AL, Judelson DA,
Rubin MR, et al. Comparison of Energy-Restrict-
ed Very Low-Carbohydrate and Low-Fat Diets
on Weight Loss and Body Composition in Over-
weight Men and Women. Nutr Metab (Lond).
2004; 1: 13.
42. Nielsen JV, Joensson EA. Low-Carbohydrate Diet
Metabolic Syndrome
in Type 2 Diabetes: Stable Improvement of Body-
weight and Glycemic Control During 44 Months
Follow-Up. Nutr Metab (Lond). 2008; 5: 14.
43. Hu T, Mills KT, Yao L, Demanelis K, Eloustaz M,
et al. Eects of Low-Carbohydrate Diets Versus
Low-Fat Diets on Metabolic Risk Factors: A Meta-
Analysis of Randomized Controlled Clinical Tri-
als. Am J Epidemiol. 2012; 176: S44–S54.
44. Volek JS, Phinney SD, Forsythe CE,Quann EE,
Wood RJ, et al. Carbohydrate Restriction has a
More Favorable Impact on the Metabolic Syn-
drome than a Low Fat Diet. Lipids. 2009; 44: 297–
45. Warensjö E, Risérus U, Vessby B. Fatty Acid Com-
position of Serum Lipids Predicts the Develop-
ment of the Metabolic Syndrome in Men. Diabe-
tologia. 2005; 48: 1999–2005.
46. King IB, Lemaitre RN, Kestin M. Eect of a Low-
Fat Diet on Fatty Acid Composition in Red Cells,
Plasma Phospholipids, and Cholesterol Esters: In-
vestigation of a Biomarker of Total Fat Intake. Am
J Clin Nutr. 2006; 83: 227–236.
47. Forsythe CE, Phinney SD, Feinman RD, Volk BM,
Freidenreich D, et al. Limited Eect of Dietary
Saturated Fat on Plasma Saturated Fat in the Con-
text of a Low Carbohydrate Diet. Lipids. 2010; 45:
Metabolic Syndrome
48. Volk BM, Kunces LJ, Freidenreich DJ, Kupchak
BR, Saenz C, et al. Eects of Step-Wise Increases
in Dietary Carbohydrate on Circulating Saturated
Fatty Acids and Palmitoleic Acid in Adults with
Metabolic Syndrome. PLoS One. 2014; 9: 1–16.
49. Mansoor N, Vinknes KJ, Veierød MB, Retterstøl
K. Eects of Low-Carbohydrate Diets v. Low-Fat
Diets on Body Weight and Cardiovascular Risk
Factors: A Meta-Analysis of Randomised Con-
trolled Trials. Br J Nutr. 2016; 115: 466–479.
50. Yao-Borengasser A, Varma V, Bodles AM, Rasouli
N, Phanavanh B, et al. Retinol Binding Protein
4 Expression in Humans: Relationship to Insu-
lin Resistance, Inammation, and Response to
Pioglitazone. J Clin Endocrinol Metab. 2007; 92:
51. Graham TE, Yang Q, Blüher M, Hammarstedt A,
Ciaraldi TP, et al. Retinol-Binding Protein 4 and
Insulin Resistance in Lean, Obese, and Diabetic
Subjects. N Engl J Med. 2006; 354: 2552–2563.
52. Poppitt SD, Keogh GF, Prentice AM, Willians
DEM, Sonnemans HMW, et al. Long-Term Eects
of ad libitum Low-Fat, High-Carbohydrate Diets
on Body Weight and Serum Lipids in Overweight
Subjects with Metabolic Syndrome. Am J Clin
Nutr. 2002; 75: 11–20.
... The intake of refined carbohydrates, such as bread, pasta, and sweeteners in drinks, increases the risk of obesity and type 2 diabetes mellitus. However, a high-carbohydrate high-fiber diet helps to prevent cardiovascular diseases and MetS [6,7,[13][14][15]. ...
Full-text available
Metabolic syndrome (MetS) has become a global problem. With the increasing prevalence of MetS worldwide, understanding its pathogenesis and treatment modalities are essential. Animal models should allow an appropriate representation of the clinical manifestations of human conditions. Rats are the most commonly used experimental animals for the study. The development of a proper MetS model using rats will contribute to the successful application of research findings to the clinical setting. Various intervention methods are used to induce MetS through diet induction with various compositions, chemicals, or a combination of both. This review will provide a comprehensive overview of several studies on the development of rat MetS models, along with the characteristics of the clinical manifestations resulting from each study.
Full-text available
Objective: Whole grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. Research Design & Methods: Via meta-analysis of data from 14 cohorts comprising approximately 48,000 participants of European descent, we studied interactions of whole grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a p-value <0.0028 (0.05/18 tests) as statistically significant. Results: Greater whole grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (? [95% CI] per 1-serving greater whole grain intake: ?0.009 mmol/L glucose [?0.013, ?0.005], p <0.0001 and ?0.011 pmol/L (ln) insulin [?0.015, ?0.007], p =0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole grain intake was rs780094 (GCKR) for fasting insulin (p = 0.006), where greater whole grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele. Conclusions: Our results support the favorable association of whole grain intake with fasting glucose and insulin and suggest potential interaction between variation in GCKR and whole grain intake in influencing fasting insulin concentrations.
Full-text available
Background: -Dietary intake of fruit and vegetables is associated with lower incidence of hypertension, but the mechanisms involved have not been elucidated. Here we evaluated the effect of a high fibre diet and supplementation with the short-chain fatty acid (SFCA) acetate on the gut microbiota and the prevention of cardiovascular disease. Methods: -Gut microbiome, cardiorenal structure/function and blood pressure were examined in sham and mineralocorticoid-excess treated mice with a control diet, high fibre diet or acetate supplementation. We also determined the renal and cardiac transcriptome of mice treated with the different diets. Results: -We found that high consumption of fibre modified the gut microbiota populations and increased the abundance of acetate-producing bacteria, independently of mineralocorticoid-excess. Both fibre and acetate decreased gut dysbiosis, measured by the ratio of Firmicutes to Bacteroidetes, and increased the prevalence of Bacteroides acidifaciens Compared to mineralocorticoid-excess mice fed a control diet, both high fibre diet and acetate supplementation significantly reduced systolic and diastolic blood pressure, cardiac fibrosis and left ventricular hypertrophy. Acetate had similar effects and also markedly reduced renal fibrosis. Transcriptome analyses showed that the protective effects of high fibre and acetate were accompanied by the down-regulation of cardiac and renal Egr1, a master cardiovascular regulator involved in cardiac hypertrophy, cardiorenal fibrosis and inflammation. We also observed the up-regulation of a network of genes involved in circadian rhythm in both tissues, while down-regulated the renin-angiotensin system in the kidney and mitogen-activated protein kinases (MAPK) signalling in the heart. Conclusions: -A diet high in fibre led to changes in the gut microbiota which played a protective role in the development of cardiovascular disease. The favourable effects of fibre may be explained by the generation and distribution of one of the main metabolites of the gut microbiota, the SCFA acetate. Acetate effected several molecular changes associated with improved cardiovascular health and function.
Full-text available
We have previously addressed that fructose rich diet (FRD) intake for three weeks increases the adipogenic potential of stromal vascular fraction cells from the retroperitoneal adipose tissue (RPAT). We have now evaluated the effect of prolonged FRD intake (eight weeks) on metabolic parameters, number of adipocyte precursor cells (APCs) and in vitro adipogenic potential from control (CTR) and FRD adult male rats. Additionally, we have examined the direct fructose effects on the adipogenic capacity of normal APCs. FRD fed rats had increased plasma levels of insulin, triglyceride and leptin, and RPAT mass and adipocyte size. FACS studies showed higher APCs number and adipogenic potential in FRD RPAT pads; data is supported by high mRNA levels of competency markers: PPARγ2 and Zfp423. Complementary in vitro experiments indicate that fructose-exposed normal APCs displayed an overall increased adipogenic capacity. We conclude that the RPAT mass expansion observed in eight week-FRD fed rats depends on combined accelerated adipogenesis and adipocyte hypertrophy, partially due to a direct effect of fructose on APCs.
Full-text available
The impact of sugar consumption on health continues to be a controversial topic. The objective of this review is to discuss the evidence and lack of evidence that allows the controversy to continue, and why resolution of the controversy is important. There are plausible mechanisms and research evidence that supports the suggestion that consumption of excess sugar promotes the development of cardiovascular disease (CVD) and type 2 diabetes (T2DM) both directly and indirectly. The direct pathway involves the unregulated hepatic uptake and metabolism of fructose, leading to liver lipid accumulation, dyslipidemia, decreased insulin sensitivity and increased uric acid levels. The epidemiological data suggest that these direct effects of fructose are pertinent to the consumption of the fructose-containing sugars, sucrose and high fructose corn syrup (HFCS), which are the predominant added sugars. Consumption of added sugar is associated with development and/or prevalence of fatty liver, dyslipidemia, insulin resistance, hyperuricemia, CVD and T2DM, often independent of body weight gain or total energy intake. There are diet intervention studies in which human subjects exhibited increased circulating lipids and decreased insulin sensitivity when consuming high sugar compared with control diets. Most recently, our group has reported that supplementing the ad libitum diets of young adults with beverages containing 0%, 10%, 17.5% or 25% of daily energy requirement (Ereq) as HFCS increased lipid/lipoprotein risk factors for CVD and uric acid in a dose-response manner. However, un-confounded studies conducted in healthy humans under a controlled, energy-balanced diet protocol that enables determination of the effects of sugar with diets that do not allow for body weight gain are lacking. Furthermore, recent reports conclude that there are no adverse effects of consuming beverages containing up to 30% Ereq sucrose or HFCS, and the conclusions from several meta-analyses suggest that fructose has no specific adverse effects relative to any other carbohydrate. Consumption of excess sugar may also promote the development of CVD and T2DM indirectly by causing increased body weight and fat gain, but this is also a topic of controversy. Mechanistically, it is plausible that fructose consumption causes increased energy intake and reduced energy expenditure due to its failure to stimulate leptin production. Functional magnetic resonance imaging (fMRI) of the brain demonstrates that the brain responds differently to fructose or fructose-containing sugars compared with glucose or aspartame. Some epidemiological studies show that sugar consumption is associated with body weight gain, and there are intervention studies in which consumption of ad libitum high-sugar diets promoted increased body weight gain compared with consumption of ad libitum low- sugar diets. However, there are no studies in which energy intake and weight gain were compared in subjects consuming high or low sugar, blinded, ad libitum diets formulated to ensure both groups consumed a comparable macronutrient distribution and the same amounts of fiber. There is also little data to determine whether the form in which added sugar is consumed, as beverage or as solid food, affects its potential to promote weight gain. It will be very challenging to obtain the funding to conduct the clinical diet studies needed to address these evidence gaps, especially at the levels of added sugar that are commonly consumed. Yet, filling these evidence gaps may be necessary for supporting the policy changes that will help to turn the food environment into one that does not promote the development of obesity and metabolic disease.
Background: Despite the association between uric acid and cardiovascular disease has been known for decades, the prognostic value of serum uric acid (UA) in all clinical manifestations of acute coronary syndrome (ACS), namely ST-elevation myocardial infarction (STEMI), NSTEMI and unstable angina, has not been definitively assessed. Methods: This retrospective analysis included patients from previous SPAI and FAMI studies with the aim to investigate the association between serum uric acid and major adverse cardiovascular events at 180days from hospital admission. Results: 1548 patients were considered and divided in four groups, according UA concentration. Uricemia was significantly associated with gender, BMI, arterial hypertension, HDL-cholesterol, triglycerides, metabolic syndrome and glomerular filtration rate in univariate analysis. Multivariate logistic regression indicated that UA >6.0mg/dL on admission increased the risk of in-hospital mortality in overall population (OR 2.9, 95%CI 1.4-6.1; p=0.0057) and in patients with de novo ACS (OR 3.2, 95%CI 1.5-6.8; p=0.0033). Comparable results were also obtained after adjusting the model for age, gender, body mass index, glomerular filtration rate, metabolic syndrome, acute revascularization and ethnicity. A positive correlation was observed between UA and C reactive protein concentrations in in-hospital deaths only (rho 0.41, p=0.027). Conclusion: In patients with acute coronary syndrome, uricemia levels above the current international reference limit (6.0mg/dl) were associated with in-hospital mortality, independently from ethnicity and renal function.
Dietary polyphenols constitute a large family of bioactive substances potential beneficial effect on metabolic syndrome (MetS). This review summarizes the results of clinical studies on patients with MetS involving the chronic supplementation of a polyphenol-rich diet, foods, extracts or with single phenolics on the features of MetS (obesity, dyslipidemia, blood pressure and glycaemia) and associated complications (oxidative stress and inflammation). Polyphenols were shown to be efficient, especially at higher doses, and there were no specific foods or extracts able to alleviate all the features of MetS. Green tea, however, significantly reduced body mass index and waist circumference and improved lipid metabolism. Cocoa supplementation reduced blood pressure and blood glucose. Soy isoflavones, citrus products, hesperidin and quercetin improved lipid metabolism, whereas cinnamon reduced blood glucose. In numerous clinical studies, antioxidative and anti-inflammatory effects were not significant after polyphenol supplementation in patients with MetS. However, some trials pointed towards an improvement of endothelial function in patients supplemented with cocoa, anthocyanin-rich berries, hesperidin or resveratrol. Therefore, diets rich in polyphenols, such as the Mediterranean diet, which promote the consumption of diverse polyphenol-rich products could be an effective nutritional strategy to improve the health of patients with MetS. © 2016 World Obesity.
The gut is home to trillions of microorganisms that have fundamental roles in many aspects of human biology, including immune function and metabolism(1,2). The reduced diversity of the gut microbiota in Western populations compared to that in populations living traditional lifestyles presents the question of which factors have driven microbiota change during modernization. Microbiota-accessible carbohydrates (MACs) found in dietary fibre have a crucial involvement in shaping this microbial ecosystem, and are notably reduced in the Western diet (high in fat and simple carbohydrates, low in fibre) compared with a more traditional diet(3). Here we show that changes in the microbiota of mice consuming a low-MAC diet and harbouring a human microbiota are largely reversible within a single generation. However, over several generations, a low-MAC diet results in a progressive loss of diversity, which is not recoverable after the reintroduction of dietary MACs. To restore the microbiota to its original state requires the administration of missing taxa in combination with dietary MAC consumption. Our data illustrate that taxa driven to low abundance when dietary MACs are scarce are inefficiently transferred to the next generation, and are at increased risk of becoming extinct within an isolated population. As more diseases are linked to the Western microbiota and the microbiota is targeted therapeutically, microbiota reprogramming may need to involve strategies that incorporate dietary MACs as well as taxa not currently present in the Western gut.
The effects of low-carbohydrate (LC) diets on body weight and cardiovascular risk are unclear, and previous studies have found varying results. Our aim was to conduct a meta-analysis of randomised controlled trials (RCT), assessing the effects of LC diets v . low-fat (LF) diets on weight loss and risk factors of CVD. Studies were identified by searching MEDLINE, Embase and Cochrane Trials. Studies had to fulfil the following criteria: a RCT; the LC diet was defined in accordance with the Atkins diet, or carbohydrate intake of <20 % of total energy intake; twenty subjects or more per group; the subjects were previously healthy; and the dietary intervention had a duration of 6 months or longer. Results from individual studies were pooled as weighted mean difference (WMD) using a random effect model. In all, eleven RCT with 1369 participants met all the set eligibility criteria. Compared with participants on LF diets, participants on LC diets experienced a greater reduction in body weight (WMD –2·17 kg; 95 % CI –3·36, –0·99) and TAG (WMD –0·26 mmol/l; 95 % CI –0·37, –0·15), but a greater increase in HDL-cholesterol (WMD 0·14 mmol/l; 95 % CI 0·09, 0·19) and LDL-cholesterol (WMD 0·16 mmol/l; 95 % CI 0·003, 0·33). This meta-analysis demonstrates opposite change in two important cardiovascular risk factors on LC diets – greater weight loss and increased LDL-cholesterol. Our findings suggest that the beneficial changes of LC diets must be weighed against the possible detrimental effects of increased LDL-cholesterol.
Recent attention has focused on fructose as having a unique role in the pathogenesis of cardiometabolic diseases. However, because we rarely consume fructose in isolation, the major source of fructose in the diet comes from fructose-containing sugars, sucrose and high fructose corn syrup, in sugar-sweetened beverages and foods. Intake of sugar-sweetened beverages has been consistently linked to increased risk of obesity, type 2 diabetes, and cardiovascular disease in various populations. Putative underlying mechanisms include incomplete compensation for liquid calories, adverse glycemic effects, and increased hepatic metabolism of fructose leading to de novo lipogenesis, production of uric acid, and accumulation of visceral and ectopic fat. In this review we summarize the epidemiological and clinical trial evidence evaluating added sugars, especially sugar-sweetened beverages, and the risk of obesity, diabetes, and cardiovascular disease and address potential biological mechanisms with an emphasis on fructose physiology. We also discuss strategies to reduce intake of fructose-containing beverages.