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LIFESTYLE MANAGEMENT TO REDUCE DIABETES/CARDIOVASCULAR RISK (B CONWAY AND H KEENAN, SECTION EDITORS)
Table 1 Common fasts and their dietary restrictions in some religions Disturbances in circadian rhythms are linked with cardio-
Religion Timing of fast Etiquette metabolic diseases onset, as Ramadan fasting may affect the
timing of acute coronary event presentation [11] and moreover
Baha’i 19 days (2–10 March) No food/drinks from sunrise to that systemic cortisol levels are disrupted during Ramadan in a
sunset Saudi Arabian cohort, with high levels during the evenings
Buddhist Usually on full-moon days and No solid food; some liquids
other holidays allowed compared to mornings [12]. Of note, such changes in cortisol
Catholics Ash Wednesday and Good No meat (and no meat on levels are typically associated with the metabolic syndrome,
Friday Fridays during Lent). Small e.g., hypercortisolemia is linked to insulin resistance due to
meals allowed
Eastern Fast periods include Lent, No meat, dairy products, eggs. impaired insulin secretion and increased hepatic glucose out-
Orthodox Apostles’ Fast, Dormition Fish prohibited on some put [13, 14]. Sleep deprivation also triggers a pro-
Fast, Nativity Fast. Also fast days inflammatory milieu and micro/macro-vascular changes
includes every Wednesday
and Friday linked to impaired vascular stimulation following a flow-
Hindu New moon days, some Can involve 24 h of full mediated dilation test. Altered adipokine levels also occur,
festivals such as Shivaratri, abstinence from al foods with increased circulating leptin and decreased adiponectin
Saraswati Puja, and Durga and liquids; commonly
Puja practiced with abstinence in a Saudi Arabian cohort during Ramadan. Such an altered
from solid food adipokine signature is usually linked to insulin resistance. To
Islam 28–30 days of Ramadan No food /water from sunrise to further compound the issue, there is excessive food intake
(obligatory) and each sunset
Monday and Thursday
[“gorging”] during Ramadan nights in some of these countries
(voluntary) that will further fuel metabolic syndrome-like features such as
Jewish Yom Kippur, the Day of No food/drinks from sunset to increased weight gain and insulin resistance [15]. In addition,
Atonement, and 6 other sunset (and from sunrise to
active/passive smoking is widespread in this region and fur-
days of “minor fasts” sunset for “minor fasts”
Mormon First Sunday of each month No food/water for two ther fuels cardio-metabolic diseases [16, 17]. For example,
consecutive meals Ramahi et al. [17] examined a Jordanian cohort and
established that indoor pollution (due to increased smoking
activity) increased to unsafe levels during Ramadan after
breaking of the fast. In light of these findings, we propose that
altered circadian rhythms during Ramadan trigger down-
intake is also allowed [6]. The data on the health benefits of stream effects that eventually contribute to the onset of
fasting remain inconclusive as some studies show lower, cardio-metabolic diseases (Fig. 1).
higher, or no changes in nutrient intake during Ramadan [7].
Similar findings exist for BMI, blood metabolites profile (glu-
cose, lipids), and the onset of cardio-metabolic diseases [7]. Intermittent Caloric Restriction [Fasting]
Fasting times vary according to geographical location and
season. There are also cultural differences that likely impact Calorie restriction (CR) is associated with health improve-
dietary intake and smoking patterns. ment, increased longevity, and a reduction of morbidity and
Unique cultural practices in the Middle East and North mortality in animal studies [19–22]. Calorie control also ben-
Africa (MENA) region during Ramadan likely offset potential efits cardiovascular status, weight reduction, insulin sensitiv-
benefits usually achieved by caloric restriction. A meta- ity, diabetes control, cognitive function, and cancer prevention
analysis reports that East Asian individuals displayed more among its many effects in humans [23–26]. However, CR is
significant weight loss during Ramadan when compared to difficult to practice and increases the risk of malnutrition.
West Asian populations [7]. Furthermore, others established Intermittent fasting (IF) reduces the risk of malnutrition and
increased energy intake in Saudi Arabia when compared to is easier to follow and is gaining popularity with health ex-
other countries [e.g., India] during Ramadan [8]. Thus, we perts. We review some mechanistic insights for the health
hypothesize that individuals within the MENA countries dis- benefits of IF.
play unique cultural/behavioral patterns that pre-dispose them
to increased risk for the onset of cardio-metabolic diseases.
Although the major factor[s] driving this process remain un- Tissue Changes Following Energy Intake
clear, we propose that altered circadian rhythms during Restriction: Putative Mechanisms
Ramadan may have a central role as the usual circadian
rhythm among fasting Muslims in this region is significantly Stress-Activated Pathways
altered during Ramadan, with fasting individuals generally
remaining awake during the night while spending most of IF activates stress-induced pathways and increases transcrip-
the day sleeping [9, 10]. tion of stress-induced proteins such as heat shock protein
Curr Diab Rep (2017) 17:123 Page 3 of 11 123
suggests that it is the amount of calories, rather than the fat and endocrine (production of adipocytokines with depot-
content, that is the major determinant of adiponectin secretion specific signature).
[65]. Adiponectin also mediates the cardiovascular benefits of IF affects WAT cellularity at the level of the size of
IF as shown in animal studies [66]; however, its prognostic adipocytes. Studies in humans show that enlarged sub-
value in human disease has been questioned as higher levels of cutaneous abdominal adipocyte size, but not obesity it-
adiponectin are associated with less favorable outcomes in self, predicts type II diabetes [69]. Increases in fat cell
congestive heart failure [54] (Fig. 2). size (“hypertrophic obesity”) play a more important role
in metabolic diseases than increases in fat cell number
(“hyperplastic obesity”) [70]. The authors suggest that
Tissue and Metabolic Changes larger adipocytes have higher capacity for TAG synthe-
sis and lipolysis. Consequently, higher FA release from
Adipose Tissue WAT and flux of FFA in circulations contribute to met-
abolic diseases [70]. Another study [71] reports that
The complex role of adipose tissue (AT), white and brown inguinal (subcutaneous depot) and epididymal (visceral
(WAT and BAT, respectively) in overall energetic homeosta- depot) fat cells were smaller in IF. The large reduction
sis, in both physiological and pathological conditions is intri- in adipocyte size of both WAT depots correlates with
cately linked with lipid (fatty acid, FA) metabolism in AT- and their increased insulin sensitivity, likely due to increases
non-AT (muscle, heart), where the liver acts as an integrative in insulin receptor number [72]. Studies in animals and
metabolic organ (Figs. 3 and 4). humans demonstrate that IF and CR positively modulate
There are three sources of FA: food intake, storage from the secretory signatures of adipocyte cytokines by de-
white adipose tissue (WAT), and de novo synthesis (mainly in creasing secretion of pro-inflammatory mediators and
liver and also in AT). Together with other lipids, FA from the development of a pro-inflammatory phenotype in
different sources (in the form of triacylglycerols, TAG) are WAT [73, 74••].
packaged in lipoprotein particles: chylomicrons in the intes- Experiments by Ding et al. [75•] showed that fasting
tine and VLDL (very-low-density lipoproteins) in the liver for up to 24 h significantly reduced the body weight of
and through lymphatic or blood vessels move to capillary of both male and female mice, with moderate reductions in
extrahepatic tissues [67, 68]. weight of subcutaneous visceral fat depots. Recent results
All aspects of AT biology are connected with the develop- of Fabbiano et al. [76] show that long-term CR or IF
ment of metabolic disorders, including metabolic syndrome, regimens stimulate browning of WAT. Indeed, induction
obesity, cardiovascular diseases, type II diabetes, cancer, and of “browning” in WAT or transplantation of BAT is con-
neurodegenerative disorders. This involves the following spe- sidered by some to have a therapeutic potential [77].
cific alterations: morphological and cellular (hypertrophy/hy- Stimulation of “browning” in WAT by dietary means can
perplasia/atrophy), metabolic (ratio of lipolysis/lipogenesis influence body weight and the potential success of anti-
and degree of re-esterification and releasing of adipocyte obesity therapies. Hence, even though induction of
FA, level of FFA in circulation, and balance of re- “browning” in WAT is logically contrary to the physiolog-
esterification of FA between AT and liver), and physiological ical response to negative energy balance due to IF and
Ghrelin ↑
AMPK ↑ Lepn ↓ ROS ↓ Nrf2 ↑ ? Insulin/IGF-1 ↓
BDNF ↑
?
CR, it should be kept in mind that different food constit- Diabetes Mellitus
uents and intermediary metabolites can induce browning
of WAT. For example, lactate and the ketone body β- A popular method of IF involves 1 day of eating followed by a
hydroxybutyrate [78] are strong “browning” inducers, day of fasting, while others suggest 20 h of fasting followed
while the amino acid L-arginine improves all metabolic by 4 h of eating time or 16 h of fasting followed by 8 h of
aspects in WAT and BAT, and has the potential to induce eating [81]. Several clinical trials have compared IF vs CR;
“browning” [79, 80]. Similar effects are also produced by however, to our knowledge, there is no clinical study compar-
exercise training where “browning” of WAT occurs in vis- ing the various IF protocols with each other. For instance,
ceral and especially subcutaneous adipose depots [80]. Adrienne et al. compared IF and CR in type II diabetic patients
123 Page 6 of 11 Curr Diab Rep (2017) 17:123
Fig. 4 The main depots of human adipose tissue (AT) types according to numbers of mitochondria. In contrast, brown and beige/bright adipocytes
their relative amounts, functional specificities and the clinical significance contain significantly more mitochondria that are rich in uncoupling
are listed (a). Discrete functional-metabolic, endocrine and expanding protein-1 (UCP1), which regulates oxidative phosphorylation from ATP
characteristics of human AT depots, primarily that of subcutaneous- and synthesis and energy dissipating as heat. Some depots of AT in newborn
the visceral depots, can influence metabolic health/risk. Thus, in contrast babies (interscapular), as well as in adults (deep neck, supraclavicular) are
to subcutaneous depots, visceral depots are less sensitive to insulin, brown fat (a, right), and bright UCP1 containing adipocytes can be found
express higher levels of pro-inflammatory adipocytokines and grow within various AT depots, visceral and subcutaneous. Increases of the
mostly by adipocyte hypertrophy. Accordingly, subjects with more relative amounts of brown adipose tissue, brown/bright adipocytes in
visceral AT can have a restricted (short term) capacity to buffer high white AT, and the brown-like functional characteristics of white
calorie (nutritional) overload, and ultimately develop a higher risk adipocytes—browning (b), may have greater relevance in obesity and
insulin resistance and diabetes. Depots of AT in humans are diabetes type 2 treatment
predominantly white fat which is able to store lipids and have limited
Curr Diab Rep (2017) 17:123 Page 7 of 11 123
[82]. They found that even though CR is superior in terms of [101]. Increased levels ROS inhibit the activity of
weight reduction, CR and intermittent fasting had comparable glyceraldehyde-3-phosphate dehydrogenase [GAPDH] and
effects in visceral fat mass reduction, fasting insulin, and in- lead to increased concentrations of glyceraldehyde-3-
sulin resistance. IF also improves metabolic parameters in phosphate [GA3P] and other upstream glycolytic interme-
non-diabetic individuals [83]. Data related to adherence rates diates. Levels of methylglyoxal, which are elevated by
were not reported in the study [83]. Intermittent fasting dimin- GA3P, lead to [i] increased production of AGE and [ii]
ishes fat mass while preserving lean body mass, as opposed to activation of protein kinase C (PKC), which has a number
daily CR, which results in reduced fat and lean body mass of effects including reduced activity of endothelial nitric
[74••, 84]. oxide synthase [eNOS], production of ROS by the phago-
Dietary modification is a critical factor in the management cyte NADPH oxidase isoform, over-activity of the coagu-
of diabetes. In a 20-year longitudinal study of Rhesus mon- lation system, increased expression of some growth fac-
keys, CR lowered age-related diseases including diabetes, tors, and stimulation of NF-κB all of which promote an
where 5 of 38 control animals developed diabetes and another inflammatory state. Non-mitochondrial origins of ROS in-
11 being pre-diabetic, while animals experiencing CR showed clude NAD[P]H oxidase, xanthine oxidase, uncoupled
no impairment of glucose homeostasis [85]. IF leads to similar eNOS, lipoxygenase, cyclooxygenase, cytochrome P450
outcomes in both diabetic and pre-diabetic individuals, as a 1- enzymes, and other hemoproteins [102].
kg reduction of body weight is associated with 16% reduction CR boosts the activity of endogenous antioxidant systems.
in diabetes risk [86]. A number of studies confirm the effec- In a study of 46 overweight [BMI 25–29.9] individuals,
tiveness of IF in reducing risk factors for diabetes or its com- 6 months of CR increased plasma glutathione peroxidase ac-
plications. For instance, intermittent fasting reduces visceral tivity and reduced plasma protein carbonyl levels, which were
fat, an important site for producing TNF-α in diabetic patients associated with non-significant decreases in plasma 8-epi-
[87]. Reductions of visceral fat after 6 to 24 weeks of IF have prostaglandin F2α levels [103]. The antioxidant effects of
been reported in several studies [74••, 88–91]. In almost all of CR manifest several days after initiation of the diet, as shown
these investigations, reductions of visceral fat paralleled loss in a study of 40 overweight/obese women [BMI 32 ± 5.8]
of body weight. IF decreases fasting glucose and insulin levels where F2-isoprostane concentrations were reduced after 5 days
in non-obese [92], overweight/obese [90, 91], and diabetic of a 25% CR diet [104].
individuals [93] with simultaneous improvements in insulin Many epidemiologic studies indicate an association
sensitivity. between reduced food intake and lower cardiovascular
Several mechanisms have been proposed to explain the diseases [105, 106]. As mentioned before, CR reduces
modifying effects of CR on glucose metabolism. First, re- oxidative stress in endothelial cells, a phenomenon that
duced energy intake reduces pancreatic cell apoptosis, as is associated with increased expression of eNOS. SIRT-1
shown in diabetic rats where caloric restriction attenuates beta acetylates lysine residues to enhance eNOS activity
cell apoptosis [94]. Improved insulin sensitivity increases the [107]. Greater bioavailability of eNOS-derived nitric ox-
expression of SIRT-1 [94]. It is likely that SIRT-1 adjusts ide (NO), associated with decreased ROS, reduces blood
hepatic gluconeogenic/glycolytic pathways in response to pressure in both animal and human studies following
CR. SIRT-1 increases hepatic glucose output by affecting CR [108, 109]. Apart from its vasodilating effects, NO
PPARγ co-activator alpha [PGC]-1α [95]. Overexpression also reduces oxidative stress and has anti-inflammatory
of SIRT-1 in mice increases metabolic rate and reduces properties [110]. Furthermore, the anti-proliferative ef-
weight, blood cholesterol, adipokines, fasting blood sugar, fects of NO in vascular smooth muscle coupled with
and insulin levels [96]. In other words, SIRT-1 activity pro- its inhibitory action on platelet aggregation and inflam-
motes the beneficial effects of CR. The life extending effects matory cell adhesion play a significant role in preven-
of CR is lost in SIRT1 deficient mice [97]. Six months of CR tion of atherosclerosis [105]. Several cytokines [e.g., IL-
in overweight adolescents also increased expression of SIRT-1 6, IL-1β, IL-17A, TNF-α] are positively correlated with
and other genes whose protein products are essential for mi- cardiovascular outcome [111] and CR suppresses in-
tochondrial function [98]. flammatory pathways.
The aggravating effects of oxidative stress in the pathogen- In light of the fact that the majority of parameters that are
esis of diabetes and its complications [99] include impeding changed by caloric restriction and IF [e.g., nuclear factor ery-
the ability of endothelial cells to combat glucotoxicity associ- throid 2-related factor 2 (Nrf2) activation, decreased oxidative
ated with an array of the cardiovascular consequences of stress, lower leptin levels, activation of AMP-activated protein
diabetes [100]. Hyperglycemia triggers several pathways kinase (AMPK), higher adiponectin levels, suppressed AGE/
that lead to the mitochondrial and non-mitochondrial pro- RAGE signaling and inflammation] is associated with de-
duction of reactive oxygen species [ROS] that participates creased cardiovascular risk and mortality, it is not surprising
in the pathogenesis of diabetes-induced vascular damage that CR/IF is highly beneficial for the aging heart and
123 Page 8 of 11 Curr Diab Rep (2017) 17:123
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