Journal of Diabetes Mellitus and Metabolic Syndrome

Journal of Diabetes Mellitus and Metabolic Syndrome Zygoscient Research

Insights 1
doi.org/10.28967/jdmms.2018.01.18002

Diet Composition for the Management of Obesity and Obesity-related
Disorders

*Rachel Botchlett1
, Chaodong Wu2
1
Pinnacle Clinical Research, Live Oak, TX, 78233, USA
2
Department of Nutrition and Food Science, Texas A&M University, College Station, TX, 77843, USA
Review Article
Citation: Rachel Botchlett (2018) “Diet Composition for the Management of Obesity and Obesity-related Disorders.” j. of diabetes mellit. and metab. syndr. vol. 3,
10-25
Received 14/06/2018
Accepted 14/09/2018
Published 19/09/2018
*For Correspondence
Rachel Botchlett
Pinnacle Clinical Research,
Live Oak, TX, 78233, USA
Email: rbotchlett@gmail.com
Fax: 210 572 5766
Keywords: Obesity, Type 2 Diabetes, Hypertension, NonAlcoholic
Fatty Liver Disease, Dietary Interventions, Diet
Composition
Running Title: Diet composition in obesity

ABSTRACT

Healthy nutrition is essential for the prevention of disease and for
maintenance or promotion of health; although healthy
nutrition remains to be precisely defined. Over the past
several decades, various types of nutrients have been
functionally validated and considered as critical components
of healthy nutrition, which commonly includes fiber-enriched
carbohydrates, mono- or poly-unsaturated fatty acids,
essential amino acids, and certain micronutrients. When
managing obesity and obesity-associated metabolic diseases,
much attention has been paid to the content of nutrients that
is considered as healthy nutrition. Accumulating evidence
also suggests that nutrient composition could be more
important than the content of individual nutrients in the
context of reducing body weight and obesity-associated risk
for metabolic diseases. Consistently, it would be more
important to focus on a diet with differences in nutrient ratios
rather than individual type(s) of nutrients in terms of
managing obesity and metabolic diseases. In this review,
recent advances in the dietary management of obesity and
obesity-related metabolic diseases have been discussed. This
the review also has highlighted several specific diet compositions
and their differences in managing hypertension, type 2
diabetes, and non-alcoholic fatty liver disease.
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INTRODUCTION

Prevalence rates of overweight and obesity have dramatically increased within the United States over the past
several decades. The most recent data from the CDC and nutritional health and examination surveys (NHANES)
estimate that 70% of American adults are overweight or obese [1]. The prevalence rate of obesity specifically, from
2011-2014, was roughly 36.5% of adults aged 20 and older [1]. Given the significant association between obesity
and chronic metabolic disorders, the increased prevalence of concomitant comorbidities is no surprise. In fact, the
rate of type 2 diabetes mellitus (T2DM) within North America and the Caribbean has increased from 7.6% to
approximately 10% from 2003-2013 [2]. Rates of hypertension and chronic liver diseases, such as non-alcoholic
fatty liver disease (NAFLD), have also increased over recent years[3]
.
Given the epidemic nature of obesity, much research has focused on lifestyle and pharmaceutical interventions [4,
5]. Weight loss remains the most effective approach for obesity and reducing the risk of related diseases; however,
weight loss can be difficult to achieve and maintain [6, 7]. Multiple pharmaceuticals have thus attempted to reverse
obesity and offer “fast weight loss”; however, virtually all have been unsuccessful for various reasons. More
effective are the pharmaceuticals to manage obesity-related diseases. For example, angiotensin-converting
enzyme (ACE) inhibitors are useful for managing hypertension, while biguanides, thiazolidinediones, and
sulfonylureas are successful treatments for managing insulin signaling and systemic glucose utilization and thus,
hyperglycemia/T2DM [8-10]; Blood Pressure Lowering Treatment Trialists’ Collaboration, 2015 #3368. The
interventions for T2DM can subsequently aid in the management of NAFLD given their actions on stimulating
adipogenesis and uptake of free fatty acids, thereby reducing fat accumulation in the liver. Although great progress
has been made in the pharmaceutical industry, many of these interventions may be undesirable due to cost or risk
of side effects. Therefore, continued education on the benefits of diet as a lifestyle intervention is important now
more than ever. Several diets have proven very successful in maintaining obesity and obesity-related diseases [11]
.
The purpose of this review is to highlight such diets, particularly the specific diet compositions proven to be
effective in managing hypertension, T2DM, and NAFLD including details on the underlying mechanism(s).

DIET COMPOSITION FOR OBESITY AND PREVENTING EXCESS WEIGHT GAIN

The biggest factor leading to excess weight gain and the development of obesity is overnutrition. Energy
consumption that exceeds metabolic requirements leads to lipogenesis and fat storage within white adipose tissue
(WAT), the primary storage site of fat within the body. Overconsumption of dietary fat can lead to weight gain
relatively quickly since dietary fat is metabolized to free fatty acids, the primary substrate for triglycerides (TG) and
subsequently, lipid synthesis. However, overconsumption of any macronutrient can ultimately lead to fat synthesis
and accumulation. Therefore, the key dietary habit of reducing obesity is twofold: manage total caloric intake and
fat content within the diet.
Total Caloric Intake
The estimated daily caloric need for the average American male and female is approximately 2500 and 2000
calories, respectively (2015 – 2020 Dietary Guidelines for Americans, 8th Edition, December 2015;
http://health.gov/dietaryguidelines/2015/guidelines/). This estimate pertains to moderately active adults and has
remained relatively stable over the past several decades despite arguments as to the appropriate dietary
composition. Interestingly, much research has demonstrated that caloric restriction (CR) is highly beneficial in
managing obesity and stimulating weight loss. The majority of research focuses on three methods of CR: alternate
day fasting (ADF), which consists of a fasting day (0% – 25% of caloric need) alternating with a fed day (ad libitum
consumption), daily acute restriction (DAR) of ~ 25% of total calories, and intermittent fasting (IF). All three are
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shown to successfully induce weight loss in multiple obese populations [12, 13]; however, no one intervention seems
to be more beneficial than another [14]. Further, compliance rates are similar between the three approaches. It
seems that the success of each method is attributable to the slower rate of weight loss which stimulates lipolysis
while preserving lean body mass. Perhaps, ADF, DAR or IF may be more easily incorporated and maintained by
obese populations vs other methods of weight loss (“no-carb” diets, increased physical activity, etc). In addition to
weight loss, all three methods improve HBA1c, insulin levels, HOMA-IR score and several aspects of lipid
metabolism [15], all of which can be significantly impaired in obesity.
The overall mechanism tying CR to weight loss is obvious: fewer calories in equates to fewer calories stored. However,
the underlying mechanisms of CR and an improved metabolic profile are less understood. The majority of studies
conclude that CR, even periodically, leads to reduced inflammatory responses and production of oxidative stress.
For example, diet-induced obese rats subjected to CR of 40 % of ad libitum showed reduced hepatic triglycerides,
hepatic levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2) and thus, levels of lipid
peroxidation and reduced impairment of fasting glucose [16]. Additional studies have demonstrated similar results
in other obese rodent models [17, 18]. Mechanistic studies in humans are limited, but few have demonstrated these
same findings in obese individuals [19-21]. It seems these mechanisms of CR also contribute to increased life span,
although this aspect is outside the scope of this review.

Fat Content

Dietary fat can have a significant impact on overall health and metabolism. Inadequate fat intake impairs
absorption of fat-soluble vitamins and leads to reduced production of hormones and lipoprotein particles, whereas
excess fat can contribute to inflammation, obesity, and steatosis in distal organs, for example, the liver. There is no
specific recommended daily intake (RDI) for total fat, but the current acceptable macronutrient distribution range
(AMDR) is 20-35% of total daily calories. Diets that exceed this range are labeled as high-fat diets (HFD) and
contribute to weight gain and a worsened metabolic profile. In rodents, this equates to weight gain relatively
quickly and increased inflammation and oxidative damage throughout the body [22-24]. HFD can result in similar
effects in humans, especially following chronic HFD, including weight gain/obesity, systemic inflammation, and
impaired glucose homeostasis. The primary mechanism underlying the metabolic effects of HFD is adipocyte
hypertrophy, which in turn contributes to increased expression of proinflammatory cytokines, impaired lipid
metabolism and ultimately, increased free fatty acids in the circulation which have damaging effects to many
tissues and cell types [5]. To prevent excess weight gain and/or promote weight loss and thus, limit this mechanism,
obese individuals are recommended to ingest a lower amount of total fat, all the while staying within the AMDR to
prevent metabolic problems caused by malnutrition.
Arguably more important than total fat for the management of obesity is monitoring the type of fat ingested.
Certain types of fat are known to be more detrimental than others and thus, can further exacerbate obesity-related
metabolic impairments. Saturated fat, in particular, is significantly more inflammatory compared to
unsaturated fat [25, 26] primarily through its potent ability to activate multiple inflammatory mechanisms including
macrophage infiltration and/or proinflammatory activation, and the c-Jun-N terminal kinase and TLR4 signaling
pathways [22, 23, 27, 28]. Saturated fat is also known to directly interfere with the insulin signaling cascade at multiple
steps [22, 23, 29, 30]. For these reasons numerous agencies, including the American Heart Association, American
Diabetes Association and USDA, recommend low saturated fat intake.
Micronutrients
Micronutrients play an active role in virtually all aspects of metabolism including glucose homeostasis, fat
deposition, and protein metabolism. Thus, adequate intake is paramount in maintaining health and an appropriate
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body weight, and staving off metabolic disorders. Obesity is associated with several micronutrient deficiencies
including vitamins A, C and D, selenium, and thiamine [31-33]. In turn, these deficiencies can exacerbate the obese
phenotype and significantly contribute to the development of comorbidities, namely T2DM [31, 32]. For example,
an insufficient status of vitamin A and C are associated with leptin concentrations, and increased adipogenesis and fat
deposition [32, 34], while the deficiency in vitamin D is linked to reduced pancreatic ?-cell function [35]. Therefore, the
most important dietary approach related to micronutrients for the maintenance of obesity, and any subsequent
comorbidities, is adequate intake. This can be attained either through consumption of a wide variety of foods or
supplementation. It is important to note that the exact relationship between obesity and micronutrient
deficiencies remains unclear. Thus, additional research is needed to further explore the direction of causality.

DIET COMPOSITION FOR MANAGING INSULIN RESISTANCE

The relationship between obesity and insulin resistance is well established. Excess weight gain and maximum lipid
storage ability of adipose tissue lead to abnormally enlarged adipocytes and subsequently, impaired lipid
metabolism and secretion of inflammatory cytokines within adipose tissue. Chronic overnutrition and/or obesity
and thus, inflammation within the adipose contribute to low-grade systemic inflammation, a major defining
characteristic of obesity. In fact, the term “metainflammation” is commonly used to describe the idea that
inflammation is the primary causal factor in many obesity-associated metabolic diseases, including insulin
resistance [36]. Indeed, several inflammatory cytokines are known to impair the insulin signaling cascade at multiple
sites in numerous tissues [37, 38]. Therefore, diet composition for managing obesity-related insulin resistance is
primarily aimed at preventing additional weight gain, with diets low in fat and simple carbohydrates but high in
fiber, and reducing the generation of inflammation and promoting insulin signaling via adequate intake of
micronutrients.
Carbohydrates and Fiber
Overconsumption of carbohydrates, as with any macronutrient, can contribute to overnutrition and thus,
exacerbate the obese phenotype. However, monitoring the type of carbohydrate consumed seems more vital in
managing obesity-related insulin resistance. In both obese and non-obese patients, complex carbohydrates (such
as amylose and fibers) are associated with a reduced-risk for T2DM and insulin resistance compared with
consumption of primarily simple carbohydrates [39-41]. Animal studies using rodent models of diet-induced obesity
demonstrate similar results [42-44] and attribute the insulin desensitizing effects of simple carbohydrates to elevated
spikes in plasma glucose, stimulation of lipogenesis, and the promotion of proinflammatory mechanisms [45-47]
. For
this reason the current Dietary Guidelines for Americans (DGA) suggests limiting simple/refined grains such as
ready-to-eat cereals and white bread, and increasing intake of whole grains such as whole-wheat bread and
oatmeal (USDHHS). The underlying mechanisms and full effect(s) of simple versus complex carbohydrates on
human metabolism, especially in the context of obesity, remain relatively controversial; however, several clinical
trials are underway to further elucidate their role in insulin resistance and obesity [48]
.
Dietary fiber, which the DGA recommends 25g and 38g per day for women and men, respectively, promotes
colonic health regulates satiety and cholesterol levels, and slows the release of chyme into the small intestine,
which culminates in slower nutrient absorption (including glucose) through intestinal epithelial cells and ultimately,
reduced postprandial glucose responses. Indeed, multiple clinical trials and/or intervention studies in humans have
demonstrated that increased dietary fiber reduces fasting plasma glucose and HOMA-IR scores and is associated
with weight loss in obese and non-obese diabetic individuals [49-52]. Mechanistic studies in animal models
demonstrate that dietary fiber exerts these effects by improving lipid metabolism, reducing adiposity, and
increasing lean body mass [53, 54]
.
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Fat Content

A low-fat diet can greatly aid in the management of T2DM since it can help prevent weight gain and/or promote
weight loss. However, specific types of fats are more detrimental than others for managing insulin sensitivity. For
instance, because of their proinflammatory abilities, saturated fats are associated with impaired insulin signaling
throughout the body [22, 23, 55]. Multiple studies in both obese and non-obese diabetic adults have confirmed these
effects. For this reason, the DGA suggests the higher intake of unsaturated compared with saturated fats. Specifically,
adults should consume less than 10% of daily calories from saturated fat, and ingest a variety of unsaturated fats,
including mono- and polyunsaturated fats. Indeed, intervention studies have confirmed the benefits of following
such a diet. For example, a recent meta-analysis by Qian et al. concluded that diets higher in monounsaturated
fatty acids improve metabolic risk factors, including fasting glucose and HOMA-IR in patients with T2DM [56]
.
Replacing carbohydrates with either mono- or polyunsaturated fats can also greatly improve these factors [57]
.
Similarly, replacing saturated with polyunsaturated fats not only improves these factors but also reduces C-peptide,
which is known to have a significant negative correlation with insulin sensitivity [57]. It seems polyunsaturated fats
can also indirectly improve insulin sensitivity through its anti-inflammatory properties. For example, increased
intake of omega-3 polyunsaturated fatty acids lead to increased production of 3-series prostaglandins, which are
generally less inflammatory and more beneficial in several disease states than the otherwise produced 2-series [58]
.
For this reason a Mediterranean-style diet, which recommends a variety of healthy oils (i.e. mono- and
polyunsaturated fats), has been shown beneficial for maintaining T2DM [59]

Micronutrients

Several micronutrients are shown to promote insulin signaling in humans, even in the presence of obesity,
including vitamins D and E, thiamine, and several minerals. Specifically, supplementation with vitamins D and E
contributes to enhanced systemic insulin sensitivity, as evidenced by improved HOMA-IR scores [60, 61], while the intake
of thiamine and zinc regulate fasting blood glucose and/or post-prandial glucose levels [62, 63] in patients with T2DM.
The latter dietary components and their subsequent effects are also likely to benefit patients with impaired fasting
glucose as they may slow the progression of hyperglycemia to diabetes. In overweight, diabetic individuals supplementation
with vitamin D, K and calcium similarly improves HOMA-IR scores, but also significantly increases
high-density lipoprotein (HDL) cholesterol and reduces fasting plasma glucose, insulin levels, and C-reactive protein
[64], an inflammatory marker linked to an increased risk for diabetes. Interestingly, it seems that vitamin D
supplementation is also beneficial in reducing the development of gestational diabetes [65], another condition
closely linked to obesity, although continued clinical research is necessary to further confirm its full effects.

Meal Timing

Meal timing can also be a key tool in successfully managing obesity-associated insulin resistance/T2DM. Much
research has previously established the relationship between circadian rhythm (i.e. sleep-wake cycles) and
metabolic elements in mammals, including genes that regulate glycolysis and insulin signaling [66-68]. More recently,
the association between disrupted sleep cycles and obesity and obesity-related diseases, including T2DM, has
been defined [69, 70]. Research to date has primarily revealed the cellular mechanisms but has yet to fully elucidate
how such mechanisms may be influenced by or interact within complex systems. Although clinical trials and/or
intervention studies specifically relating meal timing to circadian rhythm parameters are lacking, it is reasonable to
assume that syncing meals to specific points within the sleep-wake cycle would be beneficial to manage T2DM.
More research and clinical trials in this area are therefore warranted. Additionally, meal timing seems significant to
achieve successful weight loss [71], which is among the prescribed methods for preventing and managing T2DM.
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There are no current recommendations related to specific meal timing, but overall the DGA recommends multiple,
smaller meals throughout the day rather than a few, large meals.

DIET COMPOSITION FOR MANAGING CARDIOVASCULAR DISEASE

Risk factors for cardiovascular disease (CVD) including hypertension and dyslipidemia are commonly found in
overweight and obese individuals. In fact, NHANES data from 2007-2010 showed prevalence rates of these
disorders at 35.7% and 49.7%, respectively in obese adults [72]. The link between obesity and CVD is a combination
of dietary factors, metabolic imbalances, and endothelial and vascular dysfunction [10]. Much research also points
to obesity-induced inflammation as a major contributing factor [10, 73]. Thus, interventions and dietary components,
including those discussed in previous sections, aimed to reduce obesity are of utmost importance. Indeed, weight
loss remains the key recommendation to manage all obesity-related conditions; however, additional dietary
components can greatly support heart health. These components collectively named the Dietary Approach for
Stopping Hypertension (DASH), and their underlying mechanism(s) are discussed in this section. Increased physical
activity is also a key intervention for managing excess weight gain and CVD; however, that topic is outside the
scope of this review.

Sodium Content

Sodium is an essential micronutrient that plays a critical role in maintaining blood volume and promoting nerve cell
transmission and muscle contraction. Because of the widespread use of sodium/table salt, sodium deficiencies are
infrequent in the average American adult. Excess intake, on the other hand, is exceptionally common, with average
daily consumption by Americans aged 2 and older at 3,400 mg. Overconsumption is linked to many metabolic
diseases with and without obesity [74-76]. The DGA, therefore, recommends a maximum intake of 2,300 mg sodium
per day, which is equivalent to about one teaspoon of table salt, although the DASH diet targets a maximum of
1,500 mg. Obese individuals who follow these dietary recommendations have shown reduced rates of
hypertension, atherosclerosis and lipid-induced oxidative stress and thus, a lowered risk of developing CVD [77]
.
Many studies show that even a moderate reduction in salt intake improves blood pressure both short and long-term.
Although perhaps less enjoyable, low-sodium diets seem to be a great dietary approach to manage obesity associated
disorders related to CVD as they are typically low risk and are generally easy to adhere. Another benefit
of reducing dietary sodium is that salt intake seems to be a potential risk factor for obesity itself, independent of
energy intake[78]

Carbohydrates, Fiber, and Cholesterol

The DASH diet recommends 55% of total daily intake from carbohydrates, including at least 3 servings of whole
grains per day. Indeed, evidence from clinical trials demonstrates that obese individuals who increase their intake
of whole grains show improvements in many factors associated with cardiovascular health [79, 80]. Additionally,
DASH targets 30 g of fiber per day for all individuals, which is in line with the DGA for average adults. Fiber is
specifically beneficial to heart health through its ability to reduce total and low-density lipoprotein (LDL)
cholesterol [81]. Interestingly, when compared with a low-carbohydrate diet, a diet high in fiber significantly
lowered atherogenic lipids, although both diets were effective for weight loss. It is well known that increased fiber
intake also reduces high blood pressure [82, 83]. Thus, these dietary components of the DASH diet help to manage
obesity-associated CVD through improvements in many known risk factors.
Although the DASH diet does not provide specific recommendations for cholesterol intake, it does target increased
consumption of fruits and vegetables and less caloric intake from non-lean meats. The mechanisms underlying the
success of these dietary approaches are the reductions in total and LDL cholesterol, increased HDL, and improved
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blood pressure [84, 85]. In fact, following the DASH diet seems to reduce most of the risks associated with the
metabolic syndrome which ultimately, contributes to improved cardiovascular health.

Micronutrients

Unsurprisingly, the major micronutrients targeted by the DASH diet are the electrolytes. In addition to sodium
(discussed in detail above), potassium, magnesium, and vitamin D are important for proper management of heart
health. Obesity is associated with deficiencies of all three, which partially clarifies the mechanisms of obesity-associated
hypertension. For instance, in primary hypertension potassium depletion interrupts the normal functioning
of sodium pumps, increases sympathetic activity and angiotensin II production, and indirectly interferes with
calcium signaling [86]. Vitamin D deficiency, especially when paired with BMI ? 30, is also linked to arterial
hypertension and coronary artery disease, likely through inappropriate activation of the renin angiotensinaldosterone
system (RAAS) along with other mechanisms [87, 88]. Magnesium deficiency, commonly seen in in the
The United States, as evidenced by NHANES data from 2001-2010 [89], is shown to enhance angiotensin-induced
aldosterone synthesis and contribute to impaired insulin action [90, 91]. Thus, interventions to replete low
magnesium levels may be key to improving hypertension in diabetic individuals. Indeed, controlled interventions
using the DASH diet show repletion of all three macronutrients and subsequently, improvements in several risk
factors of CVD [92-94]. Interestingly, one trial demonstrated that the DASH diet lowered blood pressure in obese
hypertensive patients more effectively than an intervention of only potassium, magnesium, and fiber [95]. The
added success of the complete DASH diet was attributed to the intake of additional bioactive nutrients such as the
antioxidant vitamins C and E, and folate, arginine, and lycopene. Additional research is needed to further confirm
the effects of these nutrients and determine if others (i.e. phytochemicals, etc) participate in the management of
obesity-induced hypertension. Other intervention trials have demonstrated similar beneficial effects following
compliance to a DASH diet [87, 88, 96, 97]. In addition, weight loss of approximately 5% has been shown to significantly
reduce and manage the RAAS and positively contribute to reduced blood pressure [96]. Therefore, dietary
approaches to adequately manage obesity-induced hypertension should focus on proper micronutrient intake and
at least moderate weight loss.

DIET COMPOSITION FOR MANAGING OBESITY-RELATED CHRONIC LIVER DISEASES

Obesity significantly increases the incidence of NAFLD, with hepatic fat deposition (steatosis) being the primary
feature. Simple steatosis may be benign but progresses to non-alcoholic steatohepatitis (NASH) when the liver
exhibits overt inflammatory damage. NASH is now considered as one of the most common causes of terminal liver
diseases including liver cirrhosis and hepatocellular carcinoma. Due to the close relationship between obesity and
NAFLD, most dietary approaches used for obesity management are also applicable to NAFLD [98, 99]

Fat Content

It is accepted that inflammation drives the progression from simple steatosis to NASH. Accordingly, anti-inflammatory
nutritional approaches have been considered for managing NAFLD. In 2012, the Practice Guideline
by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the
American Gastroenterological Association stated that omega-3 fatty acids may be beneficial for NAFLD; although it
was not recommended to treat NAFLD [98]. Six years later, the Guideline regarding omega-3 fatty acids remains the
same
[99]. This guideline, interestingly, can be interpreted in either a positive or negative way. On the one hand,
there is a lack of convincing clinical evidence to consistently support the effect of omega-3 fatty acids on improving
or reserving liver histology and serum ALT [100]. On the other hand, supplementation with omega-3 fatty acids
brings about beneficial effects on NAFLD. For example, treatment with docosahexaenoic acid (DHA) plus
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eicosapentaenoic acid (EPA) for 15 -18 months is associated with a decrease in liver fat content; although the
treatment did not improve fibrosis scores [101]. Moreover, a significant number of studies using rodent models of
NAFLD have attributed the beneficial effects of omega-3 fatty acids to mechanisms varying from decreasing
hepatic inflammation [102] and suppression of liver oxidative stress [103] to attenuating the TGF?-Smad3 pathway [104]
.
It should be noted that omega-3 fatty acids are also beneficial to obesity-associated insulin resistance. As such, the
systemic benefits of omega-3 fatty acids are expected to also account for its anti-NAFLD effect.

Antioxidants

During NASH, oxidative stress is viewed as a critical factor underlying the development of hepatocellular damage.
Given this, vitamin E has been used to treat NASH [105-107]. The results consistently support the effects of vitamin E
on reducing ALT and improving fibrosis scores in NASH patients. Based on convincing evidence, vitamin E has been
continuously recommended to treat non-diabetic adults with biopsy-proven NASH [98, 99]. However, vitamin E is not
recommended to treat NASH in diabetic patients, NAFLD without a liver biopsy, NASH cirrhosis, or cryptogenic
cirrhosis [98, 99]

DIET COMPOSITION AND IMPACT BEYOND NUTRIENT RATIOS

While a number of nutrients have been considered to treat obesity-associated metabolic disease, it is worth noting
that diet composition appears to be more important in terms of generating a profound impact on health. As
supported by evidence from studies of either animal or human subjects, differences in diet composition have been
shown to alter biomarkers related to metabolic diseases varying from metabolites to lifespan [108-110]

Low Protein and High Carbohydrate Diet

The benefits of CR have been previously reviewed [5]. Interestingly, recent evidence also suggests that altering diet
composition, but not energy intake, is sufficient enough to modulate lifespan and metabolic aspects. For instance,
upon altering primarily protein and carbohydrate amount, Solon-Biet et al. demonstrated that replacing protein
with carbohydrate is capable of optimizing longevity and health in mice likely by suppressing hepatic mammalian
target of rapamycin (mTOR) [109]. A similar study in mice further indicated that low protein and high carbohydrate
diet under ad libitum conditions generates metabolic benefits comparable with those achieved by CR [110]. To be
noted, these findings were made from mice under CR or ad libitum conditions, which are different from obese or
diseased conditions. Indeed, in terms of managing metabolic diseases, high protein and low carbohydrate (HPLC)
diet, but not low protein high carbohydrate (LPHC) diet, is more beneficial. In support of this, certain studies
involving human subjects with stage 1 hypertension have shown that partial substitution of carbohydrate with
either protein or monounsaturated fat can lower blood pressure, improve lipid levels, and reduce estimated
cardiovascular risk [108]. Thus, the benefits and optimal use of HPLC vs. LPHC diet appear to be dependent on the
presence (or absence) of diseases.

High Protein and Low Carbohydrate Diet

As mentioned above, the HPLC diet is beneficial for subjects with certain health issues associated with metabolic
syndrome. This is true when the ratios of macronutrients are within a relatively balanced range. For example, a
the trial that examined the effect of altering the composition of a DASH diet indicated that each of the three diets in
which saturated fats were replaced by carbohydrate, protein, or mono-unsaturated fatty acids was able to lower
blood pressure compared with baseline [111]. In this study, the composition of carbohydrate: fat: protein is 58: 27:
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15 for the carbohydrate diet, 48: 27: 25 for the protein diet, and 48: 37: 15 for the unsaturated fat diet [111]
.
Similarly, the trial by Furtado et al. demonstrated that the protein diet generates the most favorable benefits on
plasma lipoprotein profile and the lowest plasma total apoB concentrations while reducing plasma levels of
triglycerides [112]. Additional to lowering blood pressure and plasma apoB levels, partially replacing carbohydrate
with unsaturated fat also improves systemic insulin sensitivity [113]. These results not only validate the benefits of
replacing saturated fats with carbohydrate, protein, and/or unsaturated fat, but also demonstrate that the protein
diet appears to be able to maximize benefits relative to the carbohydrate diet and/or unsaturated fat diet. The
underlying mechanisms by which the protein diet is superior are not clear. However, it is likely that the protein diet,
at the given diet composition, does not induce mTOR activation as does the HPLC diet [109]. Also, it cannot be ruled
out that altering diet composition likely generates distinct effects on human subjects versus laboratory mice. The
latter is normally maintained by diet with carbohydrate: fat: protein composition of 62.1: 13.2: 24.6.

Low Carbohydrate, Low Protein, and High-Fat diet

As indicated by many studies, low carbohydrate, low protein, and high-fat diets (ketogenic diet) have been
considered to manage obesity and associated problems including T2DM [114, 115]. This diet is very different from the
aforementioned diets. In the context of weight loss, a ketogenic diet appears to act through preventing an increase
in appetite, and this effect is attributable to ketosis [116]. The ketogenic diet also reduces insulin secretion. This, in turn,
favors whole body fat oxidation and contributes to weight loss [115]. The ketogenic diet also exerts a glucose-lowering
an effect, which is more pronounced than that achieved by a conventional low-calorie diet [114]. Additional to reducing
body weight and lowering glucose levels, the ketogenic diet may also benefit heart health. The latter is attributable to,
at least in part, the effect of the ketogenic diet on improving dyslipidemia and hypertension [115]
.
Although it displays metabolic benefits, the ketogenic diet may also cause some unwanted effects. This, indeed, is well
illustrated by a study in which the effects of standard diet, Western high-fat diet, and ketogenic diet on metabolic
aspects were examined in laboratory mice [117]. In this study, diet compositions were (carbohydrate: fat: protein)
62.1: 13.2: 24.6 for standard diet, 40.7: 40.6: 18.7 for Western diet, and 0.4: 95.1: 4.5 for ketogenic diet. As
expected, Western diet caused the greatest increase in body weight whereas the ketogenic diet caused the lowest.
Also, Western diet, at either 6 weeks or 12-week duration, caused the significant increase in body fat content.
Interestingly, mice on a ketogenic diet consumed more calories compared with mice on a chow diet or Western
diet. Clearly, these results confirmed the benefits of the ketogenic diet on managing body weight. In relation to
Western diet, the ketogenic diet is anti-lipogenic. However, over a time period of 12 weeks, the ketogenic diet caused
hepatic steatosis and inflammation, which is associated with hepatic endoplasmic reticulum stress. A similar study
using mice further indicated that long-term ketogenic diet leads to reduced ?- and ?-cell mass and failed to
produce weight loss[118]. Thus, the long-term ketogenic diet is associated with increased risk for NAFLD and T2DM.
However, neither of the two studies investigated the effect of the ketogenic diet on obese mice. Thus, additional
research is needed to examine whether a ketogenic diet produces unwanted effects in obese mice similar to those in
lean mice. Nonetheless, caution is needed when considering a ketogenic diet as a nutritional intervention,
particularly over long periods of time.

CONCLUSION

Healthy nutrition is effective in terms of managing obesity and related metabolic diseases. While much attention is
paid to the benefits achieved by altering the content of healthy nutrients, it may be time to shift the focus to diet
the composition which is likely of particular importance in managing obesity and other related metabolic diseases.
Consistently, diets with balanced nutrients that are capable of generating metabolic benefits should be considered
as the primary approach for managing obesity and metabolic disease. In addition, when using a dietary approach it
Journal of Diabetes Mellitus and Metabolic Syndrome Zygoscient Research Insights 10
JDMMS Volume-3 | Issue-1 September, 2018
is also important to monitor off-target effects, such as unwanted side effects, while focusing on the target goals of
weight loss and systemic metabolic benefits.

ACKNOWLEDGMENT

This work was supported in part by grants from the National Institutes of Health (R01DK095862 to C.W.) and the
American Diabetes Association (1-17-IBS-145 to C.W.). Also, C.W. is supported by the Hatch Program of the
National Institutes of Food and Agriculture (NIFA).

DECLARATION OF CONFLICTING INTEREST

The authors have no conflicts of interest (political, personal, religious, ideological, academic, intellectual,
commercial or any other) to declare in relation to this manuscript.

REFERENCES

1. Ogden CL CM, Fryar CD, Flegal KM. Prevalence of Obesity Among Adults and Youth: the United States, 2011-
2014. NCHS Data Brief. 2015:1-8.
2. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes
prevalence for 2013 and projections for 2035. Diabetes Research and Clinical Practice. 2014;103:137-49.
3. C, Tjonneland A, Joensen AM, Ruhl CE, Everhart JE. Fatty liver indices in the multiethnic United States
National Health and Nutrition Examination Survey. Alimentary Pharmacology & Therapeutics. 2015;41:65-
76.
4. Jensen MK, Chiuve SE, Rimm EB, Dethlefsen et al. Obesity, behavioral lifestyle factors, and risk of acute
coronary events. Circulation. 2008;117:3062-9.
5. Botchlett R, Woo S-L, Liu M, Pei Y, Guo X, Li H, et al. Nutritional approaches for managing obesity-associated
metabolic diseases. Journal of Endocrinology. 2017;233: R145-R71.
6. Schoeller DA, Buchholz AC. Energetics of obesity and weight control: does diet composition matter? Journal
of the American Dietetic Association. 2005;105:24-8.
7. Mark AL. Dietary therapy for obesity is a failure and pharmacotherapy is the future: a point of view. Clinical
and Experimental Pharmacology and Physiology. 2006;33:857-62.
8. Shadid S, Jensen MD. Effects of pioglitazone versus diet and exercise on metabolic health and fat
distribution in upper body obesity. Diabetes Care. 2003;26:3148-52.
9. Duan SZ, Usher MG, Mortensen RM. PPARs: the vasculature, inflammation, and hypertension. Curr Opin
Nephrol Hypertens. 2009;18:128-33.
10. DeMarco VG, Aroor AR, Sowers JR. The pathophysiology of hypertension in patients with obesity. Nature
Reviews Endocrinology. 2014;10:364-76.
11. Babio N, Toledo E, Estruch R, Ros E, Martínez-González MA, Castañer O, et al. Mediterranean diets and
metabolic syndrome status in the PREDIMED randomized trial. CMAJ. 2014;186: E649-E57.
12. Catenacci VA, Pan Z, Ostendorf D, Brannon S, Gozansky WS, Mattson MP, et al. A randomized pilot study
comparing zero-calorie alternate-day fasting to daily caloric restriction in adults with obesity. Obesity (Silver
Spring, Md). 2016;24:1874-83.
13. Trepanowski JF, Kroeger CM, Barnosky A, et al. Effect of alternate-day fasting on weight loss, weight
maintenance, and cardioprotection among metabolically healthy obese adults: A randomized clinical trial.
JAMA Internal Medicine. 2017;177:930-8.
Journal of Diabetes Mellitus and Metabolic Syndrome Zygoscient Research Insights 11
JDMMS Volume-3 | Issue-1 September, 2018
14. Harvie M, Howell A. Potential Benefits and Harms of Intermittent Energy Restriction and Intermittent
Fasting Amongst Obese, Overweight and Normal Weight Subjects—A Narrative Review of Human and
Animal Evidence. Behavioral Sciences. 2017;7:4.
15. Antoni R, Johnston KL, Collins AL, Robertson MD. Effects of intermittent fasting on glucose and lipid
metabolism. Proceedings of the Nutrition Society. 2017;76:361-8.
16. Park S, Park N-Y, Valacchi G, Lim Y. Calorie Restriction with a High-Fat Diet Effectively Attenuated
Inflammatory Response and Oxidative Stress-Related Markers in Obese Tissues of the High Diet-Fed Rats.
Mediators of Inflammation. 2012;2012:984643.
17. Wasinski F, Bacurau RFP, Moraes MR, Haro AS, Moraes-Vieira PMM, Estrela GR, et al. Exercise and Caloric
Restriction Alter the Immune System of Mice Submitted to a High-Fat Diet. Mediators of Inflammation.
2013;2013:395672.
18. Bankoglu EE, Seyfried F, Rotzinger L, Nordbeck A, Corteville C, Jurowich C, et al. Impact of weight loss
induced by gastric bypass or caloric restriction on oxidative stress and genomic damage in obese Zucker rats.
Free Radical Biology and Medicine. 2016;94:208-17.
19. Imayama I, Ulrich CM, Alfano CM, Wang C, Xiao L, Wener MH, et al. Effects of a caloric restriction weight
loss diet and exercise on inflammatory biomarkers in overweight/obese postmenopausal women: a
randomized controlled trial. Cancer Research. 2012;72:2314-26.
20. Giordani I, Malandrucco I, Donno S, Picconi F, Di Giacinto P, Di Flaviani A, et al. Acute caloric restriction
improves glomerular filtration rate in patients with morbid obesity and types 2 diabetes. Diabetes &
Metabolism. 2014;40:158-60.
21. He F, Zuo L, Ward E, Arciero PJ. Serum Polychlorinated Biphenyls Increase and Oxidative Stress Decrease
with a Protein-Pacing Caloric Restriction Diet in Obese Men and Women. International Journal of
Environmental Research and Public Health. 2017;14:59.
22. Botchlett R, Li H, Guo X, Qi T, Zhao J, Zheng J, et al. Glucose and palmitate differentially regulate
PFKFB3/iPFK2 and inflammatory responses in mouse intestinal epithelial cells. Sci Rep. 2016;6:28963.
23. Guo T, Woo S-L, Guo X, Li H, Zheng J, Botchlett R, et al. Berberine ameliorates hepatic steatosis and
suppresses liver and adipose tissue inflammation in mice with diet-induced obesity. Sci Rep. 2016;6:22612.
24. Tang Y, Purkayastha S, Cai D. Hypothalamic Micro-inflammation: A Common Basis of Metabolic Syndrome
and Aging. Trends in neurosciences. 2015;38:36-44.
25. Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, et al. Saturated Fatty Acids Produce an
Inflammatory Response Predominantly through the Activation of TLR4 Signaling in Hypothalamus:
Implications for the Pathogenesis of Obesity. The Journal of Neuroscience. 2009;29:359.
26. Teng K-T, Chang C-Y, Chang LF, Nesaretnam K. Modulation of obesity-induced inflammation by dietary fats:
mechanisms and clinical evidence. Nutrition Journal. 2014;13:12-.
27. Arkan MC, Hevener AL, Greten FR, Maeda S, Li Z-W, Long JM, et al. IKK-blinks inflammation to obesity-inducedinsulin resistance. Nat Med. 2005;11:191-8.
28. Xu H, Li H, Woo S-L, Kim S-M, Shinde VR, Neuendorff N, et al. Myeloid cell-specific disruption of Period1 and
Period2 exacerbates diet-induced inflammation and insulin resistance. J Biol Chem. 2014;289:16374-88.
29. Frøsig C, Jensen TE, Jeppesen J, Pehmøller C, Treebak JT, Maarbjerg SJ, et al. AMPK and Insulin Action –
Responses to Ageing and High Fat Diet. PLoS ONE. 2013;8:e62338.
30. Hansen PA, Han DH, Marshall BA, Nolte LA, Chen MM, Mueckler M, et al. A High Fat Diet Impairs Stimulation
of Glucose Transport in Muscle: FUNCTIONAL EVALUATION OF POTENTIAL MECHANISMS. J Biol Chem.
1998;273:26157-63.
31. Via M. The Malnutrition of Obesity: Micronutrient Deficiencies That Promote Diabetes. ISRN Endocrinology.
2012;2012:103472.
32. García OP, Ronquillo D, Caamaño MDC, Camacho M, Long KZ, Rosado JL. Zinc, vitamin A, and vitamin C
status are associated with leptin concentrations and obesity in Mexican women: results from a cross-sectional
study. Nutrition & Metabolism. 2012;9:59-.
33. Sánchez A, Rojas P, Base-for K, Carrasco F, Inostroza J, Codoceo J, et al. Micronutrient Deficiencies in
Morbidly Obese Women Prior to Bariatric Surgery. Obesity Surgery. 2016;26:361-8.
34. Jeyakumar SM, Vajreswari A. Vitamin A as a key regulator of obesity & its associated disorders: Evidence
from an obese rat model. The Indian Journal of Medical Research. 2015;141:275-84.
35. Palomar X, González-Clemente JM, Blanco-Vaca F, Mauricio D. Role of vitamin D in the pathogenesis of type
2 diabetes mellitus. Diabetes, Obesity, and Metabolism. 2008;10:185-97.
36. Egger G. In Search of a Germ Theory Equivalent for Chronic Disease. Preventing Chronic Disease.
2012;9: E95.
37. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, et al. Local and systemic insulin resistance resulting
from hepatic activation of IKK-b and NF-kB. Nat Med. 2005;11:183-90.
38. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860-7.
39. Foster-Powell K, Holt SHA, Brand-Miller JC. International table of glycemic index and glycemic load values:
2002. The American Journal of Clinical Nutrition. 2002;76:5-56.
40. Domínguez Coello S, Cabrera de León A, Rodríguez Pérez MC, Borges Álamo C, Carrillo Fernández L, Almeida
González D, et al. Association between glycemic index, glycemic load, and fructose with insulin resistance:
the CDC of the Canary Islands study. European Journal of Nutrition. 2010;49:505-12.
41. Argiana V, Kanellos P?, Makrilakis K, Eleftheriadou I, Tsitsinakis G, Kokkinos A, et al. The effect of
consumption of low-glycemic-index and low-glycemic-load desserts on anthropometric parameters and
inflammatory markers in patients with type 2 diabetes mellitus. European Journal of Nutrition.
2015;54:1173-80.
42. Koh GY, Whitley EM, Mancosky K, Loo YT, Grapentine K, Bowers E, et al. Dietary Resistant Starch Prevents
Urinary Excretion of Vitamin D Metabolites and Maintains Circulating 25-Hydroxycholecalciferol
Concentrations in Zucker Diabetic Fatty Rats. The Journal of Nutrition. 2014;144:1667-73.
43. Zhu L, Gu M, Meng X, Cheung SCK, Yu H, Huang J, et al. High-amylose rice improves indices of animal health
in normal and diabetic rats. Plant Biotechnology Journal. 2012;10:353-62.
44. Gao R, Wang Y, Wu Z, Ming J, Zhao G. Interaction of Barley ?-Glucan and Tea Polyphenols on Glucose
Metabolism in Streptozotocin-Induced Diabetic Rats. Journal of Food Science. 2012;77: H128-H34.
45. Rutledge AC, Adeli K. Fructose and the Metabolic Syndrome: Pathophysiology and Molecular Mechanisms.
Nutrition Reviews. 2007;65: S13-S23.
46. Mark G, Pannu V, Shanmugham P, Pancione B, Mascia D, Crosson S, et al. Adiponectin Resistance and
Proinflammatory Changes in the Visceral Adipose Tissue Induced by Fructose Consumption via
Ketohexokinase-Dependent Pathway. Diabetes. 2015;64:508.
47. Moreno JA, Hong E. A single oral dose of fructose induces some features of metabolic syndrome in rats: Role
of oxidative stress. Nutrition, Metabolism and Cardiovascular Diseases. 2013;23:536-42.
48. Domínguez Coello S, Carrillo Fernández L, Gobierno Hernández J, Méndez Abad M, Borges Álamo C, García
Dopico JA, et al. Effectiveness of a low-fructose and/or low-sucrose diet in decreasing insulin resistance
(DISFRUTE study): study protocol for a randomized controlled trial. Trials. 2017;18:369.
49. Post RE, Mainous AG, King DE, Simpson KN. Dietary Fiber for the Treatment of Type 2 Diabetes Mellitus: A
Meta-Analysis. The Journal of the American Board of Family Medicine. 2012;25:16-23.
50. Yu K1 KM, Li WH, Zhang SQ, Fang XC. The impact of soluble dietary fiber on gastric emptying, postprandial
blood glucose and insulin in patients with type 2 diabetes. Asia Pac J Clin Nutr. 2014;23:210-8.
51. Soare A, Khazrai YM, Del Toro R, Roncella E, Fontana L, Fallucca S, et al. The effect of the macrobiotic Ma-Pi
2 diet vs. the recommended diet in the management of type 2 diabetes: the randomized controlled MADIAB
trial. Nutrition & Metabolism. 2014;11:39.
52. Silva FM, Kramer CK, de Almeida JC, Steemburgo T, Gross JL, Azevedo MJ. Fiber intake and glycemic control
in patients with type 2 diabetes mellitus: a systematic review with meta-analysis of randomized controlled
trials. Nutrition Reviews. 2013;71:790-801.
53. Kubo K, Koido A, Kitano M, Yamamoto H, Saito M. Combined Effects of a Dietary Fiber Mixture and Wheat
Albumin in a Rat Model of Type 2 Diabetes Mellitus. Journal of Nutritional Science and Vitaminology.
2016;62:416-24.
54. Adam CL, Thomson LM, Williams PA, Ross AW. Soluble Fermentable Dietary Fibre (Pectin) Decreases Caloric
Intake, Adiposity, and Lipidaemia in High-Fat Diet-Induced Obese Rats. PLoS ONE. 2015;10:e0140392.
55. Finucane OM, Lyons CL, Murphy AM, Reynolds CM, Klinger R, Healy NP, et al. Monounsaturated Fatty Acid–
Enriched High-Fat Diets Impede Adipose NLRP3 Inflammasome–Mediated IL-1? Secretion and Insulin
Resistance Despite Obesity. Diabetes. 2015;64:2116-28.
56. Qin F, Korat AA, Malik V, Hu FB. Metabolic Effects of Monounsaturated Fatty Acid–Enriched Diets
Compared With Carbohydrate or Polyunsaturated Fatty Acid–Enriched Diets in Patients With Type 2
Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Diabetes Care.
2016;39:1448-57.
57. Imamura F, Micha R, Wu JHY, de Oliveira Otto MC, Otite FO, Abioye AI, et al. Effects of Saturated Fat,
Polyunsaturated Fat, Monounsaturated Fat, and Carbohydrate on Glucose-Insulin Homeostasis: A
Systematic Review and Meta-analysis of Randomised Controlled Feeding Trials. PLoS Medicine.
2016;13:e1002087.
58. Michalak A, Morioka P, Fichna J. Polyunsaturated Fatty Acids and Their Derivatives: Therapeutic Value for
Inflammatory, Functional Gastrointestinal Disorders, and Colorectal Cancer. Frontiers in Pharmacology.
2016;7:459.
59. Esposito K, Giugliano D. Mediterranean diet and type 2 diabetes. Diabetes/Metabolism Research and
Reviews. 2014;30:34-40.
60. Belenchia AM, Tosh AK, Hillman LS, Peterson CA. Correcting vitamin D insufficiency improves insulin
sensitivity in obese adolescents: a randomized controlled trial. The American Journal of Clinical Nutrition.
2013;97:774-81.
61. Talaei A, Mohammadi M, Adgi Z. The effect of vitamin D on insulin resistance in patients with type 2 diabetes.
Diabetology & Metabolic Syndrome. 2013;5:8-.
62. Alaei Shahmiri F, Soares MJ, Zhao Y, Sherriff J. High-dose thiamine supplementation improves glucose
tolerance in hyperglycemic individuals: a randomized, double-blind cross-over trial. European Journal of
Nutrition. 2013;52:1821-4.
63. Jayawardena R, Ranasinghe P, Galappatthy P, Malkanthi R, Constantine GR, Katulanda P. Effects of zinc
supplementation on diabetes mellitus: a systematic review and meta-analysis. Diabetology & Metabolic
Syndrome. 2012;4:13-.
64. Asemi Z, Raygan F, Bahmani F, Rezavandi Z, Talari HR, Rafiee M, et al. The effects of vitamin D, K and calcium
co-supplementation on carotid intima-media thickness and metabolic status in overweight type 2 diabetic
patients with CHD. British Journal of Nutrition. 2016;116:286-93.
65. Triunfo S, Lanzone A, Lindqvist PG. Low maternal circulating levels of vitamin D as the potential determinant in
the development of gestational diabetes mellitus. Journal of Endocrinological Investigation. 2017;40:1049-
59.
66. Hunt T, Sassone-Corsi P. Riding Tandem: Circadian Clocks and the Cell Cycle. Cell. 2007;129:461-4.
Journal of Diabetes Mellitus and Metabolic Syndrome Zygoscient Research Insights 14
JDMMS Volume-3 | Issue-1 September, 2018
67. Storch K-F, Lipan O, Leykin I, Viswanathan N, Davis FC, Wong WH, et al. Extensive and divergent circadian
gene expression in liver and heart. Nature. 2002;417:78.
68. Chen L, Zhao J, Tang Q, Li H, Zhang C, Yu R, et al. PFKFB3 control of cancer growth by responding to circadian
clock outputs. Sci Rep. 2016;6:24324.
69. Mesarwi O, Polak J, Jun J, Polotsky VY. Sleep disorders and the development of insulin resistance and
obesity. Endocrinology and metabolism clinics of North America. 2013;42:617-34.
70. Kumar Jha P, Chalet E, Kalsbeek A. Circadian rhythms in glucose and lipid metabolism in nocturnal and
diurnal mammals. Molecular and Cellular Endocrinology. 2015;418:74-88.
71. Garaulet M, Gómez-Abellán P, Alburquerque-Béjar JJ, Lee Y-C, Ordovás JM, Scheer FAJL. The timing of food
intake predicts weight loss effectiveness. International journal of obesity (2005). 2013;37:604-11.
72. Saydah S, Bullard KM, Chen Y, Ali MK, Gregg EW, Geiss L, et al. Trends in Cardiovascular Disease Risk Factors
by Obesity Level in Adults in the United States, NHANES 1999-2010. Obesity (Silver Spring, Md).
2014;22:1888-95.
73. Reho John J, Rahmouni K. Oxidative and inflammatory signals in obesity-associated vascular abnormalities.
Clinical Science. 2017;131:1689.
74. He FJ, MacGregor GA. Salt reduction lowers cardiovascular risk: a meta-analysis of outcome trials. The Lancet.
2011;378:380-2.
75. Hall ME, do Carmo JM, da Silva AA, Juncos LA, Wang Z, Hall JE. Obesity, hypertension, and chronic kidney
disease. International Journal of Nephrology and Renovascular Disease. 2014;7:75-88.
76. Grimes CA, Bolhuis DP, He FJ, Nowson CA. Dietary sodium intake and overweight and obesity in children and
adults: a protocol for a systematic review and meta-analysis. Systematic Reviews. 2016;5:7.
77. Jarl J, Tolentino JC, James K, Clark MJ, Ryan M. Supporting cardiovascular risk reduction in overweight and
obese hypertensive patients through DASH diet and lifestyle education by primary care nurse practitioners.
Journal of the American Association of Nurse Practitioners. 2014;26:498-503.
78. Ma Y, He FJ, MacGregor GA. High salt intake: an independent risk factor for obesity? Hypertension.
2015;66:843.
79. Kirwan JP, Malin SK, Scelsi AR, Kullman EL, Navaneethan SD, Pagadala MR, et al. A Whole-Grain Diet Reduces
Cardiovascular Risk Factors in Overweight and Obese Adults: A Randomized Controlled Trial. The Journal of
Nutrition. 2016;146:2244-51.
80. Aune D, Keum N, Giovannucci E, Fadnes LT, Boffetta P, Greenwood DC, et al. Whole grain consumption and
risk of cardiovascular disease, cancer, and all-cause and cause-specific mortality: a systematic review and
dose-response meta-analysis of prospective studies. The BMJ. 2016;353:i2716.
81. Tonstad S, Malik N, Haddad E. A high-fibre bean-rich diet versus a low-carbohydrate diet for obesity. Journal
of Human Nutrition and Dietetics. 2014;27:109-16.
82. Whelton SP. Effect of dietary fiber intake on blood pressure: a meta-analysis of randomized, controlled
clinical trials. 2005.
83. Streppel MT, Arends LR, van ’t Veer P, Grobbee DE, Geleijnse JM. Dietary fiber and blood pressure: A meta-analysis
of randomized placebo-controlled trials. Arch Intern Med. 2005;165:150-6.
84. Obarzanek E SF, Vollmer WM, Bray GA, Miller ER 3rd, Lin PH, Karanja NM, Most-Windhauser MM, Moore TJ,
Swain JF, Bales CW, Proschan MA, Group. DR. Effects on blood lipids of a blood pressure-lowering diet: the
Dietary Approaches to Stop Hypertension (DASH) Trial. The American Journal of Clinical Nutrition.
2001;74:80-9.
85. Azadbakht L, Mirmiran P, Esmaillzadeh A, Azizi T, Azizi F. Beneficial Effects of a Dietary Approaches to Stop
Hypertension Eating Plan on Features of the Metabolic Syndrome. Diabetes Care. 2005;28:2823.
86. Adrogué HJ, Madias NE. Sodium and Potassium in the Pathogenesis of Hypertension. New England Journal
of Medicine. 2007;356:1966-78.
Journal of Diabetes Mellitus and Metabolic Syndrome Zygoscient Research Insights 15
JDMMS Volume-3 | Issue-1 September, 2018
87. Pilz S, Tomaschitz A, Ritz E, Pieber TR. Vitamin D status and arterial hypertension: a systematic review.
Nature Reviews Cardiology. 2009;6:621.
88. Vacek JL, Vanga SR, Good M, Lai SM, Lakkireddy D, Howard PA. Vitamin D Deficiency and Supplementation
and Relation to Cardiovascular Health. The American Journal of Cardiology. 2012;109:359-63.
89. Moore-Schiltz L, Albert JM, Singer ME, Swain J, Nock NL. Dietary intake of calcium and magnesium and the
metabolic syndrome in the National Health and Nutrition Examination (NHANES) 2001–2010 data. British
Journal of Nutrition. 2015;114:924-35.
90. Nadler JL, Buchanan T, Natarajan R, Antonipillai I, Bergman R, Rude R. Magnesium deficiency produces
insulin resistance and increased thromboxane synthesis. Hypertension. 1993;21:1024.
91. Paolisso G, Barbagallo M. Hypertension, Diabetes Mellitus, and Insulin Resistance: The Role of Intracellular
Magnesium. American Journal of Hypertension. 1997;10:346-55.
92. Lin P-H, Appel LJ, Funk K, Craddick S, Chen C, Elmer P, et al. The PREMIER Intervention Helps Participants
Follow the Dietary Approaches to Stop Hypertension Dietary Pattern and the Current Dietary Reference
Intakes Recommendations. Journal of the American Dietetic Association. 2007;107:1541-51.
93. Lin PH YW, Svetkey LP, Chuang SY, Chang YC, Wang C, Pan WH. Dietary intakes consistent with the DASH
dietary pattern reduce blood pressure increase with age and risk for stroke in a Chinese population. Asia Pac
J Clin Nutr. 2013;22:482-91.
94. Pilic L, Pedlar CR, Mavrommatis Y. Salt-sensitive hypertension: mechanisms and effects of dietary and other
lifestyle factors. Nutrition Reviews. 2016;74:645-58.
95. Al-Solaiman Y, Jesri A, Mountford WK, Lackland DT, Zhao Y, Egan BM. DASH Lowers Blood Pressure in Obese
Hypertensives Beyond Potassium, Magnesium and Fiber. Journal of human hypertension. 2010;24:237-46.
96. Engeli S, Böhnke J, Gorzelniak K, Janke J, Schelling P, Bader M, et al. Weight Loss and the Renin-AngiotensinAldosterone
System. Hypertension. 2005;45:356.
97. Al-Delaimy WK1 RE, Willett WC, Stampfer MJ, Hu FB. Magnesium intake and risk of coronary heart disease
among men. J Am Coll Nutr. 2004;23:63-70.
98. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of nonalcoholic
fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases,
American College of Gastroenterology, and the American Gastroenterological Association. Hepatology.
2012;55:2005-23.
99. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of
nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver
Diseases. Hepatology. 2018;67:328-57.
100. Parker HM, Johnson NA, Burdon CA, Cohn JS, O’Connor HT, George J. Omega-3 supplementation and nonalcoholic
fatty liver disease: A systematic review and meta-analysis. Journal of Hepatology. 2012;56:944-51.
101. Scorletti E, Bhatia L, McCormick KG, Clough GF, Nash K, Hodson L, et al. Effects of purified eicosapentaenoic
and docosahexaenoic acids in nonalcoholic fatty liver disease: Results from the WELCOME* study.
Hepatology. 2014;60:1211-21.
102. Depner CM, Philbrick KA, Jump DB. Docosahexaenoic Acid Attenuates Hepatic Inflammation, Oxidative
Stress, and Fibrosis without Decreasing Hepatosteatosis in a Ldlr(?/?) Mouse Model of Western diet-induced
Nonalcoholic Steatohepatitis. The Journal of Nutrition. 2013;143:315-23.
103. Jump DB, Depner CM, Tripathy S, Lytle KA. Potential for Dietary ?-3 Fatty Acids to Prevent Nonalcoholic
Fatty Liver Disease and Reduce the Risk of Primary Liver Cancer. Advances in Nutrition. 2015;6:694-702.
104. Lytle KA, Depner CM, Wong CP, Jump DB. Docosahexaenoic acid attenuates Western diet-induced hepatic
fibrosis in Ldlr(?/?) mice by targeting the TGF?-Smad3 pathway. Journal of Lipid Research. 2015;56:1936-46.
105. Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E, and vitamin C treatment improves
fibrosis in patients with nonalcoholic steatohepatitis. American Journal of Gastroenterology. 2003;98:2485.
106. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, et al. Effect of vitamin E or
metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC
randomized controlled trial. JAMA: the journal of the American Medical Association. 2011;305:1659-68.
107. Ji H-F, Sun Y, Shen L. Effect of vitamin E supplementation on aminotransferase levels in patients with NAFLD,
NASH, and CHC: Results from a meta-analysis. Nutrition. 2014;30:986-91.
108. Sacks FM, Carey VJ, Anderson CAM, Miller ER, Copeland T, Charleston J, et al. Effects of High vs Low
Glycemic Index of Dietary Carbohydrate on Cardiovascular Disease Risk Factors and Insulin Sensitivity: The
OmniCarb Randomized Clinical Trial. JAMA. 2014;312:2531-41.
109. Solon-Biet SM, McMahon AC, Ballard JWO, Ruohonen K, Wu LE, Cogger VC, et al. The ratio of
macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed
mice. Cell Metabolism. 2014;19:418-30.
110. Solon-Biet SM, Mitchell SJ, Coogan SCP, Cogger VC, Gokarn R, McMahon AC, et al. Dietary protein to
carbohydrate ratio and caloric restriction: comparing metabolic outcomes in mice. Cell reports.
2015;11:1529-34.
111. Appel LJ, Sacks FM, Carey VJ, et al. Effects of protein, monounsaturated fat, and carbohydrate intake on
blood pressure and serum lipids: Results of the Omni heat randomized trial. JAMA. 2005;294:2455-64.
112. Furtado JD, Campos H, Appel LJ, Miller ER, Laranjo N, Carey VJ, et al. Effect of protein, unsaturated fat, and
carbohydrate intakes on plasma apolipoprotein B and VLDL and LDL containing apolipoprotein C-III: results
from the OmniHeart Trial. The American journal of clinical nutrition. 2008;87:1623-30.
113. Gadgil MD, Appel LJ, Yeung E, Anderson CAM, Sacks FM, Miller ER. The Effects of Carbohydrate, Unsaturated
Fat, and Protein Intake on Measures of Insulin Sensitivity: Results from the OmniHeart Trial. Diabetes Care.
2013;36:1132-7.
114. Hussain TA, Mathew TC, Dashti AA, Asfar S, Al-Zaid N, Dashti HM. Effect of low-calorie versus low-carbohydrate
ketogenic diet in type 2 diabetes. Nutrition.28:1016-21.
115. Abbasi J. Interest in the ketogenic diet grows for weight loss and type 2 diabetes. JAMA. 2018;319:215-7.
116. Gibson AA, Simon RV, Lee CMY, Ayre J, Franklin J, Markovic TP, et al. Do ketogenic diets really suppress
appetite? A systematic review and meta-analysis. Obesity Reviews. 2015;16:64-76.
117. Garbow JR, Doherty JM, Schugar RC, Travers S, Weber ML, Wentz AE, et al. Hepatic steatosis, inflammation,
and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet. American Journal of
Physiology-Gastrointestinal and Liver Physiology. 2011;300: G956-G67.
118. Ellenbroek JH, Dijck Lv, Töns HA, Rabelink TJ, Carlotti F, Ballieux BEPB, et al. Long-term ketogenic diet causes
glucose intolerance and reduced ?- and ?-cell mass but no weight loss in mice. American Journal of
Physiology-Endocrinology and Metabolism. 2014;306: E552-E8.

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