UNDERGRADUATE THESIS

Ketogenic Diets for weight loss: A review on the

physiology, effectiveness, and safety of their use
Presented to the University Honors Program of Colorado State University in
Partial Fulfillment of the Requirements for the University Honors Program

Brooke Danielle Duncan

I have not given, received or used any unauthorized assistance on this

assignment.

Brooke Danielle Duncan___________________________________

 Duncan 1

Abstract

As Americas obesity rate continues to climb the need for an effective weight loss
strategy is imperative. Historically, numerous dietary approaches have been considered, aiming
to reinvent weight control and reduce obesity-related diseases. Recently, a diet called the
ketogenic diet has gained recognition as a potential dietary method capable of generating
substantial weight loss. The diet is dependent on an alternative metabolic pathway, termed
ketosis, which is initiated in times of excessive caloric restriction. Weight lost occurs through the
reduction of carbohydrate intake and an increase in protein and fat intake, relative to total
calories consumed. The approach is considered controversial by many health professionals, due
to health risks associated with elevated levels of dietary fat and protein. This review examines
the physiological basis of diets that activate ketosis in the body, their effectiveness in weight loss
and the general safety of their use.
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Introduction

Distribution of Macronutrients in a Ketogenic Diet

5%
Fat Protein Carbohydrate
21%
74%

Americas incessant obesity epidemic is no secret. Health

professionals and organizations dedicated to disease prevention continue to validate the
hazardous relationship between diet and obesity-related disease. According to the Center for
Disease Control and Prevention (2015) more than 34.9% of Americans are obese.1 As this large
percentage continues to grow, people have become more aware of the need to regain control over
food consumption. A 2010 survey conducted by the Calorie Control Council indicated that nearly
54% of adults were trying to lose weight.2 Although many adults have begun to recognize the
health risks associated with obesity, the struggle to lose weight and maintain weight loss is a
common struggle. That struggle is exacerbated by a wealth of conflicting information regarding
the best dietary strategies for losing weight and reducing disease risk.

Among the numerous diets that have been introduced to the consumer market, ketogenic
diets have received a considerable amount of attention. A ketogenic diet typically consists of a
high fat and very low carbohydrate intake with moderate protein consumption, but often
ketogenic diets are presented as high-protein diets. However, a ketogenic diet is not required to
be high in fat or protein, but is simply defined as consuming a highly reduced amount of
carbohydrate <20-50g/day, and is thus often referred to as a very-low-carbohydrate ketogenic
diet (VLCKD) or a low-carbohydrate ketogenic diet (LCKD) Figure 1: Distribution of
depending on the specific amount of carbohydrate consumed.3 The Macronutrients in a Ketogenic
Diet
reduced carbohydrate consumption depletes the body of glucose
and activates an alternative metabolic pathway, termed ketosis, to provide necessary energy to
the body. Though severely reduced, a small intake of carbohydrate (( 5% of daily kcal
consumption) is allowed. The recommendation for carbohydrate intake for this diet includes: low
glycemic index carbs (typically fruits and vegetables with low carbohydrate amounts),
elimination of sugary and starchy fruits and vegetables, and a total elimination of grain products.
The most important factor regarding carbohydrates is that intake remains low enough to continue
metabolic ketogenesis. Since its introduction several decades ago, there have been many
variations of the ketogenic diet. These variations have primarily been designed for weight loss
and include diets such as: The Atkins Diet, The Zone, and the South Beach Diet. Although low-
carbohydrate regimens are similar to ketogenic diets in respect to their carbohydrate restriction,
their inconsistency or inability to induce metabolic ketosis in the body constitutes their
difference.3,4
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The original ketogenic diet was first introduced in the 1920s as a treatment for childhood
epilepsy. The use of ketogenic diets waned as more modern medications for epilepsy became
available, but in the 1990s there was a resurgence of its popularity as doctors and patients
advocated for its use in patients unresponsive to other commonly prescribed therapies.4 With the
diets revival has come the increasing popularity of its use as a weight loss treatment.

As the ketogenic diet continues to gain popularity, a more comprehensive understanding of

its function and metabolic responses is imperative. This review analyzes the physiological basis
of diets that activate ketosis in the body, their effectiveness in weight loss and the general safety
of their use.

The physiology of a ketogenic diet

In times of adequate food availability, the body prefers glucose as its primary source of
energy. However, when the body enters a prolonged state of fasting, or the amount of
carbohydrate consumed is reduced to less than 20 g per day, the bodys stored glucose becomes
depleted. This depletion, and the accompanying reduction in plasma glucose levels, has several
dangerous consequences given the bodys reliance on glucose as a fuel source. For instance,
glucose is the only macronutrient that can pass through a thin permeable membrane covering the
CNS called the blood brain barrier (BBB), and is thus the major fuel source used by the brain. In
a fed state the brain obtains necessary glucose from nutrients derived from the last meal;
however, any glucose derived from the meal is completely utilized in approximately four hours,
and thereafter the body must start to break down stored glucose (in the form of glycogen) in
order to maintain blood glucose levels and meet the bodys energy needs. After approximately 12
hours from the last meal, stored glycogen levels are depleted, and the brain and other tissues
must quickly find an additional fuel source to meet energy demands.5

At this time, lipids are mobilized and become the major fuel source for the body. During
their catabolism, lipids must undergo an activation process resulting in the production of acetyl-
CoA, which is a critical metabolic intermediate that is produced by all three macronutrients. The
production of this metabolite occurs through a multi-mechanism process. Initially, fatty acids
combine with coenzyme A to produce fatty acyl- CoA through an energy requiring reaction.
Short chains of fatty acyl CoA can passively cross both layers of the mitochondrial matrix. Long
chain fatty acids, however, are unable to cross the inner mitochondrial membrane, and the
molecule carnitine must assist in this transportation. Once across the inner membrane, acyl-CoA
and carnitine are released. Inside the mitochondrial matrix the acyl-CoA enters -oxidation,
which ultimately produces acetyl-CoA and energy in the form of FADH2 and NADH. At this
point, the acetyl CoA has several fates, one of which is to undergo oxidation to meet the bodys
energy needs; this oxidation occurs by way of the tricarboxylic acid (TCA) cycle. The TCA cycle
is the most important pathway in providing energy in the form of adenosine triphosphate (ATP),
and helps produce 90% of the bodys ATP needs.6 All macronutrient metabolites funnel into the
TCA cycle as acetyl-CoA, and through complete oxidation are released as H20, Co2, and energy.
 Duncan 4

The first step of the cycle occurs when acetyl CoA binds with the metabolic intermediate,
oxaloacetate. The most prominent source of oxaloacetate is pyruvate, a derivative of glucose.
The continuous conversion of pyruvate to oxaloacetate is necessary to maintain proper
functioning of the TCA cycle.6 If a fasting state is prolonged, or glucose consumption is severely
decreased, pyruvate becomes limited resulting in diminished oxaloacetate, which in turn reduces
TCA function because of the inability of acetyl CoA to enter the cycle. Under these
circumstances, acetyl CoA begins to accumulate and is driven towards the production of ketones
via the process of ketogenesis, which takes place in the mitochondrial matrix of the liver.7
Ketogenesis consists of a three step mechanism in which the redirected acetyl-CoA ultimately
produces three ketone bodies: acetoacetate, -hydroxybutyrate, and acetone.

During adequate glucose consumption the liver produces small amounts of ketones,
primarily acetoacetate, that are easily metabolized by various tissues of the body.The production
of these ketones occur to satisfy the bodys need for energy post-prandial, during high intensity
exercise, and for overnight fasting. These levels do not exceed 1 mg/dl, and ecessamounts will be
excreted via the renal filtration system, or exhaled by the lungs in untraceable amounts.8
However, when glucose is no longer available the liver will overproduce acetoacetate. This
increase in production triggers acetoacetate to be converted into acetone and -hydroxybutyrate.
There is no biochemical function of acetone; in fact, it is considered a highly-toxic compound
that is unable to be transformed back into acetyl CoA. As a result, the entire ketone must be
emitted from the body via exhalation by the lungs or through the urinary system. Interestingly, as
a volatile compound it emits a fruity fragrance on the breath and urine of people who have an
overproduction of ketones, making it a useful diagnostic tool as it passes through the urinary and
pulmonary systems.5

Due to their biochemical stability, -hydroxybutyrate and acetoacetate are able to be

transported via the blood system to various compatible tissues such as the brain, heart, and
muscle.5 Once in these tissues -hydroxybutyrate must be reconverted back into acetoacetate by
the enzyme -hydroxybutyrate dehydrogenase. The newly formed acetoacetate can then be
converted into two molecules of Acetyl-CoA by the enzymes found only in extra-hepatic tissue
such as Succinyl CoA: 3-ketoacyl CoA transferase; subsequently, allowing oxidization by the
TCA cycle to continue.9 The ability for these ketones to be reconverted to acetyl-CoA in
extrahepatic tissues exposes their vital role as an alternative fuel source.6

Without physiological ketosis the body would be unable to survive without the consistent
intake of carbohydrate. By allowing the body to utilize alternative forms of energy, the ketogenic
diet permits weight loss through a limited intake of carbohydrates. Although the process of
ketogenesis must be present in a ketogenic diet, it is unknown whether or not the physiological
process is the primary instigator of body mass reduction.

The Rationale behind the Ketogenic Diet

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In light of the physiology of ketone production and utilization, the primary rationale
behind a ketogenic diet is simply an increase in satiety and a decrease in appetite. Several studies
have found a correlation between ketogenic diets and participant feedback expressing adequate
fullness and an increased feeling of satiety.10-12 According to a study conducted by Boden MD et
al13 participants on a diet consisting of less than 21g of carbohydrate per day expressed
equivalent feelings of hunger and satiety compared to their normal, non-reduced carbohydrate
diet. This effect is encouraging to many dieters, as one of the most common obstacles of dieting
is overcoming the hunger that accompanies calorie restricting. Research has found that those
who are not affected by the feeling of hunger exhibit an increased ability to maintain or increase
dietary restraint; subsequently, resulting in the reduction of body mass.14 Though the basis of this
affect is not entirely understood there have been several proposals considered.

Some studies have suggested the ratio of macronutrients could contribute to the feeling of
fullness, thus leading to a suppressed appetite. This consideration is based on the generally
recognized concept that high protein diets typically provide higher satiety.15,16 Therefore, a
ketogenic diet with a higher ratio of protein to carbs may potentially provide an increased feeling
of fullness, a decreased intake of energy, and ultimately a reduction in weight. A study analyzing
the effects of meals comprised of various ratios of macronutrients found that higher protein
meals decreased later food consumption, and resulted in decreased hunger rates when compared
to meals comprised of mainly carbohydrate sources.17 Although diets with higher protein intake
may be considered more tolerable, and provide increased level of satiation, it is important to
recognize that not all ketogenic diets involve increased amounts of protein; and thus, protein is
not a conclusive cause of appetite suppression in all ketogenic diets.11

The biochemical influence of ketones has also been considered as a potential attribute to
increased satiety. The inverse relationship between an increase in ketones relative to a decrease
in body mass indicates a potential correlation between the two.9,14 There is a 3-fold increase in
ketone production during physiological ketosis, leading many researchers to believe ketones may
have an important role in the loss of body mass18. Currently, there is an absence in research
analyzing the direct role of ketones in weight loss, but studies conducted on lab-mice suggest
high plasma ketone levels (specifically, 3-betahydroxybuterate) may affect appetite; ultimately,
resulting in weight loss.19 One potential explanation is that during low carbohydrate intake the
brains function is maintained through the provisions of ketones; consequently, as the primary
appetite regulator, the brains response to hunger may be highly influenced.20,21 This explanation
still warrants further research, and future findings will be valuable in determining the required
quantity of ketone production needed to meet the minimal ketosis requirements. As long as
carbohydrate levels are reduced enough to reach a minimal threshold, the ability for people to
lose weight while consuming a diet more closely related to dietary recommendations could be
more easily managed.11 It has also been found that the increase in lipolysis associated with a
ketogenic diet causes an increase in free fatty acids, which may yield a signal to the
hypothalamus leading to an appetite reducing effect.22
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The regulation of plasma glucose may also contribute to increased satiety. One of the
primary characteristics of ketosis is steady plasma glucose levels due to reduced carbohydrate
consumption. Extreme glucose variances are observed with the consumption of carbohydrate
dense meals. Frequently, hypoglycemia occurs after post-prandial peaks in blood glucose. This
extreme rise and fall of glucose levels has been found to have an appetite stimulating effect.23
Low carbohydrate diets, such as the ketogenic diet, reduce extreme dips in glucose levels
resulting in increased satiety.1, 14,18 A study conducted on time-blinded humans analyzed the effect
of blood glucose in relation to appetite after the consumption of high-carbohydrate meals
relative to the consumption of high fat-meals. Results indicated that high-fat meals lead to
decelerated hypoglycemia, and in turn, a decrease in hunger between meals.24Additionally, the
allowed carbohydrate in this diet are low glycemic index and tend to be higher in fiber, which
may also contribute to the lack of dramatic variances in blood glucose levels

Lastly, several studies have suggested that the relationship between ketogenic diets and
concentrations of circulating hormonal regulators may contribute to an increased feeling of
fullness. It is believed that these concentrations fluctuate with the quantity of ketones present.
One study found a continuation of pre-weight-loss levels of Cholecystokinin (CCK) when
circulating -hydroxybutyrate was increased during physiological ketosis. As an appetite-
suppressing hormone, CCK may contribute to the increased satiety and the decreased caloric
consumption observed in ketogenic diets.11,25 Another hormone shown to be affected during
ketogenic diets is the appetite stimulating hormone, ghrelin. According to a study that examined
the effect of ketosis on appetite mediated nutrients and hormones, the alteration of ghrelin levels
were not seen while participants were in a state of ketosis, but instead, levels significantly
increase once ketosis ended. The decrease in appetite observed in those participating in a
ketogenic diet could be associated with decreased levels of ghrelin, thereby, decreasing appetite
stimulation.12

The Effectiveness of a Ketogenic Diet in Weight Loss:

The various theories supporting ketogenic diets as potential weight loss strategies have
brought about numerous studies in hopes of finding an effective answer to obesity. A majority of
studies conducted within the past fifty years have focused on the diets short term effectiveness,
with trials lasting no more than six months.26 A recent growth in the diets popularity has
triggered a parallel increase in long-term studies lasting at least twelve months in length.

Studies conducted on ketogenic diets within a short time-span, no longer than six months,
have reported successful weight loss results.10,18,27-32 A twenty-four week study analyzing low-
carbohydrate ketogenic diets (LCKD) and low-fat diets (LFD) in the treatment of obesity and
hyperlipidemia resulted in LCKD providing greater body weight loss and fat loss when
compared to the LFD. The study reported weight loss results comparable with those attained by
popular FDA approved weight loss medications commonly prescribed by physicians. Though the
study found significantly greater weight loss in those participating in a ketogenic diet, several
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symptomatic adverse effects were reported. The effects reported and their predominance in the
ketogenic diet compared to the low fat diet (respectively) were: headache (68% vs. 35%),
constipation (60% vs. 40%), muscle cramps (35% v. 7%), diarrhea (23% vs. 7%), general
weakness ( 25% vs. 8%), and skin rash (13% vs. 0%).29 A six month study analyzing the effects
between a low-calorie diet (LCD) and a low calorie ketogenic diet, in diabetic and non-diabetic
participants, found that diabetic participants lost 5% more weight on a low-calorie ketogenic diet
when compared to diabetics on an LCD. Non-diabetic participants experienced even greater
weight loss.28

Although there is currently more evidence supporting the beneficial effects of ketogenic
diets in short-term trials, there is growing evidence for their success in long-term applications.
According to a meta-analysis comprised of only studies lasting at least twelve months in length,
eleven out of twelve studies observed a significantly greater amount of weight loss in those
assigned a VLCKD compared to those on a LFD at twelve months, suggesting a potential long
term strategy for weight loss.26 The likelihood that these short-term studies could result in long-
term effectiveness with the addition of extended time is supported by Greenberg et al33 who
found that the adherence and success within the first six months predicted the adherence and
likelihood of accomplishment in long-term weight loss. Moreno et al34 found adherence and
continued weight loss maintenance in participants measured at twelve months after the ketogenic
phase (45 days) ended. Likewise, Bueno et al26 found short-term success in trials measured at six
months, and statistically significant weight loss when measured beyond six months. With this
consideration the initial dramatic weight loss seen in most ketogenic diets may ultimately be
associated with long term success and have a small advantage over other weight loss strategies.
The reason for this adherence is unknown, but it may be due to the reassurance and motivation
that accompanies rapid weight loss that encourages adherence and a transition into a healthier
lifestyle.34

Not all studies have found a positive correlation between weight loss and ketogenic diets.
Numerous reports have suggested little or no variance in weight loss when compared to other
strategies.35,36 A six-week trial conducted by Johnston et al35 comparing the biomarker change
between a ketogenic low-carbohydrate (KLC) diet in comparison to a non-ketogenic low-
carbohydrate (NLC) diet found no significant difference in weight loss or reduction in fat mass.
Contrary to studies supporting ketogenic diets, this study found that of the two diets, participants
were able to adhere to non-ketogenic diet more easily. Potential reasons for ineffectiveness of the
ketogenic diet are currently undetermined.

Some studies have stated that the reduction in weight reported in ketogenic studies is
merely water loss. A study examining the metabolic effects of various low consumption diets
found that although there was initial rapid weight loss seen in the ketogenic diet, the loss was
almost exclusively water loss. This consideration is based off the measured urine samples every
24 hours, and the assumption that any lost weight that was not attributed to protein and fat mass
loss (measured through energy nitrogen balance method) was water loss. 37
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Some researchers believe that some studies may be reporting on a misrepresentation of a

ketogenic diet and could be providing results based on inaccurate definitions. Johnston et al35
proposed that some past research may have inaccurately used the term ketogenic diet, and the
diets researched may or may not have induced a steady physiological ketosis; therefore, some
past studies are unreliable sources to validate the weight loss effects found in ketogenic diets.
There has not been a conclusive verification that either of these prospects determined the results
of all or any past studies analyzing the effect of weight loss in ketogenic diets.

Health considerations:

Numerous trials have exhibited the ketogenic diets ability to support weight loss;
however, there is little known information regarding potential long term health effects. The
limited number of studies, short trail durations, and an inconclusive rationale for the diets
effectiveness leads to concerns regarding potentially harmful effects on the body. These concerns
are especially heightened for those with pre-existing health conditions.

One of the major concerning conditions associated with a ketogenic diet is a negative
fluctuation in blood lipid levels associated with high protein and fat consumption. Increased
amounts of protein and fat may originate from sources high in cholesterol and saturated fat,
which contribute to chronic health problems such as cardiovascular disease and hypertension.
Unfortunately, it is likely that the individuals interested in the weight loss effects of a ketogenic
diet suffer from the characteristics of metabolic syndrome, which include the following signs:
increased triglyceride levels, increased abdominal adiposity, and elevated hypertension. As a
result, the benefits of the ketogenic diet could be outweighed by the accompanied negative
factors that increase the risks of chronic life-threating diseases.15

Although the long-term effects have not been conclusively determined in ketogenic diets,
a negative alteration of bio lipids levels would seem likely for any given duration of time.
However, the opposite has been found in many short term trials. Numerous studies have revealed
that ketogenic diets decrease fasting serum triglycerides (TG) and increase HDL-cholesterol,
both of which are associated with positive cardiovascular outcomes. 8-11, 13, 15 The increase in HDL
due to an increase in fat intake is a highly beneficial outcome, as most methods of weight loss
frequently lead to decreased HDL cholesterol.10 Additionally, some studies have found a decrease
in LDL-cholesterol. 9, 13, 15 The increase in LDL-cholesterol has been more frequently reported,
but these increased levels may have an advantageous trait. Using a lipid sub-fraction technique,
studies have found that LDL levels seen in ketogenic diets not only increase in quantity, but in
particle size as well. Contrary to the negative implications of increased LDL levels, an increase
in LDL particle size is positively associated with a decrease in cardiovascular disease in
comparison to small dense LDL particles.11 Further research is warranted regarding the
advantageous effects of the ketogenic diet on bio-lipid levels. Individuals diagnosed with
medical illness, in particular cardiovascular disease (CVD) or coronary artery disease (CAD),
 Duncan 9

should discuss the use of a ketogenic diet with their physician and frequently monitor cholesterol
levels.

An equally important concern is the influential effects of ketogenic diets on serum insulin
and glucose levels. Several studies observing the effect of VLCKD on biochemical levels
reported decreased fasting glucose levels.8,9,38 Additionally, there have been some reports of
decreased insulin resistance and increased insulin sensitivity.8 Not all studies have found positive
correlations between ketogenic diets and glucose management. Numerous in-vivo studies have
observed contradicting results. According to a study conducted by Jornayvaz et al,39 mice who
were fed a high-fat ketogenic diet showed increased hepatic insulin resistance and an
accumulation of hepatic diacylglycerides, leading to altered insulin signaling.40 According to
Westman et al,32 the positive effects on glucose levels observed in research trials have prompted
suggestion to utilize LCKD as a tactic to treat insulin resistance. The strategy would be based on
the concept that reduced dietary glucose may treat insulin-resistant tissue through diminished
glucose availability, rather than approaching insulin resistance through the increase of insulin
output and tissue sensitivity.1

Another condition of importance is renal health. The ketogenic diet may lead to an
increased risk of kidney stone and gallstone formation, which is often associated with calorie
restricting diets., 15, 32,34,41, This effect could be due to hypocitraturia. Citrate is responsible for
calcium complexation, which in turn inhibits the formation of stones formed from calcium
deposits. Calorie restrictions that directly affect the consumption of carbohydrate can cause
citrate levels to become depleted. This is because citrate is derived from the metabolism of
carbohydrate that ultimately provides the three bicarbonates that form citrate. When these levels
become depleted citrate is reabsorbed in the proximal tubules of the kidneys, in order to provide
adequate amounts of bicarbonate to buffer blood pH as it rises with ketosis. Unfortunately, this
reabsorption leads to hypocitraturia, and in turn there is an increase of stone production.42
Furthermore, an increase in dietary protein may increase the bodys protein turnover rate, leading
to increased levels of creatinine and protein that must be eliminated through the renal filtration
system. An excessive increase in glomerulus function may ultimately result in
glomerulosclerosis and decreased renal function.35

Some short term effects have been frequently reported with ketogenic diets. These
symptomatic effects are often mild and transitory and include: asthenia, orthostasis headaches,
constipation, diarrhea, muscle cramps, nausea, hyper-uricemia, and skin rash.29,32,34 Moreno et al34
suggested ample fluid intake, consumption of allowed amount of vegetables, bouillon, and
multivitamins to reduce these adverse symptoms associated with a ketogenic diet. Studies have
indicated that these effects last only a few weeks, and very few participants attribute the
termination of the diet to these effects.

Conclusion: The application of a ketogenic diet

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The true success of a diet is measured by the ability for an individual to adhere to the diet
resulting in continued or maintained weight loss. Though there is strong evidence that a
ketogenic diet may provide weight loss results, the likelihood of long-term adherence wavers.
According to Wing and O Hill43, the definition of successful long term weight loss is
intentionally losing a least ten percent of initial weight and maintaining that weight loss for at
least a year. This, however, is not the case for many popular weight loss strategies. As a result,
people often find themselves being affected by yo-yo dieting. Long-term weight loss is not
exclusively determined by a particular diet, but is influenced by the relationship between
personal factors and the requirements and expectations of that diet. Important factors that affect
successful long-term weight loss include: occupation, gender, age, behavioral and psychological
capacities, and the degree to which a person is overweight.44These factors play an extensive role
in the ability for an individual to adhere to a ketogenic diet. Additionally, the restrictive nature of
a ketogenic diet often makes long-term adherence unsustainable for some, explaining why many
ketogenic diets are most successful when followed for short time spans.11 Additionally, the large
diet alterations can impose on a persons daily routine, causing feelings of unnecessary
impracticality.26

The most important consideration when choosing to begin a diet should be to determine if
its an appropriate fit relative to the health of the person. Studies have suggested that the
ketogenic diet may provide weight loss benefits, but the numerous health uncertainties of this
diet cant be ignored. Ultimately, the decision is based on the level of comfort and confidence of
the individual considering the diet. Still, there are certain individuals who should refrain from
this diet, or greatly consider the potentially negative consequences. These individuals include
those who have been diagnosed with: reduced renal function, cardiovascular disease, congestive
heart failure, hypertension, decreased liver function, metabolic syndrome, and diabetes mellitus.
This list is not conclusive, as the use of the ketogenic diet has not been excessively studied in
order to determine all areas of concern. Until further research is completed on the long-term
health effects of the ketogenic diet, individuals should discuss the use of a ketogenic diet for
weight loss with a health care professional to determine if its an appropriate weight loss strategy.
 Duncan 11

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