The Ketogenic Diet

Abstract

The ketogenic diet (KD), a well-established treatment for childhood epilepsy, is gradually gaining acceptance as a therapeutic modality for obesity and type 2 diabetes. The perception of ketone bodies as an unhealthy or “sinful” entity has led to concerns and doubts regarding the efficacy and safety of KD in physicians. This article describes the mechanism of action of KD and shares a pragmatic approach to its usage. It highlights the importance of predietary counseling, screening for indications/contraindications, and clinico-nutritional monitoring during therapy. Robust indications for KD are mentioned, to help place KD’s utility in the management of obesity and type 2 diabetes.

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TOUCH MEDICAL MEDIA
62
Editorial Diabetes
Print Publication Date: November 19, 2018
The Ketogenic Diet
Sanjay Kalra,1 Rajiv Singla,2 Rahul Rosha,3 Munish Dhawan,4 Deepak Khandelwal,5 and Bharti Kalra6
1. Department of Endocrinology, Bharti Hospital, Karnal, India; 2. Department of Endocrinology, Kalpavriksh Healthcare, New Delhi, India;
3. Department of Nutrition, Novique Healthcare, Pune, India; 4. Department of Pediatrics, Miri Piri Hospital, Shahabad, India; 5. Department of
Endocrinology, Maharaja Agrasen Hospital, New Delhi, India; 6. Department of Gynecology, Bharti Hospital, Karnal, India
The ketogenic diet (KD), a well-established treatment for childhood epilepsy, is gradually gaining acceptance as a therapeutic modality for
obesity and type 2 diabetes. The perception of ketone bodies as an unhealthy or “sinful” entity has led to concerns and doubts regarding
the efficacy and safety of KD in physicians. This article describes the mechanism of action of KD and shares a pragmatic approach to its
usage. It highlights the importance of predietary counseling, screening for indications/contraindications, and clinico-nutritional monitoring during
therapy. Robust indications for KD are mentioned, to help place KD’s utility in the management of obesity and type 2 diabetes.
Keywords
Atkin’s diet, low calorie diet, medical
nutrition therapy, obesity, physiological
ketosis, preketogenic diet counseling, type 2
diabetes, very low calorie diet, weight loss
Disclosures: Sanjay Kalra, Rajiv Singla, Rahul Rosha,
Munish Dhawan, Deepak Khandelwal, and Bharti Kalra have
no conicts of interests to declare in relation to this article.
Review Process: This article is a short opinion piece and
has not been submitted to external peer reviewers,
but was reviewed for accuracy by the editorial board
before publication.
Authorship: All named authors meet the criteria of
the International Committee of Medical Journal Editors
for authorship for this manuscript, take responsibility
for the integrity of the work as a whole and have
given nal approval for the version to be published.
Open Access: This article is published under the Creative
Commons Attribution Noncommercial License, which
permits any non-commercial use, distribution, adaptation
and reproduction provided the original author(s) and
source are given appropriate credit. © The Authors 2018.
Received: July 30, 2018
Accepted: October 10, 2018
Citation: US Endocrinology. 2018;14(2):62–4
Corresponding Author: Sanjay Kalra, Department
of Endocrinology, Bharti Hospital, Kunjpura Road,
Karnal, 132001 India. E: brideknl@gmail.com
Support: No funding was received in
the publication of this article.
Ketogenic diet (KD) is defined as a high-fat, low-carbohydrate diet, with adequate protein content,
which makes the body utilize fat, rather than carbohydrate, as a preferred energy substrate. In a
carbohydrate-replete person, this substrate is converted to glucose, which is used as a fuel by all
organs, including the brain. In carbohydrate depletion, ketogenesis is activated in the liver, which
breaks fat into fatty acids and ketone bodies. These ketone bodies are able to cross the blood–brain
barrier and provide energy to the brain. Ketones can also be utilized by other organ systems as an
efficient energy source.
Development
The term ‘ketogenic diet’ was first used by Russel Wilder in 1923 to describe a high-fat,
low-carbohydrate diet that produced ketonemia. He used it as an alternative to fasting (then in vogue
as a therapeutic option) for the management of epilepsy.1
Various forms of KD are now used in clinical practice. The amount of carbohydrates permitted
varies from 20 to 50g/day. This depends upon personal metabolic and weight loss goals, upon
the planned duration of KD, and upon individual health status. The classic therapeutic KD, initially
created for the management of childhood seizures, has a 4:1 ratio of fats to combined protein and
carbohydrates. A medium-chain triglyceride (MCT) variant (the MCT KD) utilized to more ketogenic
MCT (present in coconut oil) to provide half of all consumed calories. The Atkins diet—popular in
lay literature—and the low glycemic index diet are less restrictive variants of KD. Fluid restriction
is not advocated in modern KD, due to the risk of constipation and nephrolithiasis. Vegetarian and
vegan KD are also available.2
Clinical approach
KD is a therapeutic intervention for diabetes and obesity.3,4 Though nonpharmacological in nature, it
has a well-delineated multifactorial mechanism of action (see Table 1). Thus, it should be approached
as a therapeutic intervention, rather than a universal suggestion. KD stands apart from other
weight-lowering options in certain ways. Most drugs that increase energy expenditure also increase
food intake, and thus create a net effect of weight maintenance, rather than loss.5 Drugs that reduce
food intake, such as phentermine, liraglutide, phentermine/topiramate, and buproion/naltrexone,
do not reduce energy expenditure. Maintenance of a lowered body weight leads to compensatory
changes in energy expenditure, which limit the potential for change. These compensatory changes
may account for the poor long-term efficacy of treatments for obesity.6
The efficacy, safety, and tolerability of KD has been studied in preclinical and clinical settings,
including randomized controlled trials. The limitations of KD, such as contraindications, limitations
of sustainability, issues in adherence, and possible adverse events, are known as well (see Tables 2
and 3). In all these matters, KD appears similar to drug therapy and should be studied as such.
DOI: https://doi.org/10.17925/USE.2018.14.2.62

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The Ketogenic Diet
US ENDOCRINOLOGY
Biochemistry
The absence of adequate dietary carbohydrates leads to a drastic reduction
in insulin levels, which leads to reduced lipogenesis and increased lipolysis,
both of which reduce fat accumulation. Continued carbohydrate starvation
leads to the inability of usual metabolic pathways (the Krebs cycle) to
provide adequate glucose supply to the central nervous system (CNS).7
To maintain CNS health, the liver kick-starts a process of ketogenesis,
producing acetoacetate, which gets converted to β-hydroxybutyrate, the
predominant circulating ketone body. High levels of acetoacetate cannot
be metabolized fast enough by the skeletal muscles and myocardium.
Hence both acetoacetate and β-hydroxy butyrate rise in the circulation,
leading to ketonemia and ketonuria. Excretion of acetone, a volatile ketone
body, through the lungs, causes the sickly-sweet odor of ketosis. Once
ketone bodies achieve a blood concentration similar to that of glucose
(4mmol/l; 80 mg% glucose), they can be transported preferentially, across
the blood brain barrier, into the brain. Here, they are a more efficient
source of energy.8
Mechanism of action
KD acts by inducing a state of physiological ketosis. This is achieved by
consuming minimal carbohydrates, thus creating a state of carbohydrate
starvation. As carbohydrate substrate is minimized, the insulin requirement
comes down. This leads to resolution of insulin resistance and reduction
in insulin secretion, with a concomitant fall in glucagon production (the
islet de-stress hypothesis) (personal communication). Caloric and nutrient
intake is maintained through fats and protein. Fats are preferentially utilized
to produce energy for the body and are burnt up.
KD’s weight reduction is thought to be mediated by a reduction in hunger
(general and protein specific) and an increase in energy expenditure
(resting and postprandial).9,10 Lipogenesis is reduced; lipolysis increased.
Gluconeogenesis, which occurs in KD, has an increased metabolic cost and
leads to use of body fat stores11,12 (see Table 1). KD-induced weight loss is
accompanied by a mitigation in increase of circulating ghrelin. This helps
avoid hunger and cravings and contribute to maintenance of weight loss.13
Pre-intervention assessment
KD must be prescribed and monitored by qualified health care professionals,
who are experienced in KD use.14,15,16 Coordinated team work, between an
endocrinologist, nutritionist, psychologist, and an exercise physiologist,
Table 1: Mechanisms of weight loss/metabolic modulation
with ketogenic diet
• Increase in energy expenditure
• Increased sympathetic activity due to FGF21
• Postprandial thermogenesis
❍ 20–30% of protein’s usable energy is needed for metabolism/storage, as
opposed to 5% of carbohydrate
❍ Resting metabolism
• Reduction in appetite
• Protein-specific appetite suppression
❍ Protein leverage hypothesis (virtuous cycle of protein/calorie intake)
• Nonspecific appetite suppression
❍ Reduction in ghrelin
❍ Increase in GLP1
❍ Increase in peptide YY
• Directly due to beta hydroxyl butyrate
• Due to excessive water drinking, mediated by FGF21
• Change in lipid metabolism
• Reduction in lipogenesis
• Increase in lipolysis
• Greater metabolic efficiency in fat consumption
• Islet distress hypothesis
• Reduction in load on both beta and alpha cell
• Reduction in both insulin and glucagon secretion
• Enhancement of mood
• Increase in will power
• Increase in adherence
FGF21 = fibroblast growth factor 21; GLP1 = GLP glucagon like peptide 1.
Table 2: Advantages and limitations of ketogenic diet
Advantages
• Psychosocial
• A form of lifestyle modification
• Encourages self-discipline, self-care and self-management
• Prevents “medicalization” of lifestyle disorders
• Biomedical
• Reduces pharmaceutical burden
• Provides comprehensive metabolic control
• Offers pleiotropic nonmetabolic benefits
Limitations
• Psychosocial
• Difficult to adhere to
• Requires family and social support
• Extremely prone to hearsay
• Biomedical
• May not be suitable for all persons—can be associated with side effects
(usually transient/self-limiting)
• Very long-term effects are not known
• Not a balanced diet
Caveats
• Requires a team of health care professionals, including a nutritionist,
endocrinologist, psychologist and an exercise physiologist
• Should be treated like any pharmacological intervention, with pre-prescription
assessment and counseling, and monitoring during use
• Micronutrient supplementation may be required
Table 3: Indications and contraindications of ketogenic diet
Contraindications for ketogenic diet
• Specific age group/life stages
• Frail elderly people (however KD can be used in the healthy obese elderly)
• Children and adolescents
• Antenatal and lactating women
• Persons at risk of ketoacidosis
• Insulin deficiency
❍ Type 1 diabetes
❍ Type 2 diabetes with inadequate insulin supplementation
• Dehydration
• Past history of ketoacidosis
• Persons with symptomatic or complicated diabetes
• Catabolic/cachexic state
• Osmotic symptoms
• Acute medical or surgical comorbidity
Robust indications for ketogenic diet
• Lack of efficacy of conventional lifestyle modification and/or pharmacological
therapy
• Lack of tolerance of conventional therapy, e.g. weight gain
• ‘High turnover’ metabolism individuals with high levels of caloric intake, physical
activity and/or drug–dose requirement
KD = ketogenic diet.

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is required to achieve optimal results. The principles, expected efficacy
and possible side effects17 must be understood. A biopsychosocial
assessment and counseling are mandatory for every patient. Indications and
contraindications of KD must be assessed prior to start. Ample information
must be shared with patients, so that they have a fair idea of what to expect
on a KD (see Table 2).8,15 This discussion should cover both expected benefits
and risks, as well as responsibilities of the patient and her/his family. KD
should be started only in motivated patients. Clarity regarding the purpose
and aim of KD, and its expected duration, must be achieved by shared and
informed decision making and must be documented.
Robust indications
The contraindications and indication for following KD are listed in Table 3.18
Though evidence is tempting19 one cannot propagate KD as a primordial
or primary preventive therapy. However, KD is certainly recommended for
secondary prevention in persons with obesity or type 2 diabetes who do
not respond to conventional dietary and pharmacological measures for
weight loss, hunger control, or glycemic management.
Monitoring
Once KD has been instituted, regular clinical and biochemical monitoring,
are required. This should be coupled with medical and psychological
support as when necessary. The frequency and intensity of monitoring and
support may decrease as the patient gains confidence and takes charge of
her/his diet, lifestyle, and health.2 Troubleshooting may be required when
sudden changes in lifestyle and health status are anticipated, suspected,
or experienced. These may include conditions such as travelling, festivals
and fasts, acute undercurrent illness, and planned or emergency surgery.
At times, temporary discontinuation of KD may be necessary till an acute
episode of illness is resolved.
Persons on glucose-lowering, antihypertensive, or lipid-lowering therapy
may need change in dosage and/or in therapeutic strategies.20 The first few
weeks of ketoadaptation may be accompanied by fluctuations in glycemia
and blood pressure, which should be preempted and managed as required.
Ketoversion (shift from nonketonuria to ketonuria) may be associated with
transient rise in blood pressure.
Side effects
The side effects of KD include those directly related to KD, such as
transient ketoflu, and those related to weight loss in general. Shifting to
KD involves a brief (days to weeks) period of keto-adaptation, during which
the body transitions from carbohydrate- to fat-based energy utilization.17
This period may be marked by ‘ketoflu’, with symptoms such as fatigue,
lethargy, and headache. We have noted that the phase of ketoversion (shift
from aketonuria to ketonuria) may not necessarily overlap the duration of
ketoadaptation, which is marked by ketoflu (personal observation).
Adverse events, in the short term, include constipation, low-grade acidosis,
hypoglycemia, and dyslipidemia.15,17,21 Constipation can be prevented by
adequate fluid intake while dyslipidemia should prompt a shift to a less KD, with
a lower fat:carbohydrate/protein ratio. Hypoglycemia should be anticipated
and prevented by proactive down titration of glucose-lowering medication. A
similar strategy should be employed with antihypertensive therapy.
Dehydration and dyselectrolytemia are other side effects of KD that must
be prevented and managed. These can result in muscle cramps and
arrhythmias.17,21 Supplementation with electrolytes, including magnesium,
and multivitamins, helps minimize these adverse events. KD has neurotropic
effects, which are utilized for management of childhood seizures.1,2 These
neurotropic effects may manifest during the initial days of KD as insomnia,
restless legs syndrome, and altered mood, including hypomania (personal
observation). Empathic explanation regarding the benign and self-limiting
nature of these symptoms is helpful.
Long-term complications include growth retardation in children,
hyperuricemia, kidney stones, and osteoporosis.21 Multivitamins, potassium
citrate supplements, calcium/vitamin D supplements, and adequate
hydration help in preventing these side effects. Rapid weight loss may be
associated with formation of gallstones: this is possible with KD as well.
Duration of ketogenic diet
There is no consensus regarding the optimal duration of KD for management
of obesity or diabetes.22 This decision must be individualized, based upon
therapeutic goals, health status, and ability/willingness of the patient to
conform to the suggested therapeutic diet. Well-conducted studies report
safety over 2 years of use,23 though the diet can be continued for longer to
take advantage of its metabolic benefits.
Conclusion
The review provides an overview of KD as a therapeutic approach in
the management of obesity and diabetes. It discusses the definition
and rationale of KD, its indications and contraindications, and the need
for detailed preprescription screening and counseling. The advantages
and limitations of KD are highlighted, as are its side effects. The KD is a
therapeutic option that may be considered in persons with obesity and
diabetes, under supervision of a qualified and experienced team of nutrition
and endocrine professionals.
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