Post-Graduate Institute of Agriculture- University of Peradeniya

M.Sc. Food & Nutrition

Seminar FT 5199

KETOGENIC DIET: THE NEW DIET FAD FOR WEIGHT LOSS

Raaidah Wahab

ID: 19412- CMB

August 08, 2020.

Words: 3487 without references

No. of References: 16

I declare that the attached work is entirely my own and that all sources have been acknowledged.
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ABSTRACT

The goal of this paper is to review current literature on the Ketogenic diet in the context of this
diet becoming the new “fad” for weight loss and weight management. It will cover the
mechanism of ketogenesis, nutritional ketosis and the ability to use ketones for fuel. It will also
review and compare different variations of the ketogenic diet (high protein ketogenic diet,
Spanish ketogenic Mediterranean diet) and its effectiveness for weight loss vs. other
conventional diets like the high-carbohydrate and low-fat diet. This review will also discuss the
effect of the ketogenic diet on satiety/hunger, and current findings of its role in certain chronic
diseases such as Diabetes Meletus (DM) and Coronary vascular disease (CVD).
This article will further examine the limitations and side effects of the ketogenic diet and draw a
final conclusion on the efficacy of the ketogenic diet for weight loss and weight management.

Keywords: Ketone bodies, Nutritional Ketosis, Ketogenic diet (KD), Very low carbohydrate
ketogenic diet (VLCKD), Low fat diet (LFD)

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INTRODUCTION

The prevalence of overweight and obesity has increased steadily over the past few years,
with the global obesity rate almost tripled since 1975.1 WHO defines, in adults, being overweight
is a BMI equal or greater than 25 and obesity is a BMI equal or great than 30.1 The importance of
weight loss through diet has become a topic of great popularity with new ‘fad’ diets surfacing
constantly.2.3 Diet is the cornerstone of any lifestyle and the main focus when it comes to weight
loss and weight management. The most common strategy of a dietary plan is one that restricts
energy in the form of fat, and based on this, several dietary strategies have been proposed; with a
high-carbohydrate low-fat diet being the most conventional form of diet therapy used.2 But
according to some studies these high-carbohydrate low-fat diets yield only modest weight losses
and suffer low long-term compliance issues because the majority of obese individuals who use
this diet therapy have adherence issues and in general it is found that they gravitate towards
highly processed food containing simple sugars and more refined carbohydrates, which worsens
their weight problems and causes weight gain.3 As a consequence, interest in the ketogenic diet
for weight loss has become popular due to the potential mechanisms of ketones for promoting
weight loss, appetite suppression, early satiety and its preferential loss of fat mass.3

The History of the ketogenic diet

Original research into the ketogenic diet began in the early 1900s as a way to manage epilepsy
and minimize seizure activity. Paoli et al.4 explain that by inducing ketosis, patients had a
reduction in the severity of seizure activity and improvements in cognitive function, highlighting
the capacity for ketones to be a fuel source to the brain. Recent research has also provided
evidence for the therapeutic potential of ketogenic diets in many conditions such as diabetes,
PCOS, CVD and metabolic syndrome.4

Mechanism of ketones
When blood glucose and liver glycogen stores are depleted (in situations such as periods of
fasting, absence of adequate carbohydrate intake, intense exercise and starvation) hormonal
activation of lipolysis and ketogenesis occurs. This is mediated by epinephrine and glucagon and
opposed by insulin. With minimal dietary carbohydrate, insulin requirement is low and glucagon

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increases. In addition to stimulating glycogenolysis in the liver, glucagon also stimulates

lipolysis (via lipase hormone) to release fatty acids from adipose tissue. These fatty acids
undergo beta-oxidation in hepatic mitochondria to produce acetyl-CoA for the generation of
ketone bodies such as acetoacetate (AcAc), beta-hydroxybutyrate (ß-OHB) and acetone. Beta-
hydroxybutyrate (ß-OHB) is the predominant circulating ketone body. High levels of AcAc
cannot be metabolized fast enough by the skeletal muscles and myocardium, therefore both
AcAc and ß-OHB rise in the circulation leading to ketonemia and ketonuria. Once the ketone
bodies achieve a blood concentration similar to that of glucose (4mmol/l), they can be
transported across blood brain barrier into the brain.5 In addition to forming ketones, fatty acids
can be converted to acetyl-CoA that enters the citric acid cycle and undergo oxidative
phosphorylation for ATP generation. Extra-hepatic tissues are able to undergo ketolysis and
convert ketones back to acetyl-CoA which again can be used for ATP generation. Therefore,
ketosis results in a shift from an insulin-mediated glucose dependent state to an increased ability
to use dietary fat and adipose stores (fatty acids and ketones) for fuel. This process provides an
alternative fuel source for almost every cell in the body and a shift in metabolism to induce a
state of “nutritional ketosis”.6

Nutritional ketosis, Keto-adaptation and metabolic shift; ketones as an alternate energy

source
Nutritional Ketosis is defined as the intentional restriction of dietary carbohydrate intake to
accelerate the production of ketones and induce a metabolic effect that stabilizes blood sugar,
minimizes insulin requirement which leads to a resolution of the effects of long standing insulin
resistance and a reduction in insulin secretion.7,8 Gershuni et al.7 describe the hallmark of
nutritional ketosis as blood ketone levels of 0.5 to 3mg/dL. This is not the same as the
pathophysiologic state of diabetic ketoacidosis (DKA) where the range of ketones is 5-10-fold
greater than the levels during nutritional ketosis. Also, in nutritional ketosis, the body is able to
maintain normal blood glucose levels and maintain a normal pH, in contrast to the extremely
high blood glucose levels and acidic pH in DKA.
After a period of many weeks, once the body is adapted and accustomed to using to ketone
bodies for fuel, “keto- adaptation occurs”.7 This signifies a metabolic shift, that, as an alternate to

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glucose metabolism, the body can metabolically flex into a state of ketosis, depending on fat-
derived ketones produced in the liver to provide fuel.
“Substrate metabolism in the normal body is flexible. Our bodies have evolved to utilize
different fuel sources depending on their availability.” As explained by Dr. Randle in the Lancet
in 1963.7,8

Ketogenic diet & variations of the diet

Hartman & Vining9 describe a well formulated ketogenic diet that is high in fat content, with a
low amount of carbohydrate (20-<50d/day), and adequate protein content (1-1.5g/kg/day). The
typical ratio of fats to carbohydrates and protein (in term of grams) is 3:1 or 4:1. The quality of
the fats used in the ketogenic diet has been the subject of study. The classical ketogenic diet used
for epilepsy patients uses long-chain triglycerides (LCT). Medium-chain triglycerides (MCT) are
more ketogenic than LCTs, as octanoic and decanoic acids are more easily transported into the
cell (Huttenlocher, 1976). Since it is more ketogenic, the MCT ketogenic diet (MCT-KD) allows
for a lower overall fat content and subsequent greater inclusion of protein and carbohydrate in
the daily intake (Sinha and Kossoff, 2005). Clinically, there does not appear to be a difference in
efficacy between the MCT and the LCT diets (Huttenlocher et al., 1971; Schwartz et al., 1989).
Patients on the MCT diet are more likely to experience abdominal bloating and diarrhea than
those on the LCT diet, which is believed by some to be less palatable than the MCT diet. Patients
on the LCT diet are more prone to constipation than those consuming an MCT diet. As the
medium-chain triglycerides (MCT) are more ketogenic, the MCT-KD (with MCT present in
coconut oil making up half of all consumed calories), has now become more widely popular in
weight loss therapy. The Atkins diet and the low glycemic index diet (Low GI diet) are less
restrictive variants of KD. Vegetarian and vegan KD are also available.5,9

Weight Loss & the ketogenic diet: Evidence-based research

The two main questions that are raised here are:
a) Do Ketogenic diets work? And how does it compare to other diet therapies?
b) Is there successful long-term weight loss & weight management?

a) Do Ketogenic Diets Work?

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Bueno et al.10 carried out a systematic review with meta-analyses of 13 randomized controlled
trials (RCT) with a total of 1577 individuals. They evaluated all 13 RCTs to determine whether
overweight and obese individuals assigned to a very low carbohydrate ketogenic diet (VLCKD)
achieve greater weight loss and manage cardiovascular risk factors more effectively than those
assigned to a low fat diet (LFD) over a long term period of 12 months.10 Individuals over 18
years of age were assigned to either a LFD ( an energy restricted diet with <30% kcal from fat)
or a VLCKD ( <50g/day or 10% of energy from carbohydrates) and followed up for 12 months.
All participants had a BMI of >27.5 kg/m2. There were no exclusions based on sex, race or co-
morbidities. The exclusion criteria were (i) studies with a concomitant pharmacological
intervention and (ii) duplicate publications of the included trials.
In all 13 studies, the individuals that were assigned a VLCKD achieved greater weight loss when
compared to those on LFD (WMD-0.91kg (95% CI -1.65, -0.17) kg, P= 0.02; I2 = 0%, P= 0.47).
This result was consistent across all subgroup analyses. Not only did it show great reductions in
body weight in subjects on VLCKD, it also showed reductions in TAG (triglyceride), and
diastolic blood pressure (DBP). They also showed a greater increase in LDL-C and HDL-C
levels over a follow-up period of 12 months, compared to subjects on LFD.10

The ketogenic diet also has an effect on hunger and improves satiety which leads to weight loss
and the ability to maintain it. Johnstone et al.11 carried out a study in obese men feeding ad
libitum to determine whether the ketotic state is a major factor in the reduced voluntary calorie
intake (and thus weight loss) associated with a low carbohydrate diet. This study also aimed to
compare the hunger, appetite and weight loss responses to a high-protein low-carbohydrate
ketogenic diet (LCKD) vs. a high-protein medium-carbohydrate non-ketogenic (MC) diet. It is
important to note that all meals within both diets had a fixed energy density of 5.5MJ/kg and
equal protein content (as protein has been identified as a more satiating macronutrient; this was
used to evaluate the impact of ketogenesis on diets with equal protein content).Twenty obese
men (out of which 3 pulled out for personal reasons), 20-65 years old, with a BMI of >30 kg/m2
were selected randomly and after confirmation of normal blood biochemistry, were started on
LCKD & MC diets. This protocol was for 65 days with 5 stages, out of which, the subjects
consumed LCKD, ad libitum, during the 2nd stage & then switched to LC diet during the 4th stage
or vice versa (each stage for a period of 4 weeks). During the 1st, 3rd and 5th stages, subjects were

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fed with a fixed mandatory maintenance diet that was calculated to meet their energy
requirements, and each of these stages lasted for 3 days. The 3-day maintenance diet was
designed to (i) neutralize the ketogenic state and replenish liver glycogen stores (ii) to return
hunger to baseline levels before ad libitum feeding period began. It was found that weight loss
during the 4-week period was significantly (P=0.0006) greater with LCKD than with MC diet
(6.34 ± 2.24 and 4.35 ± 2.61 kg respectively). It was also found that there was a significantly
greater weight loss during week 1 of the LCKD than during week 1 of the MC diet. Analysis also
showed that there was greater loss of fat mass (1.05kg; P=0.083) and free fat mass (0.94kg;
P=0.054) with LCKD than with MD diet. In the determination of hunger and satiety; it was
observed that subjects felt significantly (P=0.014) less hungry while following the LCKD diet
than the MC nonketogenic diet. The average daily hunger score for each diet showed that
subjects on LCKD had less hunger and less desire to eat than those on MC non ketogenic diet.
Hunger predicts a failure to comply with a calorie-restricted regimen; and therefore it is said that
the “holy grail” for dieters is improved satiety that leaves the dieter feeling less hungry and
therefore will, as a result, consume less whilst eating less in order to lose weight.11

The Atkins diet is a less restrictive form of the ketogenic diet and is a very popular diet fad that
has made the “Atkins diet” a household name. The Atkins diet was first published in 1973 and
again in 1992 and 2002. The main difference between the conventional ketogenic diet and Atkins
diet is that; the Atkins diet is started off with a low carbohydrate amount (<20mg/day) and then
gradually increased once the desired weight is achieved, whereas the ketogenic diet continues
with very low carbohydrate amount (<20-50mg/day) allowing the body to stay in ketosis and
burn ketones for energy. To evaluate the efficacy of the Atkin’s diet vs. a low-calorie high-
carbohydrate low-fat (conventional) diet, Foster et al.12 carried out a multicenter RCT in 63 obese
men and evaluated weight loss at 3 months, 6 months and 12 months. 33 subjects were assigned
to the low carbohydrate (<20 mg/day) high-fat high-protein diet group, with the diet program
following “Dr. Atkins’ New Diet Revolution”13 and the carbohydrate amount was gradually
increased until a stable desired boy weight was achieved. 30 subjects were assigned to the
conventional high-carbohydrate low-fat low-calorie diet (1200 to 1500 kcal/day for women and
1500-1800 kcal/day for men). In the conventional diet, approximately 60% of calories was from
carbohydrates, 25% from fat and 15% from protein. Subjects on the LC diet produced greater

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weight loss than subjects on the conventional diet at 3 months (-6.8 ± 5.0 vs. -2.7 ± 3.7 percent
of body weight) and at 6 months (-7.0 ± 6.5 vs. -3.2 ± 5.6 percent of BW), but the difference at
12 months was not significant (-4.4 ± 6.7 vs. -2.5 ± 6.3 percent of BW).

Another study carried out by Perez-Guisdao et al.14 was used to determine the dietary effects of a
“Spanish Ketogenic Mediterranean Diet” (SKMCD). The name SKMD was given due to the
incorporation of virgin olive oil as the principal source of fat (> 30 ml/day), moderate red wine
intake (200-400 ml/day), green vegetables and salads as the main source of carbohydrates and
fish as the main source of protein. No more than 2 cups of coffee or tea per day and a minimum
of 3 liters of water intake was required. 40 overweight subjects (22 male and 19 female) were
chosen through a database of medical weight loss clinic, whose BMI and age were 36.36 ± 2.22
and 38.48 ± 2.27 respectively. The exclusion criteria were; age, <18 or > 65 years, pregnant or
lactating women, current or past history of gout, under medical treatment for any existing disease
condition, and abnormal renal function. Anthropometric measurements and blood pressure
monitoring was taken at weeks 0, 4, 8 and 12 and blood biochemistry was taken at weeks 0 and
12. Data for final analysis was collected from 31 subjects (9 were not used due to several
reasons). It was found that there was an extremely significant (p<0.0001) reduction is body
weight ( 108.62 kg 94.48 kg), BMI ( 36.46 kg/m2 31.76 kg/m2), SBP( 125.71 mmHg
109.05 mmHg), DBP ( 84.52 mmHg 75.24 mmHg), total cholesterol(208.24 mg/dl 186.62
mg/dl), and glucose(109.81 mg/dl 93.33 mg/dl). There was a reduction in LDL-C and an
increase in HDL-C as well. Therefore, in the absence of calorie restriction, it was found that
SKMD is an effective therapy for weight loss and obesity. Perez-Guisdao et al.14 observe that this
significant weight loss might be due to the fact that there is a synergic effect between the high
protein ketogenic nature of the diet and its richness in MUFA and PUFA. There is no data in this
study regarding the body fat % and lean body mass lost. They hypothesized that low
carbohydrate ketogenic diets are more effective for more selective fat loss and conserving
muscle mass; as subjects showed a physical aspect similar to liposuction.

Therefore, Antonio Paoli3 summarized the hypothesized mechanisms of the ketogenic diet’s
weight loss effects as:

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1) Reduction in appetite due to higher satiety effect of proteins, effects on appetite control
hormones and to a possible direct appetite suppressant action of the ketone bodies.11,15
2) Reduction in lipogenesis and increased lipolysis.
3) Greater metabolic efficiency in consuming fats highlighted by the reduction in the resting
respiratory quotient.
4) Increased metabolic costs of gluconeogenesis and the thermic effect of proteins.

b) Is there a successful long-term weight loss & weight management?

Although there is no universally accepted definition for “successful weight loss maintenance”,
Wing and Hill in 20013 suggested the definition “individuals who have intentionally lost at least
10% of their body weight and kept it off at least one year”.
Therefore, studies indicate that the ketogenic diet demonstrates evidence of being able to
significantly reduce body weight and has been successfully used for treatment of obesity for up
to two years. While results from the ketogenic diet shows greater weight loss results than
conventional low-fat diets in the short-term, from a long-term perspective, the amount of weight
regain, and success of weight maintenance had not been tested and needs further research. Also,
studies have shown that two brief periods of ketogenic diet separated by longer periods of
maintenance of Mediterranean diet led to successful long-term weight loss and improvements in
health risk factors without weight regain effect.3,15

Other Physiologic/ metabolic effects of the ketogenic diet and its positive effects
Effect on lipid profile and CVD:
Conventional belief is that dietary fat consumption was directly related to blood cholesterol and
an increased risk of CVD, thus promoting the “diet-heart hypothesis” which was introduced in
the 1970s.7
However, although there is an increase in saturated fat intake in the ketogenic diet, studies have
shown that improvements in blood lipid profile have been significant. Studies also show a
marked reduction in blood triglyceride levels, significant positive effects on total cholesterol
reduction, increased HDL14 and an increase in the size and volume of LDL-C particles (It is
considered that the smaller LDL particles have a higher atherogenicity and therefore the
ketogenic diet reduces CVD risk).7,9,10,11,12,14

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There is also opposing views that suggest, as concluded by Nurul et al.16 that KD might increase
the risk of a cardiovascular event due to the increased consumption of saturated fat and the
subsequent increase in LDL-C levels. However, further studies are needed to address this issue.

Effect on glycaemic control, insulin sensitivity and diabetes:

Insulin resistance is a complex metabolic state that affects energy utilization and stimulates
‘ectopic’ fat deposition in non-adipose organs, notably skeletal muscle, the heart and the
pancreas.3,7 Therefore, individuals with insulin resistance have an issue with metabolizing dietary
carbohydrate and will divert most of their dietary carbohydrates to the liver where in its
converted to fat.3,7,9,14
Nutritional ketosis reduces insulin levels and therefore suppressing lipogenesis. Several studies
show that a VLCKD reduces serum glucose14, improves overall glycaemic control and even
demonstrates a greater reduction in haemoglobin A1c compared to other diets. 4,6,7,9,10,11,12,14

Renal effect:
Most opponents of the ketogenic diet have also expressed concern over the possible negative
renal effects of the diet. It is thought that the high nitrogen excretion levels during protein
metabolism can cause an increase in glomerular pressure and hyper-filteration.3 However, it is
incorrect to correlate ketogenic diet with high protein intake as conventional ketogenic diets all
have normal protein intake of 1-1.5g/kg/day. 4,6,7,9,10,11,12,14

Limitations and direct side effects of the ketogenic diet

Limitations:
As the ketogenic diet requires compliance to a very strict carbohydrate intake (<20-50mg/day)
adherence to this diet is very difficult especially in countries like Sri Lanka where our main
staple is rice and carbohydrates contribute to >60% of energy in our diet. Most fruits, certain
carbohydrate rich vegetables, all grains, and even milk and certain milk products have to be
excluded when following a strict ketogenic diet therefore, major modification in diet and lifestyle
is required.5 This diet encourages self discipling and self-management and requires family and
social support.

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Side effects:
Direct side effects of KD include transient ‘keto breath’(“fruity breath’ as a result of acetone
being eliminated mainly via respiration in the lungs), ‘ketoflu’ with symptoms of fatigue,
lethargy and heachache.5 Other adverse effects include constipation, low-grade acidosis,
dehydration and serum electrolyte imbalances which are all transient and can be prevented and
managed.5,6,7,9

Contraindications for the ketogenic diet

As categorized by Sanjay et al.5

• 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 for ketoacidosis

§ Insulin deficiency
o Type 1 DM
o Type 2 DM 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

CONCLUSION

Studies and reviews provide evidence that the ketogenic diet shows good efficacy for weight loss
and weight management for up to a certain amount of time (2 years). The transition from
ketogenic diet to a normal diet should be gradual and well controlled.3 The KD can be used as a
successful therapeutic option for obese individuals. Nutritional ketosis, the utilization of ketones
as a fuel source, metabolic shift with high glucagon and low insulin levels are all beneficial when

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it comes to appetite control and as a result successful weight loss and weight management.
Further research is needed to ascertain the long-term practicality of a VLCKD in terms of
adherence and weight regain/maintenance. Also, further studies are required to evaluate the
effect long-term and safety of ketogenic diet on cardiovascular risk.

References

1. Obesity and Overweight Fact Sheet Vol. 2020 (World Health Organization, 1 April 2020)

2. Freedman MR, King J, Kennedy E. Popular diets: a scientific review. Obes Res. 2001;9
Suppl 1:1S-40S. doi:10.1038/oby.2001.113

3. Paoli A. Ketogenic diet for obesity: friend or foe? Int J Environ Res Public Health.
2014;11(2):2092-2107. Published 2014 Feb 19. doi:10.3390/ijerph110202092

4. Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond weight loss: a review of the
therapeutic uses of very-low-carbohydrate (ketogenic) diets [published correction appears in Eur
J Clin Nutr. 2014 May;68(5):641]. Eur J Clin Nutr. 2013;67(8):789-796.
doi:10.1038/ejcn.2013.116

5. Kalra, Sanjay & Singla, Rajiv & Rosha, Rahul & Dhawan, Munish & Khandelwal,
Deepak & Kalra, Bharti. The Ketogenic Diet. US Endocrinology. 2018;14(2). 62.
10.17925/USE.2018.14.2.62.

6. Sumithran P, Proietto J. Ketogenic diets for weight loss: A review of their principles,
safety and efficacy. Obes Res Clin Pract. 2008;2(1):I-II. doi:10.1016/j.orcp.2007.11.003

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7. Gershuni VM, Yan SL, Medici V. Nutritional Ketosis for Weight Management and
Reversal of Metabolic Syndrome. Curr Nutr Rep. 2018;7(3):97-106. doi:10.1007/s13668-018-
0235-0

8. RANDLE PJ, GARLAND PB, HALES CN, NEWSHOLME EA. The glucose fatty-acid
cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet.
1963;1(7285):785-789. doi:10.1016/s0140-6736(63)91500-9

9. Hartman AL, Vining EP. Clinical aspects of the ketogenic diet. Epilepsia. 2007;48(1):31-
42. doi:10.1111/j.1528-1167.2007.00914.x

10. Bueno NB, de Melo IS, de Oliveira SL, da Rocha Ataide T. Very-low-carbohydrate
ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled
trials. Br J Nutr. 2013;110(7):1178-1187. doi:10.1017/S0007114513000548

11. Johnstone AM, Horgan GW, Murison SD, Bremner DM, Lobley GE. Effects of a high-
protein ketogenic diet on hunger, appetite, and weight loss in obese men feeding ad libitum. Am
J Clin Nutr. 2008;87(1):44-55. doi:10.1093/ajcn/87.1.44

12. Foster GD, Wyatt HR, Hill JO, et al. A randomized trial of a low-carbohydrate diet for
obesity. N Engl J Med. 2003;348(21):2082-2090. doi:10.1056/NEJMoa022207

13. Atkins RC. Dr. Atkins’ new diet revolution. Rev. ed. New York; Avon Books. 1998.

14. Pérez-Guisado J, Muñoz-Serrano A, Alonso-Moraga A. Spanish Ketogenic

Mediterranean Diet: a healthy cardiovascular diet for weight loss. Nutr J. 2008;7:30. Published
2008 Oct 26. doi:10.1186/1475-2891-7-30

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15. Paoli A, Bianco A, Grimaldi KA, Lodi A, Bosco G. Long term successful weight loss
with a combination biphasic ketogenic Mediterranean diet and Mediterranean diet maintenance
protocol. Nutrients. 2013;5(12):5205-5217. Published 2013 Dec 18. doi:10.3390/nu5125205

16. Nurul R.M. Manikam, Nico I. Pantoro, Karina Komala, Ayu Diandra. Comparing the
Efficacy of Ketogenic Diet with Low Fat Diet for Weight Loss in Obesity Patients: Evidence-
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