The Evidence for a Ketogenic Diet

PRESENTED BY: MICHELLE LIN, DO; ROMMEL DE VERA, DONOMA SPRING MEETING 2018

MAY 3, 2018

History and origin

u 1920’s Hugh Conklin DO + Faith Healeru Epilepsy caused by intoxication of brain from the intestines

u Fasting/Water Treatment up to 25 days

u Lead to studying of metabolic changes in fasting

u 1921 Mayo Clinicu High fat low carbohydrate diet + adequate protein for growth

u 1938 Rise of phenytoin, ketogenic diet fell out of favor

u 1990’s Ketogenic diet resurgenceu Jim Abrahams “First Do No Harm”

What is A Ketogenic Diet?

u Very low carbohydrate: <20g of carbs/dayu High fat: 70-90% of fat in kcal

u Variability; tailored to patient response and need

u Adequate protein (0.8g/kg/day) 20% of kcalu Variability; tailored to patient response and needs

u Natural calorie restriction due to satietyu Intermittent fasting

The Ketogenic Diet

u Fasting / Starvationu Limited carbohydrate stores

u De novo synthesis, from amino acids and proteins

u Glycerol from Fatty Acids

u Study demonstrating b-Hydroxybutyrate and acetoacetic acid adequate energy sources for CNS'

u No decrease in psychometric testing or EEG changes

The Ketogenic Diet

u Consider effects of b-Hydroxybutyrateu As an energy source and as a substrate

u Consider effects of a reduction in carbohydrates in dietu Carbohydrates as an energy source and as a substrate

u Consider effects of a subsequent reduction in endogenous insulin use

The Ketogenic Diet

u Mitochondriau Mitochondrial health and its ties to healthy agingu ATP: fundamental energy source, majority produced in

mitochondria, ETC

u Most mtROS ocurring due to the mtETCu Near proximity to the mtDNA, leading to higher chances of

dysfunctionu Moderate mtROS will cause adaptive changes to

accommodate oxidative stress, however an excess needs to be avoided

The Ketogenic Diet

u Ketosisu Indirectly promotes Mitohormesis and adaptive

changesL

u Increases Reverse Electron Transport u Source of Acetyle CoA shifts from Glycolysis to Ketosis

and production of b-Hydroxybutyrateu FADH2/NADH ratio doublesu mtROS increases, promoting Mitohormesis and

adaptive changes for increased oxidative stressL

The Ketogenic Diet

u Ketosisu Directly promotes antioxidant effectsu Ketone bodies utilized as an energy source for the

CNSu b-Hydroxybutyrate as a substrate

u Class I and II Histone Deacetylases inhibit FOXO3a and Metallothionein II à results in increased oxidation of proteins and lipids

u This is inhibited with b-Hydroxybutyrate, decreased measure of protein carbonyls and lipid peroxidases in studiesL

The Ketogenic Diet

u Ketosisu Increased fat diet, fatty acid availabilityu F. acids upregulate mitochondrial Uncoupling Proteinsu Function of UCPs includes dissipation of protons in the

mtETC independent of ATP synthase (decreased Reverse Electron Transport)

u Results in lowering excessive mtROSL

The Ketogenic Diet

u Carbohydratesu Decreased amounts result in decreased insulin release

and utilization

u Reduction of carbohydrate intake results in shift towards fatty acid oxidationv

u Lower carbohydrate availability decreases glycogen stores à stimulates AMPK

u AMPK promotes glucose uptake

u Glut 4 receptors downregulate

The Ketogenic Dietu Insulin

u Utilization is decreasedu Downregulating SREBP and

ChREBP, lipogenic genesv

u Decreased hepatic lipogenesisu Inhibits AMPK: decreases

Malonyl-CoA

u Malonyl-CoAv

u Inhibits the rate limiting step in F.A. oxidation

u Prevents carnitine acyl transferase in mitochondria

u This is decreased with decreased insulin demand

Insulin Activity

u Promotes

u GLUT 4 upregulation

u Anabolism

u Glycogen storage

u Protein synthesis

u SREBP1c*

u Inhibits

u Lipolysis

u Gluconeogenesis

u Glycogenolysis

Metabolic Syndromeu NCEP ATP III definition ¡:

u ≥130/85 mmHg or drug treatment for hypertensionu Waist ≥102 cm (men) or ≥88 cm (women)u ≥1.7 mmol/L (150 mg/dL) or drug treatment for

elevated triglyceridesu <1.0 mmol/L (40 mg/dL) (men); <1.3 mmol/L (50

mg/dL) (women) or drug treatment for low HDL-Cu ≥5.6 mmol/L (100 mg/dL) or drug treatment for

elevated blood glucose

Metabolic Syndrome

u Increased weight is a major risk factorz

u 60% of those with Metabolic Syndrome were obese

u 22% overweight

u Insulin resistance, abdominal obesity, elevated BP, elevated Triglycerides, decreased HDLc

u Primary treatment goal: weight loss

Metabolic Syndromeu Metabolic syndrome correlated with high levels of SFAs when

looking at plasma fatty acid compositionÃ

u Production of an inflammatory response¥

u Increased TNF-a, IL-18b, IL-6 expression in the hypothalamus à leptin and insulin resistance

u Higher SFA results in higher CVD incidencev

u Carbohydrate restricted diets reduce demand for insulin, decreasing lipogenesis and improving lipid profilesu Substitution for SFAsu Less inflammatoryu More monounsaturated fatty acids / polyunsaturated fatty acid in the

lipid profileu Increased levels of arachidonate, improved insulin sensitivity, reduction

in pro-inflammatory responsesv

Metabolic Syndrome

u A portion of the Ketogenic Diet includes reduction of carbohydrate intakeu Reduces Insulin utilization and Glucose availability for storage

u Promotes F.A. oxidation

u Reduction in carbohydrates without noticeable effect until reduction to 26% of diet d

u Decrease in triglycerides, ApoB, LDL molecules

u At this level, comparable to weight loss alone

Metabolic Syndrome

u Carb restricted diets compared to Low fat dietsJ

u CRB with x2 amount of weight loss, decreased abdominal fat mass

u Improved glycemic control, FBG decreased by 10% on average

u Presence of serum ketones indicating lipolysisu Reduction of atherogenic dyslipidemia (Triglycerides

decreased by 51% and increase in HDL 13%)

Metabolic Syndrome

u Long term effects of the Ketogenic Diet in obese population

u Factors measured: weight, BMI, Total Cholesterol, LDL, HDL, Triglycerides, FBG, Urea, Creatinine measured at 8, 16, 24 weeks

u Gradual decrease in weight, sustained HDL elevation, LDL decrease V

u No significant long term side-effects up to 2 years noted with dietary implementation

Neurologic Benefits

How the brain benefits

u Acetoacetate à preferred for synthesis of neural lipids

u Increased energy stores, mitochondrial biogenesis, metabolic efficiency by bypassing complex I

u Increased GABA

u Decrease of ROS by inducing glutathione peroxidase activity and increase mitochondrial uncoupling proteins

u Anti-inflammatory effectsu Peroxisome proliferator-activated receptor α inhibits proinflammatory

transcription of nuclear factor –κB and activation protein-1

u Intermittent fasting à ↑ cytokine interferon-γ protects against excitotoxic cell death

u Autophagy

How the brain benefitsu Slows aging

u Mitochondrial density increased

u Reduces oxidative stress

u Prevents Apoptosisu Intracellular calcium buffer, calbindin is increased; prevention of prodeath signal

(clusterin)

u Carbohydrate restriction benefitsu Protective against glutamate-induced and oxidative stress-induced neuronal

death in cell culture

u Induces stress proteins that suppress ROS production

u Stabilize intracellular calcium

u Maintain mitochondrial function

Epilepsy

u Antiepileptic effect associated with increase acetone + acetoacetateu Mechanism unknown

u Glucose/calorie restriction + ↑ FFA activates KATP channels àprotective against metabolic stressors (i.e. hypoxia, ischemia, hypoglycemia) & regulate seizure threshold

u Polyunsaturated Fatty Acids reduce neuronal hyperexcitability, decrease ROS

u Metabolic efficiency: up to 46% increase in mitochondria = Mitochondrial Biogenesis

Epilepsy

u Adult:u Two small case series of adult patients, ketogenic diet and a modified

Atkins diet reduced seizure frequency by 50 % or more in half of patients with drug resistant epilepsy

u Childrenu If on ketogenic diet >1 year at 3-6 year follow up >90% resolution of

intractable epilepsy

u If on ketogenic diet for 6 months or less, 32% had >90% decrease in seizures and 22% were seizure free

u No controls in the study

Ischemic & Traumatic Brain Injury

u Ketogenic diet had up to 58% reduction in cortical contusion volume at 7 days (rat study)

u 48 hr fast in a 4 vessel occlusion for 30 min was protective against neuronal loss in striatum, neocortex, hippocampus (rat)

u Cortical neuron loss prevention in ketogenic diet with insulin-induced hypoglycemia

u Exogenous β-hydroxybuterate reduces brain damage and improve neuronal function in models of brain hypoxia, anoxia, and ischemia

Ischemic & Traumatic Brain Injury

u Glutamate-mediated excitotoxicity à ROS à apoptosis ànecrosisu Acetoacetate attenuation of ROS prevents apoptosis

u Intracellular calcium overloadà apoptosisu Calbindin increased in ketogenic diet which buffers intracellular calcium

u Mitochondrial dysfunctionu Increased intake of β-hydroxybuterate

Parkinson’s Diseaseu Uncontrolled clinical study showed 43% mean reduction in

Unified Parkinson’s Disease Rating Scale (42q on function) after 28 days on ketogenic diet.

u Subjective perception of “moderate to very good” improvement from symptoms

u Increased consumption of essential fatty acids associated with lower risk of developing Parkinson’s disease

u Improved oxidative phosphorylation à enhanced ATP production

u Bypassed complex I derangements

Amyotrophic Lateral Sclerosis

u Mitochondrial dysfunction leads to neuronal cell deathu Ketogenic diet promotes ATP synthesis

u Bypass inhibition of complex I in mitochondrial respiratory chain

u Transgenic mice on ketogenic diet u lost motor function later than controls

u weighed more

u More motor neurons at end of study

u No extension in survival time

Alzheimer’s Disease

u 43 day ketogenic diet resulted in 25% reduction in soluble amyloid β(1-40) & (1-42) but no cognitive improvement in ratsu Protects against amyloid toxicity

u Improved motor function in transgenic mice with Alzheimer'su Exogenous ketone (AC-1202) for 90 days administration show

improvement in ADAS- Cognitive Behavior scores in mild to moderate Alzheimer’s disease patients without APOE4 alleleu Provides alternative, possibly superior fuel source, in the setting of

decreased brain glucose metabolism

Canceru Warburg effect- aerobic glycolysis; Deplete tumor’s metabolic energy

source to fuel activityu Ketogenic diet markedly decrease tumor growth rates (calorie restriction)u Reduction of ROS production in malignant glioma cellsu Reduction of genes encoding signal transduction pathways and growth

factors in glioma growthu Case studies

u Medium Chain Triglyceride diet showed benefit in pediatric patients with advanced malignant astrocytoma

u Elderly female with glioblastoma multiforme concomitantly treated w/ radiotherapy, temozolomide, and a ketogenic diet resulted in undetectable tumor after 2 months

u Improved emotional functioning, less insomnia u Does not apply to all cancers

Other considerations

u Autoimmune Disordersu Gastrointestinal Pathologies

u Migraine

u Psychiatric disordersu Autism

u Mitochondrial disorders (peds)

u Athletic Applications

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Dietdoctor.comKeto/Low carb: What to eathttps://www.dietdoctor.com/low-carb/keto

References

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u Dietdoctor.com