Ketogenic diet in endocrine disorders: Current perspectives.

Ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet that leads to nutritional ketosis, long known for antiepileptic effects and has been used therapeutically to treat refractory epilepsy. This review attempts to summarize the evidence and clinical application of KD in diabetes, obesity, and other endocrine disorders. KD is usually animal protein based. An empiric vegetarian Indian variant of KD has been provided keeping in mind the Indian food habits. KD has beneficial effects on cardiac ischemic preconditioning, improves oxygenation in patients with respiratory failure, improves glycemic control in diabetics, is associated with significant weight loss, and has a beneficial impact on polycystic ovarian syndrome. Multivitamin supplementations are recommended with KD. Recently, ketones are being proposed as super-metabolic fuel; and KD is currently regarded as apt dietary therapy for "diabesity."

Introduction

The ketogenic diet (KD) is described as a high-fat, adequate-protein, and low-carbohydrate diet. With the inadequate availability of carbohydrates, the body burns fats rather than carbohydrates to provide energy. The liver converts fat into fatty acids and produces ketone bodies (KB), which replace glucose as a primary energy source. This dietary accumulation of ketones in blood is also known as nutritional ketosis (NK).[1]

Since the introduction of KD in 1920, research has emerged to understand its mechanisms and uses in various clinical conditions. Because of its pleiotropic effects on central nervous system, cellular metabolism and metabolic pathways, KD has been studied and has shown promising results in variety of neurological disorders, traumatic brain injury, acne, cancers, and metabolic disorders [Table 1].[234567] Recently, ketones have been proposed as super-metabolic fuel because of their various favorable impacts on cellular metabolism in many tissues.

Table 1

Clinical use of the ketogenic diet in various disorders

Endocrine disorders

Diabetes

Obesity

Metabolic syndrome

PCOS

Congenital hyperinsulinism

Nonalcoholic fatty liver disease

Neurological disorders

Intractable epilepsy

Lennox-Gastaut syndrome

Myoclonic-astatic epilepsy

Parkinson's disease

Alzheimer's disease

Amyotrophic lateral sclerosis

Migraine/headache

Narcolepsy

Depression

Autism

Metabolic disorders

Glucose transporter type 1 deficiency

Pyruvate dehydrogenase complex deficiency

Phosphofructokinase deficiency

Others

Trauma and ischemia

Cancer/malignancy

PCOS=Polycystic ovary syndrome

This review is an attempt to summarize the evidence of KD in diabetes, obesity, and other endocrine disorders. We have also focused on application of KD in clinical practice, its benefits, as well as the cautions and contraindications to its use.

Physiology of Ketogenic Diet

Glucose and fatty acids are metabolized to acetyl coenzyme A (CoA) (a product of incomplete breakdown of free fatty acids [FFAs] in the liver) to enter the citric acid cycle (tricarboxylic acid cycle) by condensing with oxaloacetate (pyruvate being precursor). As glycolysis falls to very low levels with KD because of low carbohydrates, oxaloacetate is not available to condense with acetyl-CoA produced by fatty acid metabolism. This leads to shunting of acetyl CoA to ketogenesis and results in accumulation of ketones.[8] KB synthesized in the body are β-hydroxybutyrate (βOHB), acetoacetate, and acetone, which can also cross the blood–brain barrier to provide an alternative source of energy for the brain. Heart, muscle, and renal cortex can easily utilize KB while brain utilizes ketones only in prolonged starvation. Erythrocytes do not utilize ketones as they do not have mitochondria. Liver does not utilize ketones as it does not have the enzyme thiophorase.[9]

Ketone build-up in a particular individual depends on several physiological parameters such as body fat percentage, body mass index (BMI), and resting metabolic rate.[1] The KD should ideally be administered under controlled environment. KD is quite safe as the concentration of ketones in persons on KD is far lower than the concentration seen in diabetic ketoacidosis and is not associated with any changes in blood pH. It must be mentioned here that human nutrition begins with a KD: Colostrum is ketogenic and serves the needs of the neonate completely.[10]

It is proposed that such diet may favor more fat loss with preservation of lean body mass. This effect is partly mediated by reduced plasma insulin levels.[1112] Risk of lean body mass loss and sarcopenia can prevented with judicious supplementation of amino acids and whey protein.[1314] Studies have shown induction of fibroblast growth factor-1 (FGF-1) gene by KD. FGF-1 acts as a metabolic regulator of lipolysis, serum phosphate, active Vitamin D level, and triglyceride clearance in the liver.[1516]

Beneficial Impacts of Ketogenic Diet

KB as “super-fuel” efficiently produce more adenosine triphosphate (ATP) energy than glucose or fatty acids by reducing the mitochondrial nicotinamide adenine dinucleotide couple and oxidizing the coenzyme Q couple. 100 g of acetoacetate is able to generate 9.4 kg ATP and 100 g of 3-hydroxybutyrate yields 10.5 kg ATP while 100 g glucose produces only 8.7 kg ATP. This allows the body to maintain efficient fuel production in the face of calorie loss.[10] KB also decreases free radical damage and enhances antioxidant capacity by activation of NF E2-related factor 2, which upregulates transcription of genes involved in protection against oxidative damage.

Impact on central nervous system

There are studies supporting possible therapeutic utilization of KD in multiple neurological disorders. Potential mechanism could be neuroprotective effect by modulation in cellular energy utilization. NK has shown to improve physical and cognitive performance, improve cerebral function, and prolong survival in anoxic rats and mice. It also improves posttraumatic metabolism in man.[17] KD is considered an established part of an integrative approach, along with drug therapy, in major epilepsy centers worldwide. The bioenergetic transition from glucose to KB can metabolically target brain tumors through integrated anti-inflammatory pathways/mechanisms. Enhanced phagocytic activities of macrophages, antiangiogenic, and pro-apoptotic mechanisms reduce tumor energy metabolism and glycolytic energy required for tumor growth.[18]

Impact on heart

The cardiac muscle is an “omnivore,” which uses diverse substrates as sources of fuel, preferring FFAs, followed by glucose, KB, lactate, pyruvate, glycogen, and amino acids. NK results in shift of myocardial fuel metabolism from fat/glucose oxidation to more energy-efficient fuel KB and improves myocardial work efficiency and function.[10] The failing heart facilitates fuel metabolic shift to KB for oxidative ATP production triggered by reduced capacity for oxidizing fatty acids (the chief fuel for the normal adult mammalian heart). It attenuates free radical induced injury, improves energy reserves of the heart, increases the acetyl-CoA content of the myocardium, and improves the transduction of oxygen consumption into work efficiency at the mitochondrial level in the endangered myocardium and thereby enhancing myocardial metabolism.[1920] Studies have shown that it prevents ischemic tissue damage in animal models undergoing either myocardial infarctions or stroke, leading to dramatically smaller ischemic/necrotic lesion area.[2122] Electron microscopic studies show an increase in the number of mitochondria, tolerance to ischemia, and a faster recovery of cardiac function following reperfusion in rats fed with KD; hence, it is cardioprotective.[23]

Impact on respiratory system

KD decreases the need for glucose synthesis in liver and spares its precursor, muscle-derived amino acids, and diminishes apoptosis in lung cells in shocked rodents. It decreases the death of lung cells induced by hemorrhagic shock. Moreover, it is beneficial in respiratory problems with limited oxygen supply or substrate utilization.[17] It may decrease respiratory exchange ratio, carbon dioxide output, and carbon dioxide end-tidal partial pressure which proves beneficial for patients with increased arterial carbon dioxide partial pressure due to respiratory insufficiency or failure.[24]

Use of Ketogenic Diet

This section describes patient selection, pre-KD counseling and evaluation, implementation of KD, supplementation, follow-up/monitoring, and eventual KD discontinuation.

Patient selection and preketogenic diet assessment

The pre-KD assessment requires detailed history and physical examination, specific laboratory tests, nutritional assessment, and counseling of the patient and family members. Some patients with specific metabolic disorders may have absolute contraindications to start KD. In addition, complicating risk factors (renal stones, severe dyslipidemia, significant liver disease, failure to thrive, severe gastroesophageal reflux, poor oral intake, cardiomyopathy, and chronic metabolic acidosis) may prevent initiation of KD.[25]

Lot of therapeutic medications including many anticonvulsants may have high carbohydrate content and should be switched to lower carbohydrate preparations if option is available. Patients should be started on multivitamins containing adequate doses of essential minerals as well as calcium supplements before initiation of KD.[26]

Application

The planning of KD requires diet instructions to lower the intake of carbohydrates to <20 g/day, increase the intake of fats/oils, and include nutritional supplements to maintain the calorie requirement of the individual. The total amount of calories to be provided for a particular individual is based on anthropometric measurements, prior dietary intake, and physical activity. The various menu options are discussed in Table 2. The diet should be modified if the patient has poor dietary tolerability and frequent gastrointestinal symptoms.[2526272829303132]

Table 2

Sample menu options for ketogenic diet

Vegetarian menu	Nonvegetarian menu
Breakfast	Breakfast
Cheese/paneer pakora  Bullet coffee (coffee/tea mixed with coconut oil, cream and butter)/coffee with cream/coconut milk  Grilled mushrooms with buttered vegetables scrambled tofu  Coconut milk or almond milk	Scrambled whole eggs/hard boiled eggs with mozzarella and salami slices  Bacon wrapped meatloaf  Chicken wings with cheesy cauliflower puree  Ham and cheese omellete  Coconut milk or almond milk
Mid-morning	Mid-morning
Mushroom and onion frittata  Cabbage rolls with coconut  Apple crumb pie with walnut crust cream of tomato soup with stir fried broccoli and cheesy crackers	Pork rinds or chicken cracklings  Hamburger patties with mushroom cream sauce and bacon  Roast chicken (with the skin left on) and parmesan cream sauce  Roast pork belly with cauliflower cheese  Smoked salmon and cream cheese roll-ups
Lunch	Lunch
Spinach pancakes made with flaxseed flour and lots of cheese  Cauliflower curry in coconut milk and coconut oil  Soya nugget curry  Chilli beans with sour cream, cheese and salsa  Tofu puddings with full-fat yoghurt  Simple salad stir fried in butter topped with lots of cheese  Red channa salad with olive oil dressing	Meat pie  Chicken with herb butter chicken and hummus lettuce wraps  Baked fish with butter sauce  Cauliflower, chopped and sauteed in flaxeed or olive oil  Bacon with sugar-free sausage  Tuna salad lettuce leaves  Green salad with egg mayonnaise
Evening	Evening
Vegetable spring rolls wrapped in lettuce with peanut sauce  Pumpkin smoothie with coconut milk  Carrot and cucumber sticks with peanut butter  Cheesy muffins topped with strawberries and blueberries  Green tea/lemon water (without sugar)  Stir fried peanuts	Hamburger patties with creamy tomato sauce  Cheese burger  Poached eggs with spinach and melted cheese  Deep fried chicken wings on a bed of lettuce  Chocolate chip cookie dough  Chicken broth  Herbal tea or coffee with heavy cream without sweetener
Dinner	Dinner
Almond flour and chia seeds pancakes  Baked tofu with cheese and cream  Fried paneer pakora  Stir fried french beans with cheese topping  Cream of mushroom with ghia kofta  Stir fried lady finger with peanuts (Maharashtrian style)  Spinach cooked in milk, cream, and cheese  Stir fried veggies with spices and cream dressing  Cheesy cauliflower curry	Baked salmon with lemon and butter  Garlic chicken sprinkled with cheddar cheese chicken on salad greens with oil and vinegar  Ham and cheese rolled pancakes with cream mayonnaise  Salad greens sprinkled dressed with a tablespoon of full fat dressing and cheese  Shredded cabbage sauted in sesame oil
Dessert	Dessert
Apple and zucchini cake  Poached pears topped with cocoa butters  Soya cheesecake  Chocolate silk pie with almond crust	Chocolate mousse or chocolate truffles  Egg muffin cups

The diet is typically planned to provide 80%-90% of the energy from fat in a ratio of grams of fat to grams of protein plus carbohydrate as ‘‘4:1’’ i.e 4 g of fat to 1 g of protein plus carbohydrate. (For example=A 1500 Kcal diet can comprise 133.5 g fat with 55 g protein + 20 g carbohydrate)

KD involves flexibility to use long-chain triglycerides (LCT) or medium chain triglycerides (MCT). Omega-3 supplementation has its own positive effects.[33] Fat rich diet is prescribed with low-carbohydrate fruits and vegetables in each meal. Home-based diets (with the addition of a liquid fat source, and micronutrients supplementation) as well as commercial formulas (KetoCal, Ross Carbohydrate FreeSoy Formula Base with Iron) may be used.[2526]

Fluid restriction is not required and also individuals may be motivated to continue routine exercises. The carbohydrate-free or minimal carbohydrate-containing multivitamins and multimineral preparations should be administered to prevent nutritional deficiencies. Nutrients significantly required with KD are calcium with Vitamin D, selenium, magnesium, zinc, and phosphorus.[29] Evaluation of the diet should be done periodically to monitor the beneficial effects and associated risks.

Monitoring urine ketones is necessary to ensure that the diet is being managed correctly. It is generally advisable that patients on KD should monitor their serum glucose, albumin, total protein, total cholesterol, triglycerides, and serum creatinine once in every 3 months. Once a year, renal ultrasound, bone density, carnitine, selenium levels, and electrocardiogram are significant with regard to the prevention of long-term effects such as nephrolithiasis, osteoporosis, hyperlipidemia, carnitine deficiency, and cardiomyopathy.

Although very low carbohydrate KD was proved to be safe and effective in morbidly obese patients scheduled for laparoscopic bariatric surgery, there is a scarcity of data on KDs being used for prebariatric surgery management of morbid obesity. Most research support the use of restricted energy diets for preoperative weight loss evidenced to reduce the risk of postoperative complications, reduce liver volume, and fat content in obese patients to improve patient outcome.

Postketogenic diet assessment

The diet can be discontinued abruptly in an emergency but is more often tapered slowly over 2–3 months by gradually lowering the ketogenic ratio from 4:1–3:1–2:1. Calories and fluids are increased ad libitum, and larger amounts of carbohydrate foods and nutritional supplements are reintroduced with loss of urinary ketones.[25]

Evidence of Ketogenic Diet in Endocrine Disorders

The favorable effects of KD on caloric intake, body weight, lipid parameters, glycemic indices, and insulin sensitivity render it a therapeutic option in metabolic syndrome, obesity, and obese type 2 diabetes. Various hormones such as insulin, glucagon, cortisol, catecholamines, and growth hormone also significantly affect ketone-body metabolism.[34]

Diabetes

A variety of dietary modifications has been studied to improve glycemic control such as low calorie diet, low-fat diet, low-protein diet, high-protein diet, and low glycemic load diet.[35] Since the dietary carbohydrate is the major macronutrient that raises the blood glucose levels, researchers have aimed to reduce the amount of carbohydrate in the meals to study the effects on glycemic load, antidiabetic regimen, and drug dosage among diabetic people. Dietary carbohydrate restriction reliably reduces high blood glucose, does not require weight loss (although is still best for weight loss), and leads to the reduction or elimination of medication.[2836] Studies of KD looking into benefit on glycemic indices and other metabolic parameters in patients with type 2 diabetes are summarized in Table 3.[2837383940]

Table 3

Studies of ketogenic diet in type 2 diabetes

Year and site of the study	Sample description	Intervention and duration	Study parameters	Results
Westman et al. 2008 USA	84 obese and type 2 diabetic community volunteers 18-65 years with BMI: 27-50 kg/m2	Randomly assigned LCKD and LGID Nutritional supplements and exercise recommended 24 weeks 49 (58.3%) completed study	HbA1c, fasting glucose, fasting insulin, weight loss, cholesterol	HbA1c, fasting glucose, fasting insulin, weight loss improved in both groups Significantly greater improvement among LCKD group in HbA1c (P=0.03) Body weight (P=0.008) HDL cholesterol (P<0.001) Reduced anti-diabetic drugs to 95.2% in LCKD group versus 62% in LGID group (P<0.01)
Dashti et al. 2007	64 healthy obese diabetic subjects	Study parameters determined before and at 8, 16, 24, 48 and 58 weeks after KD being administered	Body weight, BMI, blood glucose level, total cholesterol, LDL-cholesterol, triglycerides and urea	Significant reduction in body weight, BMI, blood glucose level, total cholesterol, LDL-cholesterol, triglycerides and urea from week 1-56 (P<0.0001) HDL-cholesterol increased significantly (P<0.0001) More significant results in subjects with hyperglycemia
Boden et al. 2005 University hospital	10 obese patients with type 2 DM	Inpatient comparison of 2 diets Usual diets for 7 days followed by KD for 14 days	Weight loss, 24-h blood glucose profiles, insulin sensitivity HbA1c, triglyceride and cholesterol levels	KD resulted in significant Spontaneous reduction in energy intake Weight loss Improved 24-h blood glucose profiles, insulin sensitivity, and HbA1c Decreased plasma triglyceride and cholesterol levels
Yancy et al. 2005 Durham VAMC clinic, USA	21 type 2 diabetic overweight participants 3 white, 8 African-American Mean±SD age 56.0±7.9 years BMI 42.2±5.8 kg/m2	LCKD counseling Medication adjustment 16 weeks	HbA1c, fasting serum triglyceride, drug dosage and waist measurement	HbA1c decreased by 16% Mean body weight decreased by 6.6% Fasting serum triglyceride decreased 42% Reduction in antihyperglycemic medications Positive effect on waist measurement
Gumbiner et al. 1996	13 obese patients with type 2 diabetes	7 patients treated with high-ketogenic VLED for 3 weeks 6 patients treated with low-ketogenic VLED for 3 weeks Patients crossed over and treated with alternate diet for another 3 weeks	Fasting and OGTT plasma insulin, C-peptide concentrations and HGO	Fasting and OGTT glycemia were lower during treatment with high-ketogenic VLED (P<0.05) Strong correlation between basal HGO and fasting plasma ketone bodies (P<0.05) No significant difference in weight loss, fasting and OGTT plasma insulin and C-peptide concentrations

VLED=Very low-energy diets, HGO=Hepatic glucose output, LCKD=Low carbohydrate ketogenic diet, KD=Ketogenic diet, LGID=Low-glycemic, reduced calorie diet, HDL=High-density lipoprotein, OGTT=Oral glucose tolerance test, VAMC=Veterans Affairs Medical Center, BMI=Body mass index, SD=Standard deviation, DM=Diabetes mellitus, LDL=Low-density lipoprotein, HbA1c=Glycosylated hemoglobin

The analysis of the KD map from the diabetes perspective identifies strong relationship between the insulin resistance pathway and KD. It highlights that elements of lipid metabolism may facilitate proper cellular localization of glucose transporters, recycling, and KB can alleviate certain inflammatory processes by blocking specific cytokines.[2836] With the increased plasma ketones, there is decreased plasma glucose, decreased cerebral metabolic rate of glucose (CMRglc), and increased cerebral metabolic rate of acetoacetate (CMRa).[41] In obese patients with type 2 DM, high-ketogenic VLED treatment lowers fasting, OGTT glycemia, and improves glycemic control.[4042] High-protein, low-carbohydrate KD reduces hunger, and lowers food intake.[43] KD are significantly beneficial in improve glycemic control (glycated hemoglobin), eliminate/reduce diabetic medications, increase high-density lipoprotein-cholesterol (HDL-C), and cause weight loss in overweight and obese individuals with type 2 diabetes over a 24-week period compared to low glycemic index diet.[3944] Moreover, limiting both protein and carbohydrates in KD reverses diabetic nephropathy.[45] However, such diet may not benefit in preventing the decline in β-cell function and may not improve the insulin secretory function or β-cell mass.[46]

Sodium glucose cotransporter 2 (SGLT2) inhibitors, especially empagliflozin and canagliflozin, has been shown to have cardiovascular benefits in patients with type 2 diabetes. SGLT 2 inhibitors also exhibit pro-ketogenic effects by mediating a metabolic switch from glucose to lipid utilization. As a class they increase the production of KB in the liver, by increasing glucagon levels and reducing the insulin: glucagon ratio. One of the postulated mechanisms behind their exceptional cardiovascular and renal benefits in patients with type 2 diabetes is likely because of mild ketosis with these drugs, resulting in improvement of peripheral insulin sensitivity, reducing hyperinsulinemic stress, and inherent insulin secretion with lowered requirement for external insulin. Mild ketosis also has beneficial effects on the myocardial metabolism, for the failing diabetic heart. However, patients with type 2 diabetes who are already receiving SGLT2 inhibitors, have significantly higher risk of developing euglycemic diabetic ketoacidosis if put on low carbohydrate KD; hence, KD should not be prescribed to patients with type 2 diabetes on SGLT2 inhibitors.[10]

Among patients with diabetes, carbohydrate restriction may increase the risk of hypoglycemia, especially in patients treated with insulin and insulin secretagogues (sulfonylureas, incretin-based therapies). Hence, modification in drug dosage is recommended before initiating such diet depending on glycemic control and class of antidiabetes medication therapy.[47]

Obesity

In obese patients, KD treatment had shown greater weight loss as compared to other balanced diets. This comparative greater weight loss makes it an alternative tool against obesity.[484950] The possible mechanisms for higher weight loss may be controlled hunger due to higher satiety effect of proteins, direct appetite suppressant action of KB, and changes in circulating the level of several hormones such as ghrelin and leptin which controls appetite.[5152] Other mechanisms proposed are reduced lipogenesis, increased lipolysis, reduction in resting respiratory quotient, increased metabolic costs of gluconeogenesis, and the thermic effect of proteins.[5354]

A study conducted by Castaldo et al. in 2016 shows that short-term ketogenic EN followed by an almost carbohydrate-free oral nutrition may effectively reduce body weight, waist circumference, blood pressure, and insulin resistance in clinically healthy morbidly obese adults (BMI ≥45 kg/m2).[55] The diet significantly decreases cholesterol, blood glucose, body weight, BMI, and thereby reducing risk factors for various chronic diseases among obese hypercholesterolemic patients (BMI >35 kg/m2) without any side effects in long term.[56]

Metabolic syndrome

Insulin resistance in peripheral tissues manifests as hyperglycemia, hyperinsulinemia, abnormal fatty acid metabolism and atherogenic dyslipidemia in MetS, and cardiovascular diseases. Dietary carbohydrate modulates lipolysis, assembly, and processing of lipoprotein.[4757] KD in long term (12 months or more) results in decreased body weight, triglycerides, and diastolic blood pressure whereas it causes increased HDL-C and low-density lipoprotein-C as compared to low fat diet.[5358]

The elevated plasma βOHB correlates with decreased plasma cholesterol, mevalonate (a liver cholesterol synthesis biomarker) and lower levels of the mevalonate precursors acetoacetyl-CoA and 3-hydroxy-3-methylglutaryl-CoA in liver. Increased βOHB promotes a nonatherogenic lipid profile, improves cardiovascular risk parameters, lowers blood pressure, diminishes resistance to insulin, without any adverse impact on renal or liver functions.[5960]

Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is associated with obesity, hyperinsulinemia, insulin resistance, reproductive and metabolic implications. The metabolic and endocrine effects of low carbohydrate KD are evidenced by improvements in body weight, free testosterone percentage, luteinizing hormone/follicle-stimulating hormone ratio, and fasting insulin levels. It leads to decrease in androgen secretion and increase in sex-hormone binding globulin, improves insulin sensitivity and thereby renormalizes endocrine functions. Such dietary intervention and lifestyle management has beneficial effects in the treatment of PCOS patients affected with obesity and type 2 diabetes.[616263] It has also been shown to improve depressive symptoms, psychological disturbances, and health-related quality of life in these patients.[64]

The detailed discussion of KD in nonendocrine disorders is outside the scope of this review. The possible disease specific modifying effects of KD in nonendocrine disorders are summarized in Table 4.[365666768697071]

Table 4

Disease specific modifying effects of ketogenic diet in nonendocrine disorders

Disease condition	Beneficial effects
Metabolic conditions	Beneficial effects in GLUT1 deficiency syndrome and PDHC deficiency Improved exercise tolerance and decreased baseline creatinine kinase levels in McArdle disease Provides energy substrates in glycolysis for the conversion of fructose-6-phosphate to fructose-1, 6-bisphosphate during PFK deficiency Improved muscle strength and developmental milestones among patients with mutations in the muscle isoform of PFK, myopathy and arthrogryposis
Epilepsy	Provides alternative substrates for CNS and TCA cycle Enhanced mitochondrial function and GABA synthesis in brain Ketone metabolism generates protons and pH-lowering metabolic products, associated with its anticonvulsant activity Increased levels of acetone might activate K2P channels to hyperpolarize neurons and limit neuronal excitability Stabilizes neuronal membrane potential, produces change in neuromodulators, modifies neural circuits and normalizes neuronal function Inhibition of glutamatergic excitatory synaptic transmission improvements in infantile spasms Management of tuberous sclerosis complex with the improved seizure control
Neurodegenerative disorders  Parkinson's disease  Alzheimer disease	May regulate a family of proteins (sirtuins), which play a major role in mediating “anti-aging” effects of calorie restriction May regulate a master energy-sensing protein in the cell, 5’-AMP-activated kinase having downstream effectors that may possess neuroprotective properties Beneficial impact on glucose use and brain-derived neurotrophic factor May protect against the deposition of amyloid and allow cells to overcome amyloid-induced PDH dysfunction
Amyotrophic lateral sclerosis	Significantly more preservation of motor neurons in mice May provide substrate to bypass impaired or poorly functioning complex I However, did not significantly prolong survival among such mice
Migraine, headache, narcolepsy	Limited studies Mechanism of benefit not clear
Depression	Similar behavioral changes as antidepressants
Trauma	Ketones may be a preferred fuel in the injured brain hence protective against trauma and ischemia Significant decrease in cortical contusion area in rats
Ischemia	Increased number of mitochondria in cardiac muscle leads to improved capacity to generate energy with cardioprotective effect in face of ischemic insult
Cancer/malignancy	Brian tumor cells are less able than healthy brain tissue to use ketones as an energy source May restrict glucose required to produce components critical to proliferative cell growth in tumor cells Provide additional energy substrate to normal healthy tissues at risk of cell death

KD=Ketogenic diet, GLUT-1=Glucose transporter type 1, CNS=Central nervous system, PDH=Pyruvate dehydrogenase, TCA=Tricarboxylic acid, PFK=Phosphofructokinase, AMP=Adenosine monophosphate, PDHC=Pyruvate dehydrogenase complex, GABA= Gamma-aminobutyric acid

Adverse Effects

Adverse effects can be classified either as mild, moderate, and severe or short term and long term [Table 5].[7273] Common adverse effects are mild and include headache, constipation, diarrhea, insomnia, and backache. High level of MCTs in KD may cause gastrointestinal discomfort with reports of abdominal cramps, diarrhea, and vomiting.[25] The moderate adverse effects comprised of dyslipidemia, mineral deficiencies, metabolic acidosis, and increased risk of renal stones. It may lead to increased triglycerides within a period of 6 months.[7374] Hypoproteinemia is also commonly observed; which could be due to associated reduced protein intake.[75] The severe effects are associated with elevated levels of ketones that can lead to complications by increasing redox imbalance and thereby risk of morbidity and mortality in diabetic patients.[76] With regard to possible acidosis during KD, as the concentration of KBs never rises above 8 mmol/L, this risk is virtually nonexistent in subjects with normal insulin function.

Table 5

Adverse effects of ketogenic diets

Short-term effects

Nausea/vomiting

Constipation

Dehydration

Anorexia

Lethargy

Hypoglycemia

Acidosis

Long-term effects

Disruptions in lipid metabolism

Severe hepatic steatosis

Hypoproteinemia

Mineral deficiencies

Increase redox imbalance

Cardiomyopathy

Nephrolithiasis

Long-term KD causes glucose intolerance associated with insufficient insulin secretion, insulin resistance, and reduced beta and alpha cell mass in mice (the long-term effects on pancreatic endocrine cells).[77] There are risks of more visceral and bone marrow fat, increased leptin, decreased insulin-like growth-factor 1, reduced bone mineral density, reduced transcription factors promoting osteoblastogenesis, and hence, reduced bone formation.[78] Plasma markers associated with dyslipidemia and inflammation (cholesterol, triglycerides, leptin, monocyte chemotactic protein-1, Interleukin [IL]-1, and IL-6) were increased, and KD-fed mice showed signs of hepatic steatosis after 22 weeks of KD.[77]

Some of the adverse effects may be preventable and easily treatable such as dehydration, hypoglycemia, and mild acidosis. Less quantity of MCT combined with LCT and increased meal frequency may improve diet tolerance.[25] Supplements of calcium, selenium, zinc, vitamin D, and oral alkalis are prescribed to reduce the incidence of nutritional deficiencies and kidney stones.[66] H2-blockers or proton pump inhibitors may be prescribed to prevent gastrointestinal dysmotility and gastroesophageal reflux.[25] In addition, high-fiber vegetables, sufficient fluids, and if necessary, carbohydrate-free laxatives are recommended to overcome constipation.

Cautions and Contraindications

The metabolic adaptation to the KD involves a shift from use of carbohydrates to lipids as the primary energy source. As such, a patient with a disorder of fat metabolism might develop a devastating catabolic crisis (i.e., coma, death) in the setting of fasting or a KD. Therefore, before initiating the KD, patients must be screened for disorders of fatty acid transport and oxidation, especially for children with seizure disorders and developmental abnormalities. KD is also contraindicated in porphyria (a disorder of heme biosynthesis in which there is deficient porphobilinogen deaminase), and patients with deficiency of pyruvate carboxylase enzyme[25] [Table 6].[1079] Hence, detailed history, physical examination, growth assessment in children and routine laboratory monitoring is indispensible before KD initiation and during follow-up visits. KD should not be advised for diabetic patients on SGLT2 inhibitors, as discussed in the previous section.

Table 6

Cautions and contraindications of ketogenic diet

Inborn errors of fat metabolism and enzyme deficiencies

MCAD

LCAD

SCAD

Long-chain 3-hydroxyacyl-CoA deficiency

Medium-chain 3-hydroxyacyl-CoA deficiency

Beta-oxidation defects within the mitochondria

Pyruvate carboxylase deficiency

Carnitine deficiency

CPT I or II deficiency

Carnitinetranslocase deficiency

Porphyria

Other complicating risk factors

Renal stones

Severe dyslipidemia

Significant liver disease

Failure to thrive

Severe gastroesophageal reflux

Poor oral intake

Cardiomyopathy

Chronic metabolic acidosis

Patients receiving SGLT 2 inhibitors

SGLT 2=Sodium glucose co transporter 2, CPT=Carnitine palmitoyl transferase, SCAD=Short-chain acyl dehydrogenase deficiency, LCAD=Long-chain acyl dehydrogenase deficiency, MCAD=Medium-chain acyl dehydrogenase deficiency

Conclusion

There is clinical evidence to support the use of KD in diabetes, obesity, and endocrine disorders. KD is gaining interest but is to be performed under strict medical supervision of dieticians and physicians to be effective and may, therefore, require hospital settings for its initiation. To facilitate the patient acceptability, tolerability, and palatability, the diet protocols are gradually modified including initiation of the diet with or without fasting, regular follow-ups to minimize complications, changes in ratios of the fat versus nonfat components and fatty acids composition. Such diets may positively influence hormonal balance and endocrinological disorders, but future studies are required to assess the long-term effects on health and reversing of diabetic complications in humans. The understanding of clinical impacts, safety, tolerability, efficacy, duration of treatment, and prognosis after discontinuation of the diet is challenging and requires further studies to understand the disease-specific mechanisms.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.