Ketogenic diet in endocrine disorders: Current perspectivesL Gupta1, D Khandelwal2, S Kalra3, P Gupta4, D Dutta5, S Aggarwal6
1 Department of Dietetics, Maharaja Agrasen Hospital, New Delhi, India
2 Department of Endocrinology, Maharaja Agrasen Hospital, New Delhi, India
3 Department of Endocrinology, Bharti Hospital and Bharti Research Institute of Diabetes and Endocrinology, Karnal, Haryana, India
4 Department of Paediatrics, Maharaja Agrasen Hospital, New Delhi, India
5 Department of Endocrinology, Venkateshwar Hospitals, New Delhi, India
6 Department of Medicine, Division of Endocrinology, Pandit Bhagwat Dayal Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpgm.JPGM_16_17
Source of Support: None, Conflict of Interest: None
Keywords: Diabetes, epilepsy, ketogenic diet, metabolic syndrome, nutritional ketosis, obesity, polycystic ovary syndrome
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).
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].,,,,, Recently, ketones have been proposed as super-metabolic fuel because of their various favorable impacts on cellular metabolism in many tissues.
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.
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. 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.
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. 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.
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., Risk of lean body mass loss and sarcopenia can prevented with judicious supplementation of amino acids and whey protein., 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.,
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. 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. 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.
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. 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., 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., 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.
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. 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.
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.
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.
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.,,,,,,,
KD involves flexibility to use long-chain triglycerides (LCT) or medium chain triglycerides (MCT). Omega-3 supplementation has its own positive effects. 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.,
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. 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.
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.
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. 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., Studies of KD looking into benefit on glycemic indices and other metabolic parameters in patients with type 2 diabetes are summarized in [Table 3].,,,,
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., 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). In obese patients with type 2 DM, high-ketogenic VLED treatment lowers fasting, OGTT glycemia, and improves glycemic control., High-protein, low-carbohydrate KD reduces hunger, and lowers food intake. 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., Moreover, limiting both protein and carbohydrates in KD reverses diabetic nephropathy. 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.
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.
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.
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.,, 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., Other mechanisms proposed are reduced lipogenesis, increased lipolysis, reduction in resting respiratory quotient, increased metabolic costs of gluconeogenesis, and the thermic effect of proteins.,
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/m 2). 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/m 2) without any side effects in long term.
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., 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.,
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.,
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.,, It has also been shown to improve depressive symptoms, psychological disturbances, and health-related quality of life in these patients.
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].,,,,,,,
Adverse effects can be classified either as mild, moderate, and severe or short term and long term [Table 5]., 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. 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., Hypoproteinemia is also commonly observed; which could be due to associated reduced protein intake. 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. 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.
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). 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. 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.
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. Supplements of calcium, selenium, zinc, vitamin D, and oral alkalis are prescribed to reduce the incidence of nutritional deficiencies and kidney stones. H2-blockers or proton pump inhibitors may be prescribed to prevent gastrointestinal dysmotility and gastroesophageal reflux. In addition, high-fiber vegetables, sufficient fluids, and if necessary, carbohydrate-free laxatives are recommended to overcome constipation.
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  [Table 6].,
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.
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.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]