Very Low-Calorie Ketogenic Diet: A Potential Application in the Treatment of Hypercortisolism Comorbidities

A very low-calorie ketogenic diet (VLCKD) is characterized by low daily caloric intake (less than 800 kcal/day), low carbohydrate intake (<50 g/day) and normoproteic (1–1.5 g of protein/kg of ideal body weight) contents. It induces a significant weight loss and an improvement in lipid parameters, blood pressure, glycaemic indices and insulin sensitivity in patients with obesity and type 2 diabetes mellitus. Cushing’s syndrome (CS) is characterized by an endogenous or exogenous excess of glucocorticoids and shows many comorbidities including cardiovascular disease, obesity, type 2 diabetes mellitus and lipid disorders. The aim of this speculative review is to provide an overview on nutrition in hypercortisolism and analyse the potential use of a VLCKD for the treatment of CS comorbidities, analysing the molecular mechanisms of ketogenesis.     

Long Term Successful Weight Loss with a Combination Biphasic Ketogenic Mediterranean Diet and Mediterranean Diet Maintenance Protocol

Weight loss protocols can only be considered successful if they deliver consistent results over the long term—a goal which is often elusive, so much so that the term “yo-yo” is used to describe the perennial weight loss/weight regain battle common in obesity. We hypothesized that a ketogenic Mediterranean diet with phytoextracts (KEMEPHY) combined with the acknowledged health benefits of traditional Mediterranean nutrition may favor long term weight loss. We analysed 89 male and female obese subjects, aged between 25 and 65 years who were overall healthy apart from being overweight. The subjects followed a staged diet protocol over a period of 12 months: 20 day of KEMEPHY; 20 days low carb-non ketogenic; 4 months Mediterranean normocaloric nutrition; a second 20 day ketogenic phase followed by 6 months of Mediterranean normocaloric nutrition. For the majority of subjects (88.25%) there was significant loss of weight (from 100.7 ± 16.54 to 84.59 ± 9.71 kg; BMI from 35.42 ± 4.11 to 30.27 ± 3.58) and body fat (form 43.44% ± 6.34% to 33.63% ± 7.6%) during both ketogenic phases followed by successful maintenance, without weight regain, during the 6 month stabilization phase with only 8 subjects failing to comply. There were also significant and stable decreases in total cholesterol, LDLc, triglycerides and glucose levels over the 12 month study period. HDLc showed small increases after the ketogenic phases but over the full 12 months there was no significant change. No significant changes were observed in ALT, AST, Creatinine or BUN. The combination of a biphasic KEMEPHY diet separated by longer periods of maintenance nutrition, based on the traditional Mediterranean diet, led to successful long term weight loss and improvements in health risk factors in a majority of subjects; compliance was very high which was a key determinant of the results seen.     

The Role of the Gut Microbiota on the Beneficial Effects of Ketogenic Diets

The ketogenic diet is a dietary regime focused on strongly reducing carbohydrate intake and increasing fat intake; leading to a state of ketosis. The ketogenic diet has gained much popularity over the years due to its effects on promoting weight loss, increasing insulin sensitivity and reducing dyslipidaemia. All these factors play a crucial role in the development of cardio-metabolic diseases; one of the greatest health challenges of the time. Moreover, the ketogenic diet has been known to reduce (epileptic) seizure activity. It is still poorly understood how following a ketogenic diet can lead to these beneficial metabolic effects. However, in recent years it has become clear that diet and the gut microbiota interact with one another and thus influence host health. The goal of this review is to summarize the current state of knowledge regarding the beneficial metabolic effects of the ketogenic diet and the role of gut microbiota in these effects.     

Obesity and Circulating Levels of Vitamin D before and after Weight Loss Induced by a Very Low-Calorie Ketogenic Diet

Background: Vitamin D plays a pivotal role in calcium and phosphorus metabolism, also influencing bone tissue. Several studies have reported that vitamin D blood levels were significantly lower in people with obesity, probably due to its uptake by the adipose tissue. Clinical studies that investigated the changes of circulating levels of vitamin D following weight loss reported controversial data. A very low-calorie ketogenic diet is acknowledged as a reliable treatment to achieve a rapid weight loss. Therefore, we investigated the effect of weight loss, consequent to a very low-calorie ketogenic diet, on vitamin D blood concentrations. Methods: A cohort of 31 people with obesity underwent a very low-calorie ketogenic diet for 10–12 weeks. The serum concentrations of vitamin D, parathormone, calcium and phosphorous were measured before and after weight loss; they were compared to a control group of 20 non-obese, non-diabetic, age- and gender-matched persons. Results: Patients with obesity had a higher habitual intake of vitamin D than the control group (p < 0.05). However, the vitamin D blood levels of the obese group were significantly lower than those of the control group (p < 0.005) and they increased after weight loss (p < 0.001). At baseline, vitamin D blood concentrations of the persons with obesity were significantly correlated with both fat mass–kg (r = −0.40; p < 0.05) and body mass index (r = −0.47; p < 0.01). Following very low-calorie ketogenic diet, the change in vitamin D serum concentrations was correlated only with the change in fat mass–kg (r = −0.43; p < 0.01). Conclusion: This study confirmed that patients with obesity have lower vitamin D levels that normalize after significant weight loss, supporting the hypothesis that vitamin D is stored in the adipose tissue and released following weight loss.     

Randomized Clinical Trial to Evaluate the Morphological Changes in the Adventitial Vasa Vasorum Density and Biological Markers of Endothelial Dysfunction in Subjects with Moderate Obesity Undergoing a Very Low-Calorie Ketogenic Diet

Weight loss after bariatric surgery decreases the earlier expansion of the adventitial vasa vasorum (VV), a biomarker of early atheromatous disease. However, no data are available regarding weight loss achieved by very low calorie ketogenic diets (VLCKD) on VV and lipid-based atherogenic indices. A randomized clinical trial was performed to examine changes in adventitial VV density in 20 patients with moderate obesity who underwent a 6-month very low calorie ketogenic diet (VLCKD, 600–800 kcal/day), and 10 participants with hypocaloric diet based on the Mediterranean Diet (MedDiet, estimated reduction of 500 kcal on the usual intake). Contrast-enhanced carotid ultrasound was used to assess the VV. Body composition analysis was also used. The atherogenic index of plasma (log (triglycerides to high-density lipoprotein cholesterol ratio)) and the triglyceride-glucose index were calculated. Serum concentrations of soluble intercellular adhesion molecule 1 (sICAM-1), and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured. The impact of weight on quality of life-lite (IWQOL-Lite) questionnaire was administered. Participants of intervention groups displayed a similar VV values. Significant improvements of BMI (−5.3 [−6.9 to −3.6] kg/m², p < 0.001), total body fat (−7.0 [−10.7 to −3.3] %, p = 0.003), and IWQOL-Lite score (−41.4 [−75.2 to −7.6], p = 0.027) were observed in VLCKD group in comparison with MedDiet group. Although after a 6-months follow-up period VV density (mean, right and left sides) did not change significantly in any group, participants in the VLCKD exhibited a significantly decrease both in their atherogenic index of plasma and serum concentration of sICAM-1. A 6-month intervention with VLCKD do not impact in the density of the adventitial VV in subjects with moderate obesity, but induces significant changes in markers of endothelial dysfunction and CV risk.     

Quelle alimentation proposer aux patients présentant une stéatohépatite non-alcoolique ?

Metabolic dysfunction-associated fatty liver disease (MAFLD) affects a quarter of the world's population, some of whom will progress to a more severe form called non-alcoholic steatohepatitis (NASH). The main factor leading to this condition is an unbalanced diet. No drug treatment is approved to date and only dietary management can improve the histological lesions of NASH through weight loss. However, the efficacy of standard diets, patient compliance and the ability to maintain weight loss over the long term are common difficulties. In this review, we analyze recent scientific data on different types of diet (Mediterranean diet, intermittent fasting, ketogenic diet), which can bring benefits on general and liver health. Drawbacks or limitations are also listed. The possible benefit of other nutritional strategies (coffee consumption, omega-3, polyphenols…) is discussed. The value of dietary change could be tailored to the patient's needs without necessarily imposing an intense weight loss.     

Ketogenic low-carbohydrate diets have no metabolic advantage over nonketogenic low-carbohydrate diets

BACKGROUND: Low-carbohydrate diets may promote greater weight loss than does the conventional low-fat, high-carbohydrate diet. OBJECTIVE: We compared weight loss and biomarker change in adults adhering to a ketogenic low-carbohydrate (KLC) diet or a nonketogenic low-carbohydrate (NLC) diet. DESIGN: Twenty adults [body mass index (in kg/m(2)): 34.4 +/- 1.0] were randomly assigned to the KLC (60% of energy as fat, beginning with approximately 5% of energy as carbohydrate) or NLC (30% of energy as fat; approximately 40% of energy as carbohydrate) diet. During the 6-wk trial, participants were sedentary, and 24-h intakes were strictly controlled. RESULTS: Mean (+/-SE) weight losses (6.3 +/- 0.6 and 7.2 +/- 0.8 kg in KLC and NLC dieters, respectively; P = 0.324) and fat losses (3.4 and 5.5 kg in KLC and NLC dieters, respectively; P = 0.111) did not differ significantly by group after 6 wk. Blood beta-hydroxybutyrate in the KLC dieters was 3.6 times that in the NLC dieters at week 2 (P = 0.018), and LDL cholesterol was directly correlated with blood beta-hydroxybutyrate (r = 0.297, P = 0.025). Overall, insulin sensitivity and resting energy expenditure increased and serum gamma-glutamyltransferase concentrations decreased in both diet groups during the 6-wk trial (P < 0.05). However, inflammatory risk (arachidonic acid:eicosapentaenoic acid ratios in plasma phospholipids) and perceptions of vigor were more adversely affected by the KLC than by the NLC diet. CONCLUSIONS: KLC and NLC diets were equally effective in reducing body weight and insulin resistance, but the KLC diet was associated with several adverse metabolic and emotional effects. The use of ketogenic diets for weight loss is not warranted.     

Ketogenic Diet,Physical Activity,and Hypertension—A Narrative Review

Several studies link cardiovascular diseases (CVD) with unhealthy lifestyles (unhealthy dietary habits, alcohol consumption, smoking, and low levels of physical activity). Therefore, the strong need for CVD prevention may be pursued through an improved control of CVD risk factors (impaired lipid and glycemic profiles, high blood pressure, and obesity), which is achievable through an overall intervention aimed to favor a healthy lifestyle. Focusing on diet, different recommendations emphasize the need to increase or avoid consumption of entire classes of food, with only partly known and only partly foreseeable consequences on the overall level of health. In recent years, the ketogenic diet (KD) has been proposed to be an effective lifestyle intervention for metabolic syndrome, and although the beneficial effects on weight loss and glucose metabolism seems to be well established, the effects of a prolonged KD on the ability to perform different types of exercise and the influence of KD on blood pressure (BP) levels, both in normotensives and in hypertensives, are not so well understood. The objective of this review is to analyze, on the basis of current evidence, the relationship between KD, regular physical activity, and BP.     

Ketogenic Diet and Cardiac Substrate Metabolism

The ketogenic diet (KD) entails a high intake of fat, moderate intake of protein, and a very limited intake of carbohydrates. Ketogenic dieting has been proposed as an effective intervention for type 2 diabetes and obesity since glycemic control is improved and sustained weight loss can be achieved. Interestingly, hyperketonemia is also associated with beneficial cardiovascular effects, possibly caused by improved cardiac energetics and reduced oxygen use. Therefore, the KD has the potential to both treat and prevent cardiovascular disease. However, the KD has some adverse effects that could counteract the beneficial cardiovascular properties. Of these, hyperlipidemia with elevation of triglycerides and LDL cholesterol levels are the most important. In addition, poor diet adherence and lack of knowledge regarding long-term effects may also reduce the broader applicability of the KD. The objective of this narrative review is to provide insights into the KD and its effects on myocardial ketone body utilization and, consequently, cardiovascular health.     

Report of a National Institutes of Health--Centers for Disease Control and Prevention workshop on the feasibility of conducting a randomized clinical trial to estimate the long-term health effects of intentional weight loss in obese persons

A workshop was convened in 1997 by the National Institutes of Health and the Centers for Disease Control and Prevention to consider the need for and feasibility of conducting a randomized clinical trial to estimate the long-term health effects of intentional weight loss in obese persons. Although the benefits of weight loss in obese individuals may seem obvious, little information is available showing that intentional weight loss improves long-term health outcomes. Observational studies may be unable to provide convincing answers about the magnitude and direction of the health effects of intentional weight loss. Workshop participants agreed that a well-designed randomized clinical trial could answer several questions necessary for developing a rational clinical and public health policy for treating obesity. Such information will ultimately provide needed guidance on the risks and benefits of weight loss to health care providers and payers, as well as to millions of obese Americans.     

Lifestyle advice in preventing and treating type 2 diabetes

Dietary advice from health professionals can play a significant part in preventing and managing type 2 diabetes. Overweight and obesity are strongly associated with this condition, and individually tailored advice on weight loss and maintaining an appropriate weight are useful, together with encouragement to take appropriate exercise. Current thinking about a healthy diet and lifestyle apply to people with type 2 diabetes, but those with this condition or who are at risk from it need to understand why diet and exercise are so important in their case. The article explores these issues, including specific aspects of diet such as carbohydrates and the glycaemic index.     

Obesity and neurodegeneration: effect of a Mediterranean dietary pattern

Abstract

Obesity is a serious global health problem and is associated with a variety of chronic diseases. Increasing evidence suggests that obesity increases the risk of Alzheimer's disease. Several studies have shown that a Mediterranean diet is effective in reducing weight and epidemiological data suggest that such a diet is associated with lower risk of neurodegenerative disorders, including Alzheimer's disease. Therefore, we examined the relationship between obesity and neurodegeneration and the possible effects of Mediterranean diet on both in adult obese rats. Obese rats showed significant dyslipidaemia, insulin resistance, down-regulation of adiponectin mRNA expression in adipose tissue, up-regulation of brain amyloid precursor protein, apolipoprotein E and caspase-3 mRNA expression and a marked increase in brain oxidative stress. Treatment with Mediterranean diet induced significant weight loss and improvement in these various markers. The present study suggests that Mediterranean diet is a viable nutritional intervention in obesity and, more importantly, in the prevention and treatment of Alzheimer's disease.     

The Potential Health Benefits of the Ketogenic Diet: A Narrative Review

Considering the lack of a comprehensive, multi-faceted overview of the ketogenic diet (KD) in relation to health issues, we compiled the evidence related to the use of the ketogenic diet in relation to its impact on the microbiome, the epigenome, diabetes, weight loss, cardiovascular health, and cancer. The KD diet could potentially increase genetic diversity of the microbiome and increase the ratio of Bacteroidetes to Firmicutes. The epigenome might be positively affected by the KD since it creates a signaling molecule known as β-hydroxybutyrate (BHB). KD has helped patients with diabetes reduce their HbA1c and reduce the need for insulin. There is evidence to suggest that a KD can help with weight loss, visceral adiposity, and appetite control. The evidence also suggests that eating a high-fat diet improves lipid profiles by lowering low-density lipoprotein (LDL), increasing high-density lipoprotein (HDL), and lowering triglycerides (TG). Due to the Warburg effect, the KD is used as an adjuvant treatment to starve cancer cells, making them more vulnerable to chemotherapy and radiation. The potential positive impacts of a KD on each of these areas warrant further analysis, improved studies, and well-designed randomized controlled trials to further illuminate the therapeutic possibilities provided by this dietary intervention.     

Low-carbohydrate diets cause obesity, low-carbohydrate diets reverse obesity: a metabolic mechanism resolving the paradox

High-fat diets produce obesity in part because, per calorie, glucose produces greater post-prandial thermogenesis than lipids, an effect probably mediated by glucose-sensing neurons. A very low-carbohydrate/high-fat/high-protein Atkins-type diet produces obesity but is marginally ketogenic in mice. In contrast, high-sucrose/low-fat diets, and very low-carbohydrate/high-fat/low-protein (anti-epileptic) ketogenic diets reverse diet-induced obesity independent of caloric intake. We propose that a non-ketogenic high-fat diet reduces glucose metabolism and signaling in glucose-sensing neurons, thereby reducing post-prandial thermogenesis, and that a ketogenic high-fat diet does not reduce glucose signaling, thereby preventing and/or reversing obesity.     

生酮饮食对大鼠体重及能量代谢的影响

目的了解生酮饮食对大鼠体重及能量代谢的影响,为生酮饮食作用机制的相关研究提供参考。方法将16只雄性Wistar大鼠按单纯随机抽样法分为干预组和对照组,应用配对喂养原则,根据对照组前24h内进食量,给予干预组相等能量的生酮饲料,并在干预前和干预后第3天和第15天,测定大鼠的静息代谢率。结果生酮饲料喂养的正常大鼠能量主要来源为脂肪,体重增长落后于对照组（P〈0.05）;在干预2周后,生酮饲料喂养的正常大鼠夜间代谢率低于对照组（P〈0.05）。结论生酮饮食对正常个体也有调节体重的作用,但其对代谢率的影响不能解释对体重的调节作用。     

Medical costs are reduced when children with intractable epilepsy are successfully treated with the ketogenic diet

The ketogenic diet is used for children with drug refractory epilepsies. Although this diet was developed early in the 20th century, its use was infrequent until recently. One of the concerns about the ketogenic diet is the cost of initiating the diet. The process generally involves an inpatient visit that can last several days. In this study, the health care costs for 15 children with drug refractory epilepsy who received their care at Vanderbilt University Medical Center were compared for the period of time 6 to 12 months before they began the ketogenic diet and 6 to 12 months after they began the ketogenic diet. All comparisons within each child were done on the same amount of time before and after initiation of the diet. Total costs affiliated with care for the 15 children were: $352,820.20 for the prediet period, $41,221.91 for the diet initiation, and $149,436.86 for the postdiet-initiation period. We conclude that successful maintenance on the ketogenic diet provides a substantial financial benefit.     

Consumption of a low-carbohydrate and high-fat diet (the ketogenic diet) exaggerates biotin deficiency in mice

ObjectiveBiotin is a water-soluble vitamin that acts as a cofactor for several carboxylases. The ketogenic diet, a low-carbohydrate, high-fat diet, is used to treat drug-resistant epilepsy and promote weight loss. In Japan, the infant version of the ketogenic diet is known as the “ketone formula.” However, as the special infant formulas used in Japan, including the ketone formula, do not contain sufficient amounts of biotin, biotin deficiency can develop in infants who consume the ketone formula. Therefore, the aim of this study was to evaluate the effects of the ketogenic diet on biotin status in mice.MethodsMale mice (N = 32) were divided into the following groups: control diet group, biotin-deficient (BD) diet group, ketogenic control diet group, and ketogenic biotin-deficient (KBD) diet group. Eight mice were used in each group.ResultsAt 9 wk, the typical symptoms of biotin deficiency such as hair loss and dermatitis had only developed in the KBD diet group. The total protein expression level of biotin-dependent carboxylases and the total tissue biotin content were significantly decreased in the KBD and BD diet groups. However, these changes were more severe in the KBD diet group.ConclusionThese findings demonstrated that the ketogenic diet increases biotin bioavailability and consumption, and hence, promotes energy production by gluconeogenesis and branched-chain amino acid metabolism, which results in exaggerated biotin deficiency in biotin-deficient mice. Therefore, biotin supplementation is important for mice that consume the ketogenic diet. It is suggested that individuals that consume the ketogenic diet have an increased biotin requirement.     

Low carbohydrate diets, pro: time to rethink our current strategies.

Obesity-attributable medical expenditures in the United States are estimated at 75 billion dollars annually, half of which are financed by Medicare and Medicaid. In 2002, the estimated 80,000 bariatric surgical procedures cost between 15,000 to 30,000 dollars per patient. It is now believed that poor diet and physical inactivity may soon overtake tobacco as the leading cause of death. These findings, along with escalating health care costs and an aging population, are compelling reasons for US health care and public health systems to create more effective preventive approaches than have been used to date to reverse this epidemic. According to current trends, obesity will become the #1 cause of death by 2005, with the toll surpassing 500,000 deaths a year, rivaling the annual deaths from cancer. Conditions of overweight and obesity are associated with diabetes, hypertension, hypercholesterolemia, asthma, arthritis, and poor health status. The successful experiences by many individuals who have limited their carbohydrate intake and mounting scientific studies supporting low- or controlled-carbohydrate diets' physiologic and metabolic action warrant a closer look at this dietary regimen as a potentially viable option to current conventional approaches. For individuals with high serum triglyceride and low high-density lipoprotein (HDL) levels, truncal obesity, or insulin resistance (metabolic syndrome or hyperinsulinemia), reducing carbohydrate intake has been shown to improve these parameters without adverse clinical effects. Studies are beginning to validate the benefit of controlling carbohydrate intake for individuals with type 2 diabetes. The controlled-carbohydrate regimen could be a viable alternative dietary approach for weight management used by clinicians managing patients who are failing with conventional approaches. This can be achieved by either restricting carbohydrates initially and then adding back healthy carbohydrate choices until the individual's carbohydrate threshold is achieved or by eliminating carbohydrate foods one at a time from the diet until carbohydrates are limited enough to achieve weight loss and improve clinical parameters. One diet approach does not fit all patients. Some individuals might do best on a very-low-fat, high-carbohydrate diet, whereas others may respond to lowering carbohydrate intake. Identifying specific needs and health conditions of each individual is key to successful application of the best approach and management for long-term success of weight loss in conjunction with improved health.     

The Body Weight Planner

A health literacy tool that provides information about body weight can be found at http://www.niddk.nih.gov/health-information/health-topics/weight-control/body-weight-planner/Pages/bwp.aspx. The “Body Weight Planner” tool aims to educate adults about how diet and physical activity contribute to weight loss and weight maintenance. The tool is visually appealing, easy to use as it guides users through every step, is based on scientific research, and connects adults with reliable and accurate health information related to weight loss and weight maintenance. This may increase the likelihood of users understanding the connection between healthy eating, physical activity, and healthy outcomes. Additionally, the tool may empower users to make informed decisions regarding healthy eating and physical exercise, which will ultimately result in lower obesity rates, improved health outcomes, and decreased health care costs.     

Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis

Fibroblast growth factor 21 (FGF21) was originally identified as a member of the FGF family in homology studies and is a member of the endocrine FGF subfamily that lacks heparin binding domains and is released into the circulation. A potential role as a metabolic regulator emerged when FGF21 was shown to increase glucose uptake in adipocytes. Subsequently, marked elevations in FGF21 expression were observed in mice that ate a ketogenic diet and when fasting, which suggests that FGF21 expression plays a role in the adaptation to metabolic states that require increased fatty acid oxidation. Consistent with this evidence, FGF21 knockout mice were not able to respond appropriately to consumption of a ketogenic diet. FGF21 expression is downstream of peroxisome proliferator-activated receptor (PPAR) α in the liver and PPARγ in adipose tissue. FGF21 concentrations are higher in both rodent and human obesity, and recent data suggest that obesity may be an FGF21-resistant state. Recent data increasingly suggest that FGF21 is an important metabolic regulator that may have potential clinical implications.