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Protein Sparing Therapies in Acute Illness and Obesity: A Review of George Blackburn's Contributions to Nutrition Science
Abstract
Protein sparing therapies were developed to mitigate the harms associated with protein-calorie malnutrition and nitrogen losses induced by either acute illness or hypocaloric diets in patients with obesity. We review the development of protein sparing therapies in illness and obesity with a focus on the pioneering contributions of George Blackburn, MD, PhD. He recognized that protein-calorie malnutrition is a common and serious clinical condition and developed new approaches to its treatment in hospitalized patients. His work with stable isotopes and with animal models provided answers about the physiological nutritional requirements and metabolic changes across a spectrum of conditions with varying degrees of stress and catabolism. This led to improvements in enteral and parenteral nutrition for patients with acute illness. Blackburn also demonstrated that lean body mass can be preserved during weight loss with carefully designed very low calorie treatments which became known as the protein sparing modified fast (PSMF). We review the role of the PSMF as part of the comprehensive management of obesity.
... Also, the described metabolic changes allow a reduction of hunger due to the anorexigenic properties of ketone bodies and a reduction of the neoglucogenesis-associated body protein catabolism, allowing the organism to survive [36,37] 3 From total fasting to protein-sparing modified fast At this point, the pioneer works of Blackburn and his collaborators came as game-changer in medicine and nutrition [38,39]. First, they studied the strict connection between proteincalorie malnutrition and increased morbidity and mortality in hospitalized patients due to intense protein catabolism [40,41]. Their finding led to worldwide changes in the diagnosis and treatment of malnutrition in the hospital setting and introduction of the seminal concept of protein-sparing therapies [41]. ...
... First, they studied the strict connection between proteincalorie malnutrition and increased morbidity and mortality in hospitalized patients due to intense protein catabolism [40,41]. Their finding led to worldwide changes in the diagnosis and treatment of malnutrition in the hospital setting and introduction of the seminal concept of protein-sparing therapies [41]. As stated, the potential harmful effects of very-lowcalorie diets (VLCD) using liquid substitutes with proteins of low biological value was already known [34,42]. ...
... Then, compared to fasting, a diet providing <800 kcal/day, high biological value proteins up to 1.5 g/kg of ideal body weight and mineral/multivitamins supplementation (including potassium, sodium chloride and calcium) was associated with a 65% weight loss but only 3% lean body mass reduction [43]. These results were confirmed by following studies [44,45] and the protein-sparing modified fast (PSMF) developed by Blackburn and Bistrian become the new standard [41,46]. 4 From protein-sparing modified fast to very-low-calorie ketogenic diets Encouraged by the early results using PSMF, diets evolved to the current very-low-calorie ketogenic diets (VLCKD). ...
During the last decades, several interventions for the management of overweight and obesity have been proposed. Among diets, the first studies focused on the effect of water only and total fasting diets with or without proteins. Unfortunately, they were found to be associated with adverse events which lead to the abandon of these strategies. Interestingly, despite the radical approach, total fasting was effective and generally well tolerated. A strict connection between protein-calorie malnutrition and increased in morbidity and mortality in hospitalized patients was found at that time. Then, the seminal works of Blackburn and his collaborators lead to the introduction of the protein-sparing modified fast. Encouraged by the early results using this intervention, diets evolved to the current very-low-calorie ketogenic diets (VLCKD). In the present review, results of studies on the VLCKDs are presented and discussed, with a particular reference to the protocolled VLCKD. Also, a recent proposal on the nomenclature on the ketogenic diets is reported. Available evidence suggests VLCKDs to be effective in achieving a rapid and significant weight loss by means of an easily reversible intervention which could be repeated, if needed. Muscle mass and strength are preserved, resting metabolic rate is not impaired, hunger, appetite and mood are not worsened. Symptoms and abnormal laboratory findings can be there, but they have generally been reported as of mild intensity and transient. Preliminary studies suggest VLCKDs to be a potential game-changer in the management of type 2 diabetes too. Therefore, VLCKDs should be considered as an excellent initial step in properly selected and motivated patients with obesity or type 2 diabetes, to be delivered as a part of a multicomponent strategy and under strict medical supervision.
... This direct effect of ketones on whole body insulin disposal has been shown in other animal models, as well (11,16). Ketones can also have a protein-sparing effect in obesity by inhibiting oxidation of branched chain amino acids, mainly alanine, in muscle (17). Nonetheless, studies performed decades ago observed that this protein sparing effect is dependent on the initial weight of participants, and individuals without obesity have increased loss of muscle mass during ketosis (17)(18)(19). ...
... Ketones can also have a protein-sparing effect in obesity by inhibiting oxidation of branched chain amino acids, mainly alanine, in muscle (17). Nonetheless, studies performed decades ago observed that this protein sparing effect is dependent on the initial weight of participants, and individuals without obesity have increased loss of muscle mass during ketosis (17)(18)(19). ...
Intermittent fasting (IF) is an increasingly popular method of weight loss, as an alternative to daily caloric restriction (DCR). Several forms of IF exist, such as alternate-day fasting or time-restricted feeding regimens. Some of its proponents claim several health benefits unrelated to caloric restriction or weight loss, which rely mainly on animal models. Although several studies published in the last few years confirm that IF can be a useful and safe therapeutical option for obesity and related disorders, no superiority to conventional caloric restriction diets have emerged. There are still several questions left answered. In this Review, we discuss some of the claims, unveiling myths, facts, and presumptions about several models of IF. The focus of this article is obesity, but there is a brief discussion of the potential benefits of IF on overall human health.
... 7 The protein-sparing modified fast (PSMF) is a very-lowcalorie, high-protein diet that aims to preserve lean body mass during weight loss by having the patient ingest 1.2-1.5 g of protein per day per kilogram of body weight. 8,9 Individuals who follow the PSMF achieve ketosis, but the PSMF differs from other keto diets because the main source of calories is protein, not fat. 9,10 Individuals who adhere to the PSMF often experience rapid and substantial weight loss, which may be attractive to patients and clinicians. ...
... 8,9 Individuals who follow the PSMF achieve ketosis, but the PSMF differs from other keto diets because the main source of calories is protein, not fat. 9,10 Individuals who adhere to the PSMF often experience rapid and substantial weight loss, which may be attractive to patients and clinicians. 11,12 However, the PSMF is not meant to be maintained long term. ...
Background
Ketogenic diets have been highlighted as a way to lose weight while experiencing reduced hunger. The protein-sparing modified fast (PSMF) induces ketosis but may be difficult to maintain.
Objective
To track weight loss for individuals initiating PSMF versus all other diets (e.g., balanced, high protein) for up to 5 years.
Design
Retrospective cohort study
Participants
Adults who discussed the PSMF with a clinician between 2007 and 2014
Intervention
Initiating the PSMF diet versus other diets
Measures
The main outcome was percent weight change up to 5 years. Demographic and health data were collected using electronic health records. We fit regression models including age, sex, race, insurance, new medication prescriptions, and specialist visit to identify the effect of PSMF diet on percent weight change. We grouped patients by percent weight change at each year (≥ 5% loss, 4% loss to 4% gain, ≥ 5% gain) and used Pearson χ² tests to compare proportions.
Results
Of 1,403 eligible patients, 879 (63%) started the PSMF. The PSMF group was slightly younger (52 vs. 54 years, p < 0.01) and had a higher body mass index (41.9 kg/m² vs. 40.4 kg/m², p < 0.001). In the adjusted analysis, the PSMF group averaged 3% more weight loss than the other group over the 5-year follow-up (95% CI − 3.5, − 2.0, p < 0.001). PSMF patients lost more weight initially, but by year 4, there was no difference between diets (1.6% versus 1.3%, PSMF versus other diets, p = 0.12). Patients starting the PSMF were more likely to experience ≥ 5% weight loss at 1 year (55% vs 20%, p < 0.001) and 3 years (33% vs. 23% p < 0.05), but not 5 years (34% vs 29%, p = 0.16, PSMF versus other diets, respectively).
Conclusions
In clinical practice, the PSMF achieves rapid weight loss in the first 6 months, but only a small percentage of patients maintained significant weight loss long term.
... Extant literature on the PSMF in both adults and adolescents is encouraging [9,[13][14][15][16][17][18][19][20], yet studies on the use of the PSMF in children and adolescents to treat obesity are limited. In a study of adolescents with severe obesity who previously failed at conventional lifestyle modification, the PSMF produced a clinically significant mean decrease of 9.8% of body weight over 6 months [15]. ...
... Traditionally, the PSMF is categorized as a very low-calorie diet (VLCD), with significant calorie restriction, sometimes as low as 500-800 kcal per day [20,21]. However, VLCDs (when provided mostly as liquid meal replacements) have raised safety concerns in the past [18,22]; so recent studies using the PSMF have been less stringent with caloric restriction and have demonstrated improved safety profiles [15,16,19]. ...
Treatment options are limited for children and adolescents with severe obesity. One alternative treatment is the protein-sparing modified fast (PSMF), a low-carbohydrate, high-protein diet that can result in substantial weight loss. The aim of the study is to evaluate the adherence and efficacy of a revised PSMF (rPSMF) for severe obesity in a pediatric tertiary care weight-management program. The rPSMF with 1200–1800 calories, 40–60 g of carbohydrate/day and 1.2–1.5 g protein/kg of ideal bodyweight was implemented over 12 months. Twenty-one participants enrolled in the study. Mean age 16.2 ± 1.4 years, females (76.2%) and mean weight at baseline was 119 ± 19.9 kg. Regardless of adherence to the rPSMF, the mean weight change at 1 month was −3.7 ± 3.5 kg, (range −13.5 kg to 0.9 kg); at 3 months was −5.5 ± 5.1 kg, (range −19.3 kg to 1.8 kg) and at 6 months was −4.7 ± 6.6 kg, (range −18.3 kg to 8.6 kg). At 12 months, the mean weight change was −1.3 ± 10.6 kg (range −17.7 kg to 14.8 kg). Parent and child-reported physical and psychosocial quality of life (HRQOL) improved. Despite limited adherence, the rPSMF diet resulted in clinically significant weight loss and improved HRQOL for children and adolescents with severe obesity.
... Although these diets can only be followed for limited periods because of their extreme caloric restriction, they can induce a high rate of weight-loss with long-term maintenance [9], especially if practiced along with an active follow-up treatment [10]. Furthermore, the protein sparing modified fast (PSMF), a modified variant of VLCD, was designed to exploit quasi-fasting induced ketosis to preserve lean body mass when following major weight loss programs, as widely studied and described by Dr. George Blackburn [11]. Because of their ability to induce ketosis by the mobilization of fatty acids from adipose tissue (physiological states of prolonged fasting), PSMF protocols are also called very low-calorie ketogenic diets (VLCKDs). ...
... The VLCD is an extreme (≤800 kcal), time-restricted, nutritional protocol that mimics the effects of fasting without the side effects of starvation, to treat severe obesity [17]. Given its carbohydrate content, it could, or not, induce metabolic ketosis [11]. Both diets were based on food replacements delivered to the patients' home by the product supplier (Kalibra ® by S.D.M. srl, Savigliano (CN), Italy). ...
Here we aimed at determining the therapeutic effect of a very low-calorie diet in overweight episodic migraine patients during a weight-loss intervention in which subjects alternated randomly between a very low-calorie ketogenic diet (VLCKD) and a very low-calorie non-ketogenic diet (VLCnKD) each for one month. In a nutritional program, 35 overweight obese migraine sufferers were allocated blindly to 1-month successive VLCKD or VLCnKD in random order (VLCKD-VLCnKD or VLCnKD-VLCD). The primary outcome measure was the reduction of migraine days each month compared to a 1-month pre-diet baseline. Secondary outcome measures were 50% responder rate for migraine days, reduction of monthly migraine attacks, abortive drug intake and body mass index (BMI) change. Only data from the intention-to-treat cohort (n = 35) will be presented. Patients who dropped out (n = 6) were considered as treatment failures. Regarding the primary outcome, during the VLCKD patients experienced −3.73 (95% CI: −5.31, −2.15) migraine days respect to VLCnKD (p < 0.0001). The 50% responder rate for migraine days was 74.28% (26/35 patients) during the VLCKD period, but only 8.57% (3/35 patients) during VLCnKD. Migraine attacks decreased by −3.02 (95% CI: −4.15, −1.88) during VLCKD respect to VLCnKD (p < 0.00001). There were no differences in the change of acute anti-migraine drug consumption (p = 0.112) and BMI (p = 0.354) between the 2 diets. A VLCKD has a preventive effect in overweight episodic migraine patients that appears within 1 month, suggesting that ketogenesis may be a useful therapeutic strategy for migraines.
... This structured, multi-phase regimen has emerged as a promising strategy to address the increasing incidence of obesity and associated conditions (Chang & Kashyap, 2014;Thomas et al., 2018;Tsai & Wadden, 2006). Traditional diets have shown limited capacity to produce significant and sustained weight loss over time (Barrea et al., 2022b;Moreno et al., 2016). ...
The Very Low-Energy Ketogenic Therapy (VLEKT) is a structured, multi-phase dietary regimen characterized by a carbohydrate intake of less than 50 g/day and a daily caloric intake of fewer than 800 kcal, which induces ketosis and facilitates significant weight loss. Evidence suggests that this nutritional therapy can improve glycemic control, lipid profiles, and blood pressure, making it a promising option for managing type 2 diabetes (T2D) and reducing cardiovascular risk. These benefits are achieved through reductions in triglycerides and low-density lipoprotein cholesterol (LDL-c), alongside increases in high-density lipoprotein cholesterol (HDL-c). However, the effects of the VLEKT on lipid metabolism remain controversial. The review emphasizes the urgent need for further research to validate the long-term safety and efficacy of the VLEKT. It also highlights the critical role of personalized dietary plans, supervised by healthcare professionals, to optimize health outcomes and address individual patient needs.
... The VLCKD was inspired by the Blackburn diet (PSMF-protein-sparing modified fast) [44]. It is a non-carbohydrate diet with around 10 g of carbohydrates per day in vegetables and foods such as yogurt. ...
Background: Fibromyalgia (FM) is a chronic disorder that causes damage to the neuro-muscular system and alterations in the intestinal microbiota and affects the psychological state of the patient. In our previous study, we showed that 22 women patients subjected to a specific very low-carbohydrate ketogenic therapy (VLCKD) showed an improvement in clinical scores as well as neurotransmission-related and psychological dysfunctions and intestinal dysbiosis. Furthermore, NMR metabolomic data showed that changes induced by VLCKD treatment were evident in all metabolic pathways related to fibromyalgia biomarkers. Methods: Based on this evidence, we extend our investigation into dietary interventions for fibromyalgia by evaluating the impact of transitioning from a VLCKD to a low-glycemic insulinemic (LOGI) diet over an additional 45-day period. Therefore, participants initially following a VLCKD were transitioned to the LOGI diet after 45 days to determine whether the improvements in FM symptoms and metabolic dysfunctions achieved through VLCKD could be sustained with LOGI. Results: Our findings suggested that while VLCKD serves as an effective initial intervention for correcting metabolic imbalances and alleviating FM symptoms, transitioning to a LOGI diet offers a practical and sustainable dietary strategy. This transition preserves clinical improvements and supports long-term adherence and quality of life, underscoring the importance of adaptable nutritional therapies in chronic disease management. Control patients who adhered only to the LOGI diet for 90 days showed only modest improvement in clinical and psychological conditions, but not elimination of fibromyalgia symptoms. Conclusions: In conclusion the LOGI diet is an excellent alternative to maintain the results obtained from the regime VLCKD.
... What is important, evolution mechanisms that adapt the human body to periods of fasting preserve muscle mass and function and energy is derived from fat tissue. Ketones may promote conservation of proteins by inhibition of oxidation of branched chain amino acids, mainly in individuals with increased amount of fat tissue [21]. Thus, IF regimens that lead to metabolic switch may lead to the improvement of body composition, especially in overweight and obese patients [14]. ...
Introduction Intermittent fasting (IF) is a form of dietary intervention that includes periods of regular calorie intake alternated with periods of fasting. IF has gained a lot of attention as a potential approach to treating metabolic syndrome-related diseases. Therefore, health care professionals need to be able to provide their patients with evidence-based information on IF. The aim of this article is to review data on effectiveness of IF in weight loss, especially in comparison with calorie restriction. Methods
PubMed and Google Scholar databases were searched for studies published from 1.01.2017 to 31.12.2022 that included phrases “intermittent fasting” or “alternate day fasting”, “intermittent fasting obesity”, “alternate day fasting obesity”. Intervention studies on obese or overweight patients were included. We excluded studies of short duration and studies that focused on intercurrent medical conditions. In total, 14 articles that suited those criteria were identified. ResultsIntermittent fasting induces pronounced metabolic changes in the body due to strict and time-limited restriction of calorie intake and in animal models was proved to prolong lifespan and modulate tumorigenesis and aging. It is a proposed new approach to treating obesity, which is a a major risk factor for cardiovascular diseases and diabetes. Conclusions
In our study, IF was found as effective, but not superior to calorie restriction in reducing body mass, improving body composition and reducing other cardiometabolic risk factors. Our findings are consistent with other recent systematic reviews. Further research is needed to directly compare various IF regimens and determine patients’ characteristics that may be associated with more successful implementation of intermittent fasting regimens.
... PSMF essentially combines a very low-carb KD with a very low-calorie diet. People who adhere to the PSMF enter ketosis, but the PSMF differs from other KDs in that protein, not fat, serves as the primary source of energy [46]. People who follow PSMF often lose weight rapidly and significantly, which may appeal to patients and medical professionals [47]. ...
The ketogenic diet (KD) is a high-fat, adequate-protein, and very low-carbohydrate diet that stimulates the creation of ketones by mimicking the metabolism of the fasting state. A high level of blood ketone caused by a KD induces the state of ketosis, which has several physiological and therapeutic advantages. The KD first gained popularity as an epilepsy treatment in the 1920s and 1930s. It has rapidly attracted research interest in the last 20 years due to mounting evidence of the KD's possible therapeutic potential for other diseases besides epilepsy, including obesity, neurodegenerative diseases, and malignancies. The KD alters multiple cellular signaling cascades, receptors, and biomarker levels in various medical situations. KD therapy differs from the typical Western diet in that it focuses on nutritional supplements, electrolytes, and hydration in addition to the diet. If the KD is followed closely, significant dietary changes can positively affect the dieting individual. However, several treatable short-and long-term adverse effects are linked to the KD. It may be challenging to follow the KD long-term if some of the most enjoyable meals are not allowed. Numerous physicians are considering including KD programs in the therapeutic regimen in light of the importance of lifestyle modification in managing diseases. However, before this can be advised, doctors must ensure its efficacy and safety, and further human research is necessary. Numerous economic opportunities will soon arise as a result of the potential medical benefits of the KD. These safeguards and limitations can therefore be used to develop distinctive and personalized interventional procedures replicating the effects of a KD or as potential drug development targets.
... [8][9][10][11][12] Even though some renal-specific protein-containing supplements were found to improve the nutritional status of malnourished MHD patients, 9,13,14 high protein intake could also lead to the accumulation of acidic metabolites, thereby accelerating protein degradation. 7 It was known that sufficient energy intake played an important role in sparing protein, 15 which suggested that energy-only supplementation might be able to alleviate protein deficiency and improve the nutritional status of MHD patients with minimum side effects from excessive protein intake. Our previous study proved that intradialytic parenteral nutrition intervention with high-concentration glucose solution could replenish energy stores and improve the amino acid profile in MHD patients. ...
Protein-energy wasting (PEW) is prevalent in maintenance hemodialysis (MHD) patients, which is one of the major risk factors for poor outcomes and death. This study aimed to investigate the effects...
... In the last few years, the ketogenic diet has achieved great interest in sport, military training, as antiepileptic treatment as well as in the management of overweight and obesity [1,2]. A high number of studies, more than 300 in 2019, have been published on this topic, and a consensus statement has recently become available [3]. ...
Ketogenic diets have been proposed as a non-pharmacological strategy for the management of several chronic conditions. Their efficacy and safety have been evaluated in the field of neurology, oncology and endocrinology for disorders including cancer, dementia, drug-resistant epilepsy, migraines, obesity, polycystic ovary syndrome and type 2 diabetes mellitus. The nutritional requirements of these subjects are expected to differ significantly. Indeed, although all ketogenic diets restrict carbohydrates, each intervention is characterized by a specific daily calorie intake, macronutrient composition and duration. However, the adopted nomenclature was often unclear to the general reader; also, the same abbreviations for different protocols were used. This possibly resulted in mistakes in the interpretation of the available evidence and limited the impact of studies on the topic in the clinical practice. Adopting a clear and consistent vocabulary is key in any context. Here, we present a practical and clinically-based proposal for the classification and abbreviation of ketogenic diets.
... We also highlight the relationship between protein intake and plasma glucose homeostasis (Fig. 1). We do not cover the adverse effects of inadequate protein intake and protein insufficiency, protein needs during illness or the therapeutic use of a high-protein diet in conjunction with low-carbohydrate and low-energy intake in people with obesity and T2DM 1,6,8,[17][18][19][20][21] . ...
Dietary protein is crucial for human health because it provides essential amino acids for protein synthesis. In addition, dietary protein is more satiating than carbohydrate and fat. Accordingly, many people consider the protein content when purchasing food and beverages and report ‘trying to eat more protein’. The global market for protein ingredients is projected to reach approximately US$90 billion by 2021, largely driven by the growing demand for protein-fortified food products. This Perspective serves as a caution against the trend of protein-enriched diets and provides an evidence-based counterpoint that underscores the potential adverse public health consequences of high protein intake.
Ketogenic diets (KD) are dietary strategies low in carbohydrates, normal in protein, and high, normal, or reduced in fat with or without (Very Low-Calories Ketogenic Diet, VLCKD) a reduced caloric intake. KDs have been shown to be useful in the treatment of obesity, metabolic diseases and related disorders, neurological diseases, and various pathological conditions such as cancer, nonalcoholic liver disease, and chronic pain. Several studies have investigated the intracellular metabolic pathways that contribute to the beneficial effects of these diets. Although epigenetic changes are among the most important determinants of an organism's ability to adapt to environmental changes, data on the epigenetic changes associated with these dietary pathways are still limited. This review provides an overview of the major epigenetic changes associated with KDs.
Currently, there is an acute issue of environmental pollution and loss of vital substances for the human body and animals — fats, proteins and minerals. Scales, fins, skin, bones, and cartilage are a valuable source for these beneficial substances. The composition of fish protein contains almost all the essential amino acids, which characterizes its high biological value. A large share of the world’s catch is underutilized or simply lost, since the fish processing process usually comes down to primary cutting, resulting in a loss of 30 to 70% of the mass of raw materials in the form of biological waste. Therefore, at present, it is necessary to develop such technologies that will maximize the use of natural raw materials. It was found that the rational, to obtain the highest collagen content in the hydrolyzate, is the double extraction technology, which consists in using the electrochemically obtained hydrolyzate from fish bone waste as an extractant for the isolation of collagen from the skin. In the course of the work, the optimal treatment modes for the cartilage waste from cutting salmon fish by the electrochemical method were determined, as a result of which a protein hydrolyzate was obtained. The technological and physicochemical properties of the obtained protein hydrolyzate are studied, based on which the nutritional and biological value of the product is analyzed.
High‐protein hypocaloric nutrition, tailored to each patient's muscle mass, protein‐catabolic severity, and exogenous energy tolerance, is the most plausible nutrition therapy in protein‐catabolic critical illness. Sufficient protein provision could mitigate the rapid muscle atrophy characteristic of this disease while providing urgently needed amino acids to the central protein compartment and sites of tissue injury. The protein dose may range from 1.5 to 2.5 g protein (1.8–3.0 g free amino acids)/kg dry body weight per day. Nutrition should be low in energy (≈70% of energy expenditure or ≈15 kcal/kg dry body weight per day) because efforts to match energy provision to energy expenditure are physiologically irrational, risk toxic energy overfeeding, and have repeatedly failed in large clinical trials to demonstrate clinical benefit. The American Society for Parenteral and Enteral Nutrition currently suggests high‐protein hypocaloric nutrition for obese critically ill patients. Short‐term high‐protein hypocaloric nutrition is physiologically and clinically sensible for most protein‐catabolic critically ill patients, whether obese or not.
The long-term effect of therapeutic diets in obesity treatment is a challenge at present. The current study aimed to evaluate the long-term effect of a very low-calorie-ketogenic (VLCK) diet on excess adiposity. Especial focus was set on visceral fat mass, and the impact on the individual burden of disease. A group of obese patients (n = 45) were randomly allocated in two groups: either the very low-calorie-ketogenic diet group (n = 22), or a standard low-calorie diet group; (n = 23). Both groups received external support. Adiposity parameters and the cumulative number of months of successful weight loss (5 or 10 %) over a 24-month period were quantified. The very low-calorie-ketogenic diet induced less than 2 months of mild ketosis and significant effects on body weight at 6, 12, and 24 months. At 24 months, a trend to regress to baseline levels was observed; however, the very low-calorie-ketogenic diet induced a greater reduction in body weight (−12.5 kg), waist circumference (−11.6 cm), and body fat mass (−8.8 kg) than the low-calorie diet (−4.4 kg, −4.1 cm, and −3.8 kg, respectively; p < 0.001). Interestingly, a selective reduction in visceral fat measured by a specific software of dual-energy x-ray absorptiometry (DEXA)-scan (−600 g vs. −202 g; p < 0.001) was observed. Moreover, the very low-calorie-ketogenic diet group experienced a reduction in the individual burden of obesity because reduction in disease duration. Very low-calorie-ketogenic diet patients were 500 months with 5 % weight lost vs. the low-calorie diet group (350 months; p < 0.001). In conclusion, a very low-calorie-ketogenic diet was effective 24 months later, with a decrease in visceral adipose tissue and a reduction in the individual burden of disease.
Weight loss maintenance remains a major challenge in obesity treatment.
The objective was to evaluate the effects of anti-obesity drugs, diet, or exercise on weight-loss maintenance after an initial very-low-calorie diet (VLCD)/low-calorie diet (LCD) period (<1000 kcal/d).
We conducted a systematic review by using MEDLINE, the Cochrane Controlled Trial Register, and EMBASE from January 1981 to February 2013. We included randomized controlled trials that evaluated weight-loss maintenance strategies after a VLCD/LCD period. Two authors performed independent data extraction by using a predefined data template. All pooled analyses were based on random-effects models.
Twenty studies with a total of 27 intervention arms and 3017 participants were included with the following treatment categories: anti-obesity drugs (3 arms; n = 658), meal replacements (4 arms; n = 322), high-protein diets (6 arms; n = 865), dietary supplements (6 arms; n = 261), other diets (3 arms; n = 564), and exercise (5 arms; n = 347). During the VLCD/LCD period, the pooled mean weight change was -12.3 kg (median duration: 8 wk; range 3-16 wk). Compared with controls, anti-obesity drugs improved weight-loss maintenance by 3.5 kg [95% CI: 1.5, 5.5 kg; median duration: 18 mo (12-36 mo)], meal replacements by 3.9 kg [95% CI: 2.8, 5.0 kg; median duration: 12 mo (10-26 mo)], and high-protein diets by 1.5 kg [95% CI: 0.8, 2.1 kg; median duration: 5 mo (3-12 mo)]. Exercise [0.8 kg; 95% CI: -1.2, 2.8 kg; median duration: 10 mo (6-12 mo)] and dietary supplements [0.0 kg; 95% CI: -1.4, 1.4 kg; median duration: 3 mo (3-14 mo)] did not significantly improve weight-loss maintenance compared with control.
Anti-obesity drugs, meal replacements, and high-protein diets were associated with improved weight-loss maintenance after a VLCD/LCD-period, whereas no significant improvements were seen for dietary supplements and exercise.
There is a general perception that almost no one succeeds in long-term maintenance of weight loss. However, research has shown that ≈20% of overweight individuals are successful at long-term weight loss when defined as losing at least 10% of initial body weight and maintaining the loss for at least 1 y. The National Weight Control Registry provides information about the strategies used by successful weight loss maintainers to achieve and maintain long-term weight loss. National Weight Control Registry members have lost an average of 33 kg and maintained the loss for more than 5 y. To maintain their weight loss, members report engaging in high levels of physical activity (≈1 h/d), eating a low-calorie, low-fat diet, eating breakfast regularly, self-monitoring weight, and maintaining a consistent eating pattern across weekdays and weekends. Moreover, weight loss maintenance may get easier over time; after individuals have successfully maintained their weight loss for 2–5 y, the chance of longer-term success greatly increases. Continued adherence to diet and exercise strategies, low levels of depression and disinhibition, and medical triggers for weight loss are also associated with long-term success. National Weight Control Registry members provide evidence that long-term weight loss maintenance is possible and help identify the specific approaches associated with long-term success.
Objective:
Weight loss maintenance following very-low-calorie meal plans is poorly studied. This report describes weight loss efficacy and predictors of weight loss maintenance of a ketogenic, very-low-calorie meal plan (protein-sparing modified fast, PSMF) in people with obesity.
Methods:
127 consecutive adults in the PSMF meal plan (27.2 ±19.5 weeks) and 48 adults on a conventional, hypocaloric meal plan (23.6 ±20.8 weeks) were retrospectively studied for percent weight change from baseline to end of intervention and at 6, 12, and 24 months post-intervention. Baseline factors were analyzed for correlations with weight loss maintenance.
Results:
At end of intervention, weight loss from baseline was greater for the PSMF group compared to the conventional intervention group (-12.4% vs. -2.6%, p<0.001) but was similar between groups by 12 months post-intervention. PSMF subjects who attended follow-up visits to receive instruction on gradual and limited carbohydrate refeeding after ketosis saw significant weight loss at the end of PSMF compared to those who did not follow up to receive instruction (-17.5% vs. -8.0%, p<0.001) and maintained greater weight loss through 12 months post-PSMF (-9.8% vs. -1.5%, p<0.001). Higher baseline BMI correlated with less weight loss at 12 months post-PSMF (p=0.035).
Conclusions:
PSMF results in effective short-term weight loss of more than 5% from baseline weight. Follow-up for limited carbohydrate refeeding instruction is important for weight loss maintenance up to two years after initial weight loss.
Context:
A common concern when using low-calorie diets as a treatment for obesity is the reduction in fat-free mass, mostly muscular mass that occurs together with the fat mass loss, and the best methodologies to evaluate body composition changes.
Objective:
To evaluate the very low-calorie-ketogenic (VLCK) diet-induced changes in body composition of obese patients and to compare three different methodologies employed to evaluate that changes.
Design:
Twenty obese patients followed a VLCK diet for 4 months. Body composition was performed by dual-energy X-ray absorptiometry (DXA), multifrequency bioelectrical impedance (MF-BIA) and air displacement plethysmography (ADP) techniques. Muscular strength was also assessed. Measurements were performed at four points matched with the ketotic phases (basal, maximum ketosis, ketosis declining and out of ketosis).
Results:
After 4-months the VLCK diet induced a -20.2±4.5 kg weight loss, at expenses of reductions in fat mass (FM) of -16.5 ± 5.1 kg (DXA), -18.2 ± 5.8 kg (MF-BIA), and -17.7 ± 9.9 kg (ADP). A significant decrease was also observed in the visceral FM. The mild but significant reduction in fat-free mass occurred at maximum ketosis mainly due to changes in the total body water and was recovered thereafter. No changes in muscle strength were observed. A strong correlation was evidenced between the three methods of body composition.
Conclusion:
The VLCK diet-induced weight loss was mainly at the expense of FM and visceral mass, preserving muscle mass and strength. From the three employed body composition techniques, the multifrequency bioelectrical impedance seems more convenient in the clinical setting.
The metabolic response to yellow fever immunization was investigated in five obese patients who were consuming a protein-sparing modified fast for 3 wk. Fasting 1/2, 1, and 2 h postprandial values for insulin, glucagon, glucose, lactate, beta hydroxybutyrate, acetoacetate, and free fatty acids were assessed before and the 1st, 3rd, and 5th day after immunization. The hormone and substrate responses to meat ingestion in patients well adapted to a protein-sparing modified fast and prior to infection was a rise in glucagon, no change in insulin, lactate, or ketone bodies and slight increase in serum free fatty acid and glucose levels. Over the entire period a significant (p less than 0.01) postprandial rise in glucagon was noted. Significant increases in insulin (p less than 0.01) and lactate (p less than 0.01) and falls in beta hydroxybutyrate (p less than 0.01) and acetoacetate (p less than 0.01) were noted in the postinfection period. There was also a significant interaction of diet and infection to increase insulin levels (p less than 0.05). The clinically mild infection produced by yellow fever immunization elicits a metabolic response which thus may be useful to investigate intermediary metabolism in the hospital setting.
Twelve patients with recent weight loss to less than 85% of standard weightheight ratio and a serum albumin level of at least 3 gm/100 ml were considered to have the adult equivalent of marasmus. Cellular immune function was assessed by delayed hypersensitivity skin testing to Monilia and streptokinase-streptodornase, peripheral lymphocyte count, proportion of T and B cells, whole blood and isolated lymphocyte transformation to phytohemagglutinin, pokeweed mitogen, concanavalin A, Monilia, and streptokinase-streptodornase. Significant impairment of skin test reactivity while in vitro responsiveness remained intact was noted in the marasmic patients. No impairment was found in 12 individuals with recent weight loss who remained at a weight greater than the 85% weight-height ratio. In four marasmic individuals in whom weight loss was arrested by nutritional repletion, skin reactivity returned without substantial change in weight.In this type of marasmus, both depleted nutritional status and weight loss must be present for impairment of skin test responsiveness. These findings confirm relative sparing of more vital functions dependent on protein metabolism in adult marasmus compared to the kwashiorkorlike syndrome of hypoalbuminemic malnutrition seen in adults.(Arch Intern Med 137:1408-1411, 1977)
• Liver biopsy specimens were studied in 26 patients in whom liver function abnormalities developed during intravenous hyperalimentation (IVH). The clinical manifestations and duration of IVH were evaluated in relation to the morphological changes seen in the liver.
Early hepatic changes consisted of fatty metamorphosis, and progressive intrahepatic cholestasis developed as IVH was continued. Essential fatty acid deficiency, amino acid imbalance, caloric excess, and toxic manifestations of certain amino acids are postulated as causative factors. The hepatic steatosis secondary to IVH may be treated by lowering the dextrose concentration of the infusion or by administering dextrose-free amino acid solutions. The clinical importance of this common complication of IVH is the difficulty in distinguishing it from other causes of cholestasis in seriously ill patients.
(Arch Surg 113:504-508, 1978)
Knowledge of cellular metabolism will increasingly direct research efforts toward more precise targeting of nutritional requirements. Starvation denies the patient the substantial benefit of nutrient intake that can support many important aspects of metabolic function. We now seek nutrients that not only supply requisite energy and protein needs but also influence the aspects of cellular metabolism that affect regional blood flow, endothelial function, and cellular immune function. In the future, cellular nutritional support of early multiple organ failure using lipids such as fish oil may influence the prostaglandin milieu, while use of arginine may synergize these effects by increasing the production of endothelium-derived vasoactive substances. Cellular function in multiple organ failure will never be satisfactory in a starvation state. The challenge is to find the most beneficial nutrients and the most appropriate delivery options.
Regardless of the approach to the management of obesity, final reliance must be placed upon the induction of a negative caloric balance in order for there to be any significant loss of fat.1 In most cases this can be accomplished by restriction of the dietary intake which many patients are unable or unwilling to maintain for any significant length of time. Although a rational interpretation of nutritional data teaches us that general health can best be sustained during weight reduction by use of a balanced diet deficient only in calories and maintained over a protracted period, regimens designed for rapid weight loss continue to be attractive to many. The concept of the total starvation diet as an adjunct to the treatment of obesity has been introduced by Bloom2 and used extensively by Duncan and coworkers.3,4 The presumed success of this approach stems at least in part from
Changes in body weight, nitrogen, water, and total body fat were evaluated, with two independent techniques, in four obese patients during seven consecutive 16-day periods during which each patient was starved for 16 days and then fed an 800-calorie liquid diet for 16 days before again being fasted. The major component of the body weight loss during every starvation period was not fat, but water and protein. The periods of caloric restriction which followed each starvation period were characterized by minimal change in body weight and rapid reaccumulation of water and nitrogen. Fat loss, although variable in magnitude, was constant throughout starvation and caloric restriction. The average cumulative fat loss during 48 days of total starvation was not significantly different from the average fat loss during 48 days of caloric restriction.
In a survey of the protein nutritional status of all patients on the surgical wards of an urban municipal hospital, accepted standards indicated moderate to severe protein-calorie malnutrition (PCM) in one half of these patients as judged by triceps skin fold and arm muscle circumference measurements. Weight for height was less severely affected. Although serum albumin levels were recorded in only 43% during the perisurvey periods, the correlation between arm muscle circumference and serum albumin level was highly significant, suggesting that this measurement would substantiate a rate of approximately 50% malnutrition.
(JAMA 230:858-860, 1974)
AMERICA'S most celebrated weight loss was announced on November 15,1988, when Oprah Winfrey disclosed to her 18 million television viewers that she had lost 30.5 kg (67 lb) in 4 months by consuming a medically supervised very-low-calorie diet (New York Times. November 24,1988:B17). Ms Winfrey's announcement sparked a frenzy of interest among the nation's dieters, reminiscent of that which greeted the appearance of the liquid protein diets in 1976 and 19771 and the Cambridge Diet in the early 1980s.2 Sadly, consumption of these diets was inadequately supervised; at least 58 deaths were reported among users of liquid protein products1,3 and 6 deaths in persons who consumed the Cambridge Diet.2
Current very-low-calorie diets that provide essential nutrients and high-quality proteins are unquestionably safer than their liquid protein predecessors, as noted in a timely report prepared by the American Medical Association's Council on Scientific Affairs.4 But the
The determinants of length of survival during total fasting are unknown. Media reports of hunger strikers in Northern Ireland have provided some basis for evaluating this question. Such "data" combined with standard concepts of body composition, fuel homeostasis, and responses to therapeutic fasts suggest that death occurred when fat stores were approaching exhaustion. Thus, fat stores may play a central role.
(JAMA 1982;248:2306-2307)
Three, single-day nutritional surveys at weekly intervals were conducted in the general medical wards of an urban municipal teaching hospital. The techniques of nutritional assessment included anthropometric measures (weight/height, triceps skin fold, arm-muscle circumference, serum albumin, and hematocrit). The prevalence of protein-calorie malnutrition was 44% or greater by these criteria (weight/height, 45%; triceps skin fold, 76%; arm-muscle circumference, 55%; serum albumin, 44%; and hematocrit, 48%). These results were reproducible without significant variation between surveys. In 34% of patients, a lymphopenia of 1,200 cells/cu mm or less was found, a level likely to be associated with diminished cell-mediated immunity. Compared with a similar survey among surgical patients, the medical patients were more depleted calorically (weight/height, triceps skin fold) but had better protein status (arm-muscle circumference, serum albumin). Significant protein-calorie malnutrition occurs commonly in municipal hospitals in both medical and surgical services.(JAMA 235:1567-1570, 1976)
The value of nutrition in surgery has been well appreciated for the past two decades. Although it has become increasingly obvious that protein metabolism often plays a decisive role in the final outcome of patients who have undergone surgery, it has rarely been possible to obtain a state of positive nitrogen balance following major surgical procedures. Since many investigators have shown that it takes approximately 150 nonprotein calories to spare 1 gm of nitrogen, it was thought impossible to obtain positive nitrogen balance by parenteral routes because of the hypertonic solution required. Recently, Dudrick et al1-3 raised six Beagle puppies to full growth, utilizing only intravenous alimentation. High doses of carbohydrate and protein hydrolysate were infused to supply adequate calories and protein factors. Subsequently, Dudrick et al have supported many patients having serious chronic gastrointestinal disease with intravenous alimentation and have established a positive nitrogen balance in each.4-7
We tested the hypothesis that the use of a very-low-calorie diet (VLCD) in combination with behavior modification would promote long-term glycemic control in obese type 2 diabetic subjects. Thirty-six diabetic subjects were randomly assigned to a standard behavior therapy program or to a behavior therapy program that included an 8-week period of VLCD. The behavior therapy group consumed a balanced diet of 4200 to 6300 J/d throughout the 20-week program. The VLCD group consumed a balanced diet of 4200 to 6300 J for weeks 1 to 4, followed by a VLCD (1680 J/d of lean meat, fish, and fowl) for weeks 5 to 12. The VLCD group then gradually reintroduced other foods during weeks 13 to 16 and consumed a balanced diet of 4200 to 6300 J/d for weeks 17 to 20. Thirty-three of the 36 subjects completed the 20-week program and the 1-year follow-up. Use of the VLCD produced greater decreases in fasting glucose at the end of the 20-week program and at 1-year follow-up and greater long-term reductions in HbA1. The VLCD group also had greater weight losses at week 20, but weight losses from pretreatment to 1-year follow-up were similar in the two treatment groups. The improved glycemic control with the VLCD appeared to be due to increased insulin secretion, but further research is needed to confirm this.
(Arch Intern Med. 1991;151:1334-1340)
The protein-sparing modified fast (PSMF) is a very-low-calorie diet containing mostly protein and little carbohydrate. This article reviews the principles of the PSMF and its potential benefits in terms of weight loss, glycemic control, insulin resistance, cardiovascular risk factors, and related complications for patients with type 2 diabetes.
American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice are systematically developed statements to assist health care professionals in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. The presented recommendations may not be appropriate in all situations. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances.
Objective:
Liraglutide, a once-daily human glucagon-like peptide-1 analog, induced clinically meaningful weight loss in a phase 2 study in obese individuals without diabetes. The present randomized phase 3 trial assessed the efficacy of liraglutide in maintaining weight loss achieved with a low-calorie diet (LCD).
Methods:
Obese/overweight participants (≥18 years, body mass index ≥30 kg m(-2) or ≥27 kg m(-2) with comorbidities) who lost ≥5% of initial weight during a LCD run-in were randomly assigned to liraglutide 3.0 mg per day or placebo (subcutaneous administration) for 56 weeks. Diet and exercise counseling were provided throughout the trial. Co-primary end points were percentage weight change from randomization, the proportion of participants that maintained the initial ≥5% weight loss, and the proportion that lost ≥5% of randomization weight (intention-to-treat analysis). ClinicalTrials.gov identifier: NCT00781937.
Results:
Participants (n=422) lost a mean 6.0% (s.d. 0.9) of screening weight during run-in. From randomization to week 56, weight decreased an additional mean 6.2% (s.d. 7.3) with liraglutide and 0.2% (s.d. 7.0) with placebo (estimated difference -6.1% (95% class intervals -7.5 to -4.6), P<0.0001). More participants receiving liraglutide (81.4%) maintained the ≥5% run-in weight loss, compared with those receiving placebo (48.9%) (estimated odds ratio 4.8 (3.0; 7.7), P<0.0001), and 50.5% versus 21.8% of participants lost ≥5% of randomization weight (estimated odds ratio 3.9 (2.4; 6.1), P<0.0001). Liraglutide produced small but statistically significant improvements in several cardiometabolic risk factors compared with placebo. Gastrointestinal (GI) disorders were reported more frequently with liraglutide than placebo, but most events were transient, and mild or moderate in severity.
Conclusion:
Liraglutide, with diet and exercise, maintained weight loss achieved by caloric restriction and induced further weight loss over 56 weeks. Improvements in some cardiovascular disease-risk factors were also observed. Liraglutide, prescribed as 3.0 mg per day, holds promise for improving the maintenance of lost weight.
Total fast periods of 4 to 14 days in the management of 50 cases of intractable obesity achieved a prompt decrease in body weight of approximately 2.5 lb. per day. Subsequent shorter fast periods served to prevent a recurrence of the obese state and, also, to achieve further reduction in weight in the ensuing weeks. Non-nutritious fluids were allowed ad libitum and polyvitamins were given. Exercise was interdicted. Anorexia was the rule after the first day of fasting and paralleled the degree of hyperketonemia. A sense of well-being was associated with the fast. The patient's subsequent 1- or 2-day fasts, as an outpatient promoted his reassurance that he had within his grasp a means of effectively combating what had formerly appeared to be a hopeless situation.
READERS of both Time (March 14, 1983, pp 91-93) and Newsweek (Feb 28, 1983, pp 75-77) learned recently of "a new scientific breakthrough that works faster and is more effective than you ever thought possible." This "breakthrough," heralded in three-page advertisements, is the Cambridge Diet. Since "more than three million overweight Americans have already discovered the Cambridge Diet Plan," and millions are likely to as a result of these ads, the medical community would be well advised to familiarize itself with the diet and the controversy surrounding it.The Cambridge Diet is one of several very-low-calorie diets (300 to 600 kcal/day) currently available in this country. The goal of these diets is to induce the largest, most rapid weight loss possible, while preserving lean body mass by the provision of varying amounts of high-quality protein and carbohydrate. This was the same goal of the liquid protein diets of 1976 and
The weights of 207 morbidly obese patients were reduced via prolonged fasting. Half the patients fasted for close to two months, losing a mean of 28.2 kg; one fourth fasted for less than one month; and the other fourth fasted for more than two months, with a mean 41.4-kg loss. This latter group was heavier initially, and more than 50% attained near-normal weight. Patients with onset of obesity in childhood had the lowest tolerance for fasting and the lowest success rate in attaining normal weight. Over a 7.3-year follow-up period in 121 patients, the reduced weight was maintained for the first 12 to 18 months. Subsequently, regain proceeded equally in all groups irrespective of length of fast, extent of weight loss, or age at onset of obesity. Regain to original weight occurred in 50% within two to three years and only seven patients remained at their reduced weights. Regain to greater than original weight was more common in childhoodonset obesity.(Arch Intern Med 137:1381-1382, 1977)
Some of the reasons why so many severely obese patients fail to reach normal weight with moderate dietary restriction are the disappointingly slow weight loss and persistent hunger. Consequently, many physicians have been resorting to dietary regimens supplying 200 to 600 calories. The result is rapid and extensive weight loss without much hunger.The purpose of this communication is to emphasize the advantages of a "semistarvation" regimen and to suggest some measures which enhance the chances of success while minimizing the hazards inherent in such treatment. Severe dietary restriction does result in major physical and biochemical changes, and these can, in certain patients, cause serious complications.Patient Selection.—
Most patients with uncomplicated obesity will easily tolerate prolonged semistarvation. Children and adolescents who are still growing and pregnant women should be excluded because of possible impairment of growth. In the older-age group, the risk of complications would seem to be excessive
Objective: To determine whether the frequency rate of hyperglycemia and infectious complications can be reduced by an underfeeding strategy in patients requiring total parenteral nutrition (TPN), without deleterious effects on nitrogen balance.
Design: Prospective, randomized, controlled nonblinded trial.
Setting: A university-affiliated teaching hospital with a dedicated TPN service.
Patients: TPN was initiated in 40 adult patients and continued for ≥5 days.
Intervention: Two different TPN feeding strategies were compared: hypocaloric feeding (1 L containing 70 g protein and 1000 kcal) and standard weight-based regimen, begun in similar amounts initially, but advanced in increments toward 25 kcal and 1.5 g protein/kg dry (or adjusted ideal) weight.
Measurements and Main Results: We evaluated the frequency rate of hyperglycemia, average blood glucose, numbers and types of infections while receiving nutritional support, and nitrogen balance after 5 days of TPN. There were significant differences between the quantities of calories, dextrose, fat, and protein provided to the two groups. However, average blood glucose, frequency rate of hyperglycemia, and infection rates (from intravenous catheter, pneumonia, and wound/abdominal collection) were similar in each group. The control group showed a trend toward a higher insulin requirement. Nitrogen balance, only available as a subset, was significantly more negative in the hypocaloric group.
Conclusions: Provision of TPN to a goal of 25 kcal/kg was not associated with more hyperglycemia or infections than a deliberate underfeeding strategy. A regimen of 1.5 g/kg protein in conjunction with 25 kcal/kg did, however, provide significant nutritional benefit in terms of nitrogen balance in comparison with hypocaloric TPN.
Editor's Note: James Gamble's Harvey Lecture of 1947 described experiments that provided the foundation for modern understanding of the physiology of fluid and electrolyte balance during deprivation. The excerpt here reports Gamble's elegantly clear analysis of the role of parenteral glucose in maintenance of fluid and acid-base balance.
A prospective randomized crossover trial was conducted to determine the effect of a branched chain amino acid (BCAA)-enriched solution on whole body leucine kinetics and fractional rates of albumin synthesis in patients with intra-abdominal metastatic adenocarcinoma. Ten malnourished cancer patients were provided isonitrogenous amounts of both a conventional total parenteral nutrition (TPN) formula containing 19% BCAA and a BCAA-enriched TPN formula containing 50% of the amino acids as BCAA in a random order. Whole body protein turnover was determined by a 10 hour continuous infusion of leucine14C. Increased whole body leucine flux (68 ± 5 ųumols/kg BW/hr versus 145 ± 11; mean ± SEM; P 0.001) and oxidation (13 ± 2 ųmols/kg BW/hr to 46 ± 5; P 0.001) were determined on the BCAA-enriched TPN. Increased whole body protein synthesis (2.2 ± 0.2 g protein/kg BW/day versus 3.9 ± 0.3; P 0.005) and leucine balance (2.5 ± 0.4 g leucine/d versus 6.5 ± 0.6; P 0.001) were also observed in patients receiving the BCAA-enriched TPN solution. Leucine release from protein breakdown was not statistically elevated (1.65 ± 0.18 g protein/kg BW/d versus 2.48 ± 0.40; P >0.05) but, incorporation of leucine 14C into plasma albumin was significantly elevated (2.37 ± 0.23 ųumols/g/hr to 4.21 ± 0.33; P 0.001) when the patients received BCAA-enriched TPN. Despite the better leucine balance, the improvement in the 24-hour urinary nitrogen balance was not statistically significant (6.6 ± 3.9 g protein/d versus 11.4 ± 2.9; control versus BCAA-enriched; P=0.15). BCAA-enriched formulas improve whole body leucine kinetics, fractional rates of albumin synthesis, and leucine balance, and thus may favorably influence protein metabolism in cancer cachexia. Cancer 58:147–157, 1986.
We studied the effect of recombinant human interleukin-1β (IL-1) and recombinant human tumor necrosis factor α/cachectin (TNF) on glucose kinetics in healthy rats by means of a primed constant infusion of d-(6-3H)glucose and d-[U-14C]glucose. During the isotope (6-hour) and monokine (4-hour) infusion, plasma levels of glucagon and insulin were determined and correlated with changes in glucose metabolism. The rates of glucose appearance (Ra) and disappearance (Rd) were elevated only with IL-1 and were associated with an increase in glucagon and a concomitant decrease in the ratio of insulin to glucagon. Plasma glucose concentration was increased early after IL-1 administration and coincided with the peak in the Ra. The augmentation of the metabolic clearance rate (MCR) and percent of flux oxidized by IL-1 suggest that this monokine induces the utilization of glucose as a substrate. TNF administration failed to modify the Ra or Rd, percent of flux oxidized, or MCR. TNF-treated rats increased the percent of glucose recycling, but not the total rate of glucose production. The results of this experiment suggest that endogenous macrophage products participate in the diverse alterations of carbohydrate metabolism seen during injury and/or infection.
The present study was undertaken to compare the effectiveness of a physical mixture of long-chain and medium-chain triglycerides with an emulsion consisting of chemically synthesized triglycerides composed of medium-chain and long-chain fatty acids in similar proportions. Sprague-Dawley rats received a 25% body surface area full-thickness scald burn on the dorsum. For the next three days, all rats received 300 kcal/kg/day as 160 kcal/kg/day glucose, 50 kcal/kg/day amino acid, and an additional 90 kcal/kg/day lipid emulsion as either long-chain triglyceride, medium-chain triglyceride, a 1:1 physcial mix of medium-chain and long-chain triglycerides or a chemically structured triglyceride made up of 60% medium-chain fatty acid and a 40% safflower oil. Rats receiving the chemically structured lipid emulsion showed the greatest gain in body weight, the greatest positive nitrogen balance, and the highest serum albumin concentration, outstripping rats receiving the long-chain triglyceride, medium-chain triglyceride, and even the physical mixture long-chain and medium-chain trigylcerides (P < 0.01). A 30% increase in oxygen consumption and 35% increase in energy expenditure in rats given the medium-chain triglyceride emulsion alone (P < 0.01) was observed. This study confirms that the metabolism of chemically structured triglycerides composed of medium-chain and long-chain fatty acids markedly differs from similar physical mixtures. For these reasons, the new structured lipid emulsions may prove advantageous in feeding the severely injured patient.
A modification of the Picou and Taylor-Roberts Model was used to estimate rates of total body protein synthesis (S), breakdown (C), and amino nitrogen (N) flux (Q) in the metabolic N pool of five obese females. The subjects were fed egg white albumin at 1.5/kg ideal body weight (IBW) and total calories at 1.2 times the basal energy expenditure (fat:carbohydrate = 30%:50%) as a formula diet (period 1, 1 wk). This was followed by 3 wk during which the nonprotein calories were omitted (period 2, protein-sparing modified fast [PSMF]) and a 1-wk total fast (period 3). Estimates of body protein turnover and skeletal protein breakdown were made during the last 60 and 48 hr, respectively, of each period. Q, S, and C were 223 ± 22, 154 ± 22, and , respectively, for period 1. These values were unchanged at the end of period 2. Total fasting decreased Q and S by 36% and 27%, respectively (p < 0.001), but C remained unchanged. Skeletal protein breakdown, as estimated by urinary Nτ-methylhistidine excretion, was 108 ± 47 μmole in period 1, 79 ± 51 μmole in period 2 (p < 0.01), and 100 ± 49 μmole in period 3, representing 16 ± 5%, 12 ± 5% (p < 0.01), and 16 ± 4% of whole body breakdown. N balance was unchanged in period 1 (−0.4 ± 1.2 g N) and the final week of period 2 (−0.4 ± 1.5 g N), but was −5.8 ± 0.6 g N in period 3. These data indicate that weight reduction with a PSMF is associated with a maintenance of total body protein turnover parameters and N balance but a reduction in skeletal protein breakdown, whereas a total fast causes a marked reduction in whole body protein synthesis and amino N flux with little change in the rate of total body and skeletal protein breakdown, resulting in a negative N balance. The minimization of N losses that develops after prolonged starvation is achieved at rates of whole body and skeletal protein breakdown similar to those found when the diet is adequate, suggesting that endogenous fat-derived fuels are as effective as exogenous energy in limiting protein catabolism. However, protein intake is necessary to maintain whole body protein synthesis under these conditions.
The effects of amino acids on protein turnover in skeletal muscle were determined in the perfused rat hemicorpus preparation. Perfusion of preparations from fasted young rats (81±2 g) with medium containing either a complete mixture of amino acids at five times (5×) their normal plasma levels, a mixture of leucine, isoleucine, and valine at 5× or 10× levels, or leucine alone (10×) resulted in a 25–50% increase in muscle protein synthesis and a 30% decrease in protein degradation compared to fasted controls perfused in the absence of exogenously added amino acids. When the branched-chain amino acids were omitted from the complete mixture, the remaining amino acids (5×) had no effect on protein turnover. The complete mixture at 1× levels was also ineffective. Comparison of the effects of amino acids with those of glucose and palmitate indicated that amino acids were not acting by providing substrates for energy metabolism. The stimulatory effect of amino acids on protein synthesis was associated with a facilitated rate of peptide-chain initiation as evidenced by a relative decrease in the level of ribosomal subunits. This response was not as great as that produced by insulin, and the amino acids did not augment the effect of insulin. Although protein synthesis in preparations from fed young rats (130±3 g) was stimulated by the addition of a mixture of the branched-chain amino acids (5×) to about the same extent as that observed in the fasted young rats, protein degradation was not affected. Furthermore, neither synthesis nor degradation were affected in preparations from fasted older rats (203±9 g) suggesting that the age and or nitritional state of the animal may influence the response of skeletal muscle to altered amino acid levels.
The aim of the study was to investigate the effects of two hypocaloric (800-kcal) diets on body weight reduction and composition, insulin sensitivity, and proteolysis in 25 normal glucose-tolerant obese women. The two diets had the following composition: 45% protein, 35% carbohydrate (CHO), and 20% fat (HP diet, 10 subjects), and 60% CHO, 20% protein, and 20% fat (HC diet, 15 subjects); both lasted 21 days. A euglycemic hyperinsulinemic (25 mU/kg/h) clamp lasting 150 minutes combined with indirect calorimetry was performed before and after the diet. Both diets induced a similar decrease in body weight and fat mass (FM), whereas fat-free mass (FFM) decreased only after the HC diet. 3-Methylhistidine (3-CH3-HIS) excretion was reduced by 48% after the HP diet and remained unchanged after the HC diet (P < .05). A significant correlation was found between the changes in FFM and in 3-CH3-HIS excretion after the diet (rs = .50, P < .02). Blood glucose remained unchanged, while insulin decreased in both diets. Free fatty acids (FFA) significantly increased only after the HC diet (P < .05). During the clamp period, glucose disposal and glucose oxidation significantly increased after the HP diet and significantly decreased after the HC diet. Opposite results were found when measuring lipid oxidation. In conclusion, our experience suggests that (1) a hypocaloric diet providing a high percentage of natural protein can improve insulin sensitivity; and (2) conversely, a hypocaloric high-polysaccharide-CHO diet decreases insulin sensitivity and is unable to spare muscle tissue.
Sixteen obese patients 9 to 16 years of age were treated with a protein-sparing modified fast for four weeks in a metabolic unit, using lean meat as the sole calorie-containing nutrient. Total weight loss was 7.11±0.33 kg (mean ± SEM). One-half of the patients achieved positive daily nitrogen balance by the fourth week. Cumulative N balance was −28.8±10.0 gm. Serum albumin concentration remained normal. Hemoglobin and hematocrit values were stable, but decreases in total lymphocyte (P<0.005) and neutrophil counts (P<0.01) were noted. Cell-mediated immunity (four patients) remained normal. Protein synthetic and catabolic rates (two patients) revealed only minimal changes. Cumulative N balance correlated (P<0.01) with mean fasting serum insulin concentration, which was related (P<0.005) to body fat mass. The PSMF has therapeutic potential for achieving safe, rapid weight loss in severely obese older children and adolescents.
Metabolic changes after surgery, trauma, or serious illness have a complex pathophysiology. The early posttraumatic stress response is physiologic and associated with a state of hyperinflammation, increased oxygen consumption, and increased energy expenditure. These are part of a systemic reaction that encompasses a wide range of endocrinological, immunologic, and hematological effects. Surgery initiates changes in metabolism that can affect virtually all organs and tissues; the metabolic response results in hormone-mediated mobilization of endogenous substrates that leads to stress catabolism. Hypercatabolism has been associated with severe complications related to hyperglycemia, hypoproteinemia, and immunosuppression. Proper metabolic support is essential to restore homeostasis and ensure survival.