Science dialogue mapping of knowledge and knowledge gaps related to the effects of dairy intake on human cardiovascular health and disease.

Dairy has been described as everything from a superfood to a poison; yet, arguments, assumptions, and data justifying these labels are not always clear. We used an issue-based information system, "dialogue mapping™," to summarize scientific points of a live panel discussion on the putative effects of dairy on cardiovascular diseases (CVD) from a day-long session among experts in nutrition and CVD. Dialogue mapping captures relations among ideas to explicitly, logically, and visually connect issues/questions, ideas, pro/con arguments, and agreements, even if discussed at different times. Experts discussed two propositions: for CVD risk, consumption of full-fat dairy products 1) should be minimized, in part because of their saturated fat content, or 2) need not be minimized, despite their saturated fat content. The panel discussed the dairy-CVD relation through blood lipids, diabetes, obesity, energy balance, blood pressure, dairy bioactives, biobehavioral components, and other putative causal pathways. Associations and effects reported in the literature have varied by fat content of dairy elements considered, study design, intake methods, and biomarker versus disease outcomes. Two conceptual topics emerged from the discussion: 1) individual variability: whether recommendations should be targeted only to those at high CVD risk; 2) quality of evidence: whether data on dairy-CVD relations are strong enough for reliable conclusions-positive, negative, or null. Future procedural improvements for science dialog mapping include using singular rather than competing propositions for discussion.

Proposals for Upper Limits of Safe Intake for Methionine, Histidine, and Lysine in Healthy Humans.

Based on research presented during the 10th Amino Acid Assessment Workshop, no observed adverse effect levels (NOAELs) for supplemental methionine at 46 mg/(kg·d) (∼3.2 g/d), for supplemental histidine at 8.0 g/d, and for supplemental lysine at 6.0 g/d have been proposed. These NOAELs are relevant to healthy adults and are applicable only to high-purity amino acids administered in fortified foods or dietary supplements. Because individuals are exposed to the above supplemental amino acids in the context of complex combinations of essential amino acids or individually in dietary supplements for various physiologic benefits, such as body fat reduction, skin conditioning, mental energy increase, or herpes simplex treatments, the above safety recommendations will make an important contribution to regulatory and nutritional practices.

Nutrition from the Inside Out.

Nearly 50 years ago, I set out to investigate the clinical problem of hypoglycemia in children with illnesses that limited their food intake. My goal was to gather accurate and precise measurable data. At the time, I wasn't interested in nutrition as a discipline defined in its more general or popular sense. To address the specific problem that interested me required development of entirely new methods based on stable, nonradioactive tracers that satisfied the conditions of accuracy and precision. At the time, I had no inclination of the various theoretical and practical problems that would have to be solved to achieve this goal. Some are briefly described here. Nor did I have the slightest idea that developing the field would result in a fundamental change in how human clinical investigation was conducted, with the eventual replacement of radiotracers with stable isotopically labeled ones, even for adult clinical investigation. Additionally, I had no inclination that the original questions would open avenues to much broader questions of practical nutritional relevance. Moreover, only much later as the editor of The American Journal of Clinical Nutrition did I appreciate the policy implications of how nutritional data are presented in the scientific literature. At least in part, less accurate and precise measurements and less than full transparency in reporting nutritional data have resulted in widespread debate about the public policy recommendations and guidelines that are the intended result of collecting the data in the first place. This article provides a personal recollection (with all the known faults of self-reporting and retrospective memory) of the journey that starts with measurement certainty and ends with policy uncertainty.

Proposals for Upper Limits of Safe Intake for Arginine and Tryptophan in Young Adults and an Upper Limit of Safe Intake for Leucine in the Elderly.

On the basis of research presented during the 9th Amino Acid Assessment Workshop, a No Observed Adverse Effect Level (NOAEL) for diet-added arginine (added mostly in the form of dietary supplements) of 30 g/d and an upper limit of safe intake (ULSI) for diet-added tryptophan (added mostly in the form of dietary supplements) of 4.5 g/d have been proposed. Both recommendations apply to healthy young adults. The total dietary leucine ULSI proposed for elderly individuals is 500 mg · kg-1 · d-1 All 3 recommendations are relevant only to high-quality amino acid-containing products with specifications corresponding to those listed in the US Pharmacopeia Because the above amino acids are extensively utilized as dietary supplements for various real or perceived benefits, such as vasodilation, spermatogenesis, sleep, mood regulation, or muscle recovery, the above safety recommendations will have an important impact on regulatory and nutritional practices.

Saturated Fats and Cardiovascular Disease: Interpretations Not as Simple as They Once Were.

Historically, the so-called "lipid hypothesis" has focused on the detrimental role of saturated fats per se in enhancing the risks of cardiovascular disease. Recently, a body of new information and systematic analyses of available data have questioned simple interpretation of the relationship of dietary saturated fats and of individual saturated fatty acids to CVD risk. Thus, current assessments of risks due to dietary fat consumption that emphasize the confounding nature of the dietary macronutrients substituted for dietary saturated fats and give broader recognition to the effect of patterns of food intake as a whole are the most productive approach to an overall healthy diet.

Summary of workshop discussions on establishing upper limits for amino acids with specific attention to available data for the essential amino acids leucine and tryptophan.

The morning of the first day of the 8th Amino Acid Assessment Workshop was organized and co-sponsored by the International Council on Amino Acid Science (ICAAS) and the International Life Sciences Institute Research Foundation and was focused on the International Life Sciences Institute Research Foundation's approach to establishing upper limits of nutrients. The remainder of d 1 and all of d 2 were focused on the safety of leucine and tryptophan, with special emphasis on determining the upper level of the safe range of intake. It was recognized that some toxicological frameworks, mainly the key-events dose response framework, might be applicable to amino acids and provide appropriate assistance to regulators in establishing upper limits for amino acids as a group of nutrients used in dietary supplements. ICAAS-funded projects for determining the upper intake limits for the essential amino acid leucine provided the main pool of leucine data discussed at the workshop. The acute clinical study suggests 500 mg/(kg · d) as a possible upper limit for leucine in healthy humans, but the safety margin needed to widen this limit to the general population has not been determined. For tryptophan, the workshop participants found less ground for consensus. Older efficacy studies suggested that tryptophan at 8-15 g/d was well tolerated, but human research was abruptly terminated in the late 1980s and no new data are available. Animal results obtained in pigs and rodents were discussed and 2 possible strategies for applying those outcomes to humans were described.

A proposal for an upper limit of leucine safe intake in healthy adults.

Based on recent research, an upper limit of safe intake (ULSI) for leucine is proposed for healthy adults: 0.53 g/(kg·d). Because leucine has been used as a dietary supplement for many years in people practicing exercise and sport, further study with long-term exposure to leucine in this specific subpopulation should be performed to eventually adjust the ULSI.

Safety standards in infant nutrition: a United States perspective.

In the United States, the general standard for food safety is reasonable certainty of causing no harm under the intended conditions of use. In contrast to food safety policy in some other countries, the United States treats foods for infants and children no differently than foods for adults, other than requiring additional standards for infant formulas. In the United States, food safety falls under the regulatory control of more than a dozen government agencies. The principal responsibility is shared by the US Food and Drug Administration (FDA) and the US Department of Agriculture (USDA), but significant additional oversight authority is granted to the Environmental Protection Agency (EPA), the Centers for Disease Control and Prevention (CDC), and others. Furthermore, while a large number of legislative statutes provide the basis for regulatory oversight, the principal laws that govern food safety are the Federal Food, Drug and Cosmetic Act, the Federal Meat, Poultry Products and Egg Products Inspection Acts, and the Food Safety Modernization Act. The latter statute, enacted in 2011, has provided for a broad range of new industry responsibilities for the safe manufacture of food products and has significantly expanded federal enforcement authority for violations.

An analysis of the recent US dietary guidelines process in light of its federal mandate and a National Academies report.

The US Dietary Guidelines for Americans is an enormously influential policy that has guided US nutrition programs since 1980. During these last 40 years, some researchers have expressed concern that the guidelines are based on an insufficiently rigorous assessment of the scientific evidence, a view that was largely substantiated by a Congressionally mandated 2017 report by the National Academies of Sciences, Engineering, and Medicine, which identified a need for enhanced transparency, greater scientific rigor, and updates to the scientific methodology for the DGA process. This paper traces the history of these ideas and contextualizes the DGA within the law and regulations that govern its process. The paper also discusses how recent iterations of the Dietary Guidelines have not fully adhered to these guiding documents, which has resulted in diminished independence of the expert committee in charge of evaluating the science for the DGA and a continued lack of a fully rigorous scientific process for producing consistent and trustworthy guidelines for the public.

Subchronic Tolerance Trials of Graded Oral Supplementation with Phenylalanine or Serine in Healthy Adults.

Phenylalanine and serine are amino acids used in dietary supplements and nutritional products consumed by healthy consumers; however, the safe level of phenylalanine or serine supplementation is unknown. The objective of this study was to conduct two 4-week clinical trials to evaluate the safety and tolerability of graded dosages of oral phenylalanine and oral serine. Healthy male adults (n = 60, 38.2 ± 1.8y) completed graded dosages of either phenylalanine or serine supplement (3, 6, 9 and 12 g/d) for 4 weeks with 2-week wash-out periods in between. Primary outcomes included vitals, a broad spectrum of circulating biochemical analytes, body weight, sleep quality and mental self-assessment. At low dosages, minor changes in serum electrolytes and plasma non-essential amino acids glutamine and aspartic acid concentrations were observed. Serine increased its plasma concentrations at high supplemental dosages (9 and 12 g/day), and phenylalanine increased plasma tyrosine concentrations at 12 g/day, but those changes were not considered toxicologically relevant. No other changes in measured parameters were observed, and study subjects tolerated 4-week-long oral supplementation of phenylalanine or serine without treatment-related adverse events. A clinical, no-observed-adverse-effect-level (NOAEL) of phenylalanine and serine supplementation in healthy adult males was determined to be 12 g/day.

Dietary Saturated Fats and Health: Are the U.S. Guidelines Evidence-Based?

The last decade has seen nearly 20 papers reviewing the totality of the data on saturated fats and cardiovascular outcomes, which, altogether, have demonstrated a lack of rigorous evidence to support continued recommendations either to limit the consumption of saturated fatty acids or to replace them with polyunsaturated fatty acids. These papers were unfortunately not considered by the process leading to the most recent U.S. Dietary Guidelines for Americans, the country's national nutrition policy, which recently reconfirmed its recommendation to limit saturated fats to 10% or less of total energy intake, based on insufficient and inconsistent evidence. Continuation of a cap on saturated fat intake also fails to consider the important effects of the food matrix and the overall dietary pattern in which saturated fatty acids are consumed.

Dietary Sugars: Not as Sour as They Are Made Out to Be.

Over the course of evolution, Mother Nature preserved the ability of humans to make every sugar they need for metabolic functions. Glucose is the almost exclusive fuel preferred by the human brain. Human infants are born with sweet taste receptors, sugars are a significant energy source in human milk, and mammals have a direct gut-to-brain sugar-sensing system that enhances development of a preference for sugars. If sugars are as toxic as many postulate, what species advantage was conferred by this evolutionary progression? Observational studies have reported that sugar consumption is associated with various adverse health risks. However, observational studies can never prove causality, dietary intake records are known to be highly problematic, and the huge number of correlation interdependencies among environmental "exposome" variables makes it impossible to attribute causality to individual dietary components. Additionally, these studies overall have been graded as low quality, and many reported the small effect sizes are likely within the propagated methodological "noise." With several exceptions, data from randomized controlled trials that ensured isocaloric energy intakes have failed to confirm the causal implications of the observational data. Likewise, the comprehensive UK Scientific Committee on Nutrition Report on Carbohydrates and Health also failed to confirm the vast majority of widely postulated detrimental effects of sugar consumption per se. Current data on intakes of sugar-sweetened beverages and on the risks associated with high intakes of dietary fructose remain under debate.

Saturated Fats and Health: A Reassessment and Proposal for Food-Based Recommendations: JACC State-of-the-Art Review.

The recommendation to limit dietary saturated fatty acid (SFA) intake has persisted despite mounting evidence to the contrary. Most recent meta-analyses of randomized trials and observational studies found no beneficial effects of reducing SFA intake on cardiovascular disease (CVD) and total mortality, and instead found protective effects against stroke. Although SFAs increase low-density lipoprotein (LDL) cholesterol, in most individuals, this is not due to increasing levels of small, dense LDL particles, but rather larger LDL particles, which are much less strongly related to CVD risk. It is also apparent that the health effects of foods cannot be predicted by their content in any nutrient group without considering the overall macronutrient distribution. Whole-fat dairy, unprocessed meat, and dark chocolate are SFA-rich foods with a complex matrix that are not associated with increased risk of CVD. The totality of available evidence does not support further limiting the intake of such foods.

The Philosophy of Evidence-Based Principles and Practice in Nutrition.

The practice of evidence-based nutrition involves using the best available nutrition evidence, together with clinical experience, to conscientiously work with patients' values and preferences to help them prevent (sometimes), resolve (sometimes), or cope with (often) problems related to their physical, mental, and social health. This article outlines the 3 fundamental principles of evidence-based practice as applied to the field of clinical nutrition. First, optimal clinical decision making requires awareness of the best available evidence, which ideally will come from unbiased systematic summaries of that evidence. Second, evidence-based nutrition provides guidance on how to decide which evidence is more or less trustworthy-that is, how certain can we be of our patients' prognosis, diagnosis, or of our therapeutic options? Third, evidence alone is never sufficient to make a clinical decision. Decision makers must always trade off the benefits with the risks, burden, and costs associated with alternative management strategies, and, in so doing, consider their patients' unique predicament, including their values and preferences.

Short-term high dietary fructose intake had no effects on insulin sensitivity and secretion or glucose and lipid metabolism in healthy, obese adolescents.

UNLABELLED: There is virtually no information on the metabolic impact of dietary fructose intake in adolescents despite their high fructose consumption, particularly via sweetened beverages. AIM: To determine the short-term metabolic effects of dietary fructose intake in obese adolescents. METHODS: Six volunteers (3 M/3 F; 15.2 +/- 0.5 yr; 35 +/- 2 kg/m2; 39 +/- 2% body fat) were studied twice following 7 d of isocaloric, isonitrogenous high carbohydrate (60% CHO; 25% fat) diets with fructose accounting for 6% and 24% of total energy intake, respectively (random order). Insulin sensitivity and secretion were analyzed by the stable labeled intravenous glucose tolerance test and glucose and lipid kinetics using GCMS. RESULTS: A fourfold increase in dietary fructose intake did not affect insulin sensitivity or secretion, glucose kinetics, lipolysis or glucose, insulin, C-peptide, triglycerides, HDL- and LDL-cholesterol concentrations. CONCLUSIONS: In the short term, when energy intake is constant, dietary fructose per se is not a contributor to insulin resistance and hypersecretion in obese adolescents.

Options for basing Dietary Reference Intakes (DRIs) on chronic disease endpoints: report from a joint US-/Canadian-sponsored working group.

Dietary Reference Intakes (DRIs) are used in Canada and the United States in planning and assessing diets of apparently healthy individuals and population groups. The approaches used to establish DRIs on the basis of classical nutrient deficiencies and/or toxicities have worked well. However, it has proved to be more challenging to base DRI values on chronic disease endpoints; deviations from the traditional framework were often required, and in some cases, DRI values were not established for intakes that affected chronic disease outcomes despite evidence that supported a relation. The increasing proportions of elderly citizens, the growing prevalence of chronic diseases, and the persistently high prevalence of overweight and obesity, which predispose to chronic disease, highlight the importance of understanding the impact of nutrition on chronic disease prevention and control. A multidisciplinary working group sponsored by the Canadian and US government DRI steering committees met from November 2014 to April 2016 to identify options for addressing key scientific challenges encountered in the use of chronic disease endpoints to establish reference values. The working group focused on 3 key questions: 1) What are the important evidentiary challenges for selecting and using chronic disease endpoints in future DRI reviews, 2) what intake-response models can future DRI committees consider when using chronic disease endpoints, and 3) what are the arguments for and against continuing to include chronic disease endpoints in future DRI reviews? This report outlines the range of options identified by the working group for answering these key questions, as well as the strengths and weaknesses of each option.

Perspective: Improving Nutritional Guidelines for Sustainable Health Policies: Current Status and Perspectives.

A large body of evidence supports the notion that incorrect or insufficient nutrition contributes to disease development. A pivotal goal is thus to understand what exactly is appropriate and what is inappropriate in food ingestion and the consequent nutritional status and health. The effective application of these concepts requires the translation of scientific information into practical approaches that have a tangible and measurable impact at both individual and population levels. The agenda for the future is expected to support available methodology in nutrition research to personalize guideline recommendations, properly grading the quality of the available evidence, promoting adherence to the well-established evidence hierarchy in nutrition, and enhancing strategies for appropriate vetting and transparent reporting that will solidify the recommendations for health promotion. The final goal is to build a constructive coalition among scientists, policy makers, and communication professionals for sustainable health and nutritional policies. Currently, a strong rationale and available data support a personalized dietary approach according to personal variables, including sex and age, circulating metabolic biomarkers, food quality and intake frequency, lifestyle variables such as physical activity, and environmental variables including one's microbiome profile. There is a strong and urgent need to develop a successful commitment among all the stakeholders to define novel and sustainable approaches toward the management of the health value of nutrition at individual and population levels. Moving forward requires adherence to well-established principles of evidence evaluation as well as identification of effective tools to obtain better quality evidence. Much remains to be done in the near future.

Effects of dietary macronutrient intake on insulin sensitivity and secretion and glucose and lipid metabolism in healthy, obese adolescents.

CONTEXT: Adolescent obesity is a serious public health concern. OBJECTIVE: The aim of the study was to determine whether obese adolescents can adapt metabolically to changes in dietary macronutrient intake. PATIENTS AND DESIGN: Using a random cross-over design, 13 healthy obese volunteers (six boys and seven girls; age, 14.7 +/- 0.3 yr; body mass index, 34 +/- 1 kg/m2; body fat, 42 +/- 1%) were studied twice after 7 d of isocaloric, isonitrogenous diets with 60% carbohydrate (CHO) and 25% fat (high CHO), or 30% CHO and 55% fat (low CHO). MAIN OUTCOME MEASURES AND METHODS: Glucose metabolism, insulin sensitivity, and first- and second-phase insulin secretory indices were measured by stable isotope techniques and the stable labeled iv glucose tolerance test. The results were compared with those of previously studied lean adolescents. RESULTS: Obese adolescents increased first- and second-phase insulin secretory indices by 18 (P = 0.05) and 36% (P = 0.05), respectively, to maintain normoglycemia during the high-CHO diet because they failed to increase insulin sensitivity as did the lean adolescents. Regardless of diet, in obese adolescents, insulin sensitivity was half (P < 0.05) and first- and second-phase insulin secretory indices twice (P < 0.01), compared with the the corresponding values in lean subjects. In obese adolescents, gluconeogenesis increased by 32% during the low-CHO (high-fat diet) (P < 0.01). CONCLUSION: In obese adolescents, insulin secretory demands were increased regardless of diet. Failure to increase insulin sensitivity while receiving a high-CHO diet required a further increase in insulin secretion, which may lead to earlier beta-cell failure. A low-CHO/high-fat diet resulted in increased gluconeogenesis, which may be a prelude to the increased glucose production and hyperglycemia observed in type 2 diabetics.

Effects of dietary macronutrient content on glucose metabolism in children.

Effects of carbohydrate, fat, and fructose intake on substrate and hormone concentrations, glucose production, gluconeogenesis, and insulin sensitivity were determined in healthy, nonobese prepubertal children (n = 12) and adolescents (n = 24) using a cross-over design. In one group (12 prepubertal children and 12 adolescents), subjects were studied after 7 d of isocaloric, isonitrogenous diets providing either 60% carbohydrate and 25% fat [high carbohydrate (H(CHO))/low fat (L(F))] or 30% carbohydrate and 55% fat [low carbohydrate (L(CHO))/high fat (H(F))], and in a second group (12 adolescents) H(CHO)/L(F) diets containing either 40% or 10% fructose was used. All subjects adapted to changes in carbohydrate and fat intakes primarily by appropriately adjusting their substrate oxidation rates to match the intakes, with only minor changes in parameters of glucose metabolism. Changing from a L(CHO)/H(F) to H(CHO)/L(F) diet resulted in increased insulin sensitivity (stable labeled iv glucose tolerance test) in adolescents [from 3.2 +/- 0.7 x 10(-4) to 5.0 +/- 1.4 x 10(-4) (min(-1))/( micro U.ml(-1)) (mean +/- SE)] but not in prepubertal children [9.4 +/- 2.5 x 10(-4) to 9.9 +/- 1.5 x 10(-4) (min(-1))/( micro U.ml(-1))], whereas beta-cell sensitivity was unaffected in both groups. Insulin sensitivity was higher in prepubertal children than in adolescents (P < 0.05). The dietary fructose content did not affect any measured parameter. We conclude that in the short term, dramatic changes in fat and carbohydrate intakes (regardless of fructose content) did not adversely affect glucose and lipid metabolism in healthy nonobese children. In the adolescents, the high carbohydrate diet resulted in increased insulin sensitivity, thus facilitating insulin-mediated glucose uptake.