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Objective: Pathological, age-related loss of muscle function, commonly referred to as sarcopenia, contributes to loss of mobility, impaired independence, as well as increased risk of adverse health events. Sarcopenia has been attributed to changes in both neural and muscular integrity during aging. Current treatment options are primarily limited to exercise and dietary protein fortification, but the therapeutic impact of these approaches are often inadequate. Prior work has suggested that a ketogenic diet (KD) might improve healthspan and lifespan in aging mice. Thus, we sought to investigate the effects of a KD on neuromuscular indices of sarcopenia in aged C57BL/6 mice. Design: A randomized, controlled pre-clinical experiment consisting of longitudinal assessments performed starting at 22-months of age (baseline) as well as 2, 6 and 10 weeks after the start of a KD vs. regular chow intervention. Setting: Preclinical laboratory study. Sample size: Thirty-six 22-month-old mice were randomized into 2 dietary groups: KD [n = 22 (13 female and 9 male)], and regular chow [n = 15 (7 female and 8 male)]. Measurements: Measures included body mass, hindlimb and all limb grip strength, rotarod for motor performance, plantarflexion muscle contractility, motor unit number estimations (MUNE), and repetitive nerve stimulation (RNS) as an index of neuromuscular junction transmission efficacy recorded from the gastrocnemius muscle. At end point, muscle wet weight and blood samples were collected to assess blood beta-hydroxybutyrate levels. Statistical analysis: Primary analyses were two-way mixed effects ANOVA (diet and time × diet) to determine the effect of a KD on indices of motor function (grip, rotarod) and indices of motor unit (MUNE) and muscle (contractility) function. Results: Beta-hydroxybutyrate (BHB) was significantly higher at 10 weeks in mice on a KD vs control group (0.83 ± 0.44 mmol/l versus 0.42 ± 0.21 mmol/l, η2 = 0.265, unpaired t-test, p = 0.0060). Mice on the KD intervention demonstrated significantly increased hindlimb grip strength (diet, p = 0.0001; time × diet, p = 0.0030), all limb grip strength (diet, p = 0.0005; time × diet, p = 0.0523), and rotarod latency to fall (diet, p = 0.0126; time × diet, p = 0.0021). Mice treated with the KD intervention also demonstrated increased MUNE (diet, p = 0.0465; time × diet, p = 0.0064), but no difference in muscle contractility (diet, p = 0.5248; time × diet, p = 0.5836) or RNS (diet, p = 0.3562; time × diet, p = 0.9871). Conclusion: KD intervention improved neuromuscular and motor function in aged mice. This pre-clinical work suggests that further research is needed to assess the efficacy and physiological effects of a KD on indices of sarcopenia.

There is a substantial body of clinical evidence supporting the beneficial effects of lower-carbohydrate dietary patterns on multiple established risk factors associated with insulin resistance and cardiovascular diseases in adult populations. Nutrition and health researchers, clinical practitioners, and stakeholders gathered for, “The Scientific Forum on Nutrition, Wellness, and Lower-Carbohydrate Diets: An Evidence- and Equity-Based Approach to Dietary Guidance” to discuss the evidence base around lower-carbohydrate diets, health outcomes, and dietary guidance. Consensus statements were agreed upon to identify current areas of scientific agreement and spotlight gaps in research, education, and practice to help define and prioritize future pathways. Given the evidence base and considering that most American adults are living with at least one nutrition-related chronic disease, there was consensus that including a lower-carbohydrate dietary pattern as one part of the Dietary Guidelines for Americans could help promote health equity among the general population.

Abstract Rucksack marches (‘rucks’) are strenuous, military‐relevant exercises that may benefit from pre‐event fuelling. The purpose of this investigation was to explore whether acute ingestion of carbohydrate‐ or lipid‐based nutritional bars before rucking can elicit unique advantages that augment exercise performance. Recreationally active and healthy males (n = 29) were randomized and counterbalanced to consume 1000 kcal derived from a novel, energy‐dense (percentage energy from carbohydrate/fat/protein: 5/83/12) ketogenic bar (KB), or isocaloric high‐carbohydrate bars (CB; 61/23/16) 3 h before a time‐to‐exhaustion (TTE) ruck. Conditions were separated by a 1‐week washout. The rucksack weight was standardized to 30% of bodyweight. Steady‐state treadmill pace was set at 3.2 km/h (0.89 m/s) and 14% grade. TTE was the primary outcome; respiratory exchange ratio (RER), capillary ketones (R‐β‐hydroxybutyrate), glucose and lactate, plus subjective thirst/hunger were the secondary outcomes. Mean TTE was similar between conditions (KB: 55 ± 25 vs. CB: 54 ± 22 min; P = 0.687). The RER and substrate oxidation rates revealed greater fat and carbohydrate oxidation after the KB and CB, respectively (all P

Nutrition security - access to food that promotes well-being and prevents or treats disease, particularly among racial and ethnic minority populations, lower income populations, and rural and remote populations - is a national priority. Leading causes of death and disability in America, such as heart disease, stroke, cancer, and diabetes that disproportionately affect minorities are linked to preventable diet-related risk factors. Mounting evidence indicates that adherence to a lower-carbohydrate dietary pattern is associated with weight maintenance, improved blood glucose and insulin control, lower blood pressure, reduced markers of inflammation, and a more favorable lipid profile. Additionally, prior concerns regarding the higher fat and cholesterol content of this dietary pattern are less founded in modern research. The inclusion of a lower-carbohydrate option that meets all essential nutrient requirements aligns with the contemporary movement toward more flexibility and precision nutrition. Most important, a lower-carbohydrate option positions the Dietary Guidelines for Americans to more accurately reflect the current scientific evidence and more effectively address the metabolic health of the nation. Further, it has the potential to improve nutrition security by addressing metabolic diseases that disproportionately affect people from historically marginalized racial, ethnic, socioeconomic, and cultural backgrounds. Given that most American adults are living with at least one diet-related chronic metabolic disease, updating the Dietary Guidelines for Americans to recognize and reflect the poor health status of the general population is prudent and urgent.

Abstract Background In a previous study, we assessed a novel, remotely monitored carbohydrate restricted diet regimen including nutritional ketosis in patients with type 2 diabetes and reported significant improvements in weight, glycemic control, abdominal fat and inflammation from baseline to 2 years. Knee outcome measures were collected as a secondary outcome in the trial. This study aims to assess the effect of this intervention on knee functional scores and to identify if changes in weight, central abdominal fat (CAF), glycemic status and high sensitivity C-reactive protein (hsCRP) were associated with its improvement. Methods This prospective analysis included continuous care intervention (CCI, n = 173) and usual care (UC, n = 69) trial participants with type 2 diabetes that reported knee pain at baseline. Knee outcome measures included the Knee injury and Osteoarthritis Outcome Score (KOOS) pain, symptoms, activities of daily living (ADL), sports and recreation function, and knee-related quality of life subscales, and total KOOS score were assessed from baseline to 2 years. Missing data at each time point were replaced with multiple imputation under the assumption of missing at random. To assess if the primary analysis of the knee scores changed under plausible missing not at random assumptions, sensitivity analysis was also performed using pattern mixture models. In CCI, we also assessed factors associated with the improvement of knee scores. Results In the primary analysis, CCI participants demonstrated a statistically significant improvement in total KOOS and all KOOS individual subscale scores at 1 year and maintained through 2 years as opposed to UC patients who showed no significant changes from baseline to 2 years. The significant improvement in total KOOS and its individual subscale scores from baseline to 2 years remained relatively stable in CCI in the sensitivity analysis under different missing not at random scenarios confirming the robustness of the findings from the primary analysis. Approximately 46% of the CCI participants met the 10 points minimal clinically important change at 2 years. A reduction in CAF was associated with improvement in total KOOS and KOOS ADL, while a decrease in hsCRP was associated with improvement in KOOS symptoms scores. Conclusion A very low carbohydrate intervention including nutritional ketosis resulted in significant improvements in knee pain and function among patients with T2D. The improvements in knee function were likely secondary to a reduction in central adiposity and inflammation. Future research on the applicability of this intervention in radiographically confirmed OA patients is important. Trial registration Clinical trial registration: NCT02519309 (10/08/2015).

High carbohydrate, low fat (HCLF) diets have been the predominant nutrition strategy for athletic performance, but recent evidence following multi-week habituation has challenged the superiority of HCLF over low carbohydrate, high fat (LCHF) diets, along with growing interest in the potential health and disease implications of dietary choice. Highly trained competitive middle-aged athletes underwent two 31-day isocaloric diets (HCLF or LCHF) in a randomized, counterbalanced, and crossover design while controlling calories and training load. Performance, body composition, substrate oxidation, cardiometabolic, and 31-day minute-by-minute glucose (CGM) biomarkers were assessed. We demonstrated: (i) equivalent high-intensity performance (@∼85%VO2max), fasting insulin, hsCRP, and HbA1c without significant body composition changes across groups; (ii) record high peak fat oxidation rates (LCHF:1.58 ± 0.33g/min @ 86.40 ± 6.24%VO2max; 30% subjects > 1.85 g/min); (iii) higher total, LDL, and HDL cholesterol on LCHF; (iv) reduced glucose mean/median and variability on LCHF. We also found that the 31-day mean glucose on HCLF predicted 31-day glucose reductions on LCHF, and the 31-day glucose reduction on LCHF predicted LCHF peak fat oxidation rates. Interestingly, 30% of athletes had 31-day mean, median and fasting glucose > 100 mg/dL on HCLF (range: 111.68-115.19 mg/dL; consistent with pre-diabetes), also had the largest glycemic and fat oxidation response to carbohydrate restriction. These results: (i) challenge whether higher carbohydrate intake is superior for athletic performance, even during shorter-duration, higher-intensity exercise; (ii) demonstrate that lower carbohydrate intake may be a therapeutic strategy to independently improve glycemic control, particularly in those at risk for diabetes; (iii) demonstrate a unique relationship between continuous glycemic parameters and systemic metabolism.

BackgroundKetogenic diets are a commonly used weight loss method, but little is known how variations in sodium content and ketones influence cognition and mood during the early keto-adaptation period.ObjectivesTo investigate the effects of an exogenous ketone salt (KS) as part of a hypocaloric KD on mood and cognitive outcomes in overweight and obese adults. A secondary objective was to evaluate changes in biochemical markers associated with inflammatory and cognitive responses.Materials and methodsAdults who were overweight or obese participated in a 6-week controlled-feeding intervention comparing hypocaloric diets (∼75% of energy expenditure). KD groups received twice daily ketone salt (KD + KS; n = 12) or a flavor-matched placebo, free of minerals (KD + PL; n = 13). A separate group of age and BMI matched adults were later assigned to an isoenergetic low-fat diet (LFD; n = 12) as comparison to KD. Mood was assessed by shortened Profile of Mood States and Visual Analog Mood Scale surveys. Cognitive function was determined by the Automated Neuropsychological Assessment Metrics mental test battery.ResultsBoth KD groups achieved nutritional ketosis. Fasting serum glucose decreased in both KD groups, whereas glucose was unaffected in the LFD. Insulin decreased at week 2 and remained lower in all groups. At week 2, depression scores in the KD + PL group were higher compared to KD + KS. Performance in the math processing and go/no-go cognitive tests were lower for KD + PL and LFD participants, respectively, compared to KD + KS. Serum leptin levels decreased for all groups throughout the study but were higher for KD + KS group at week 6. Serum TNF-α steadily increased for LFD participants, reaching significance at week 6.ConclusionDuring a short-term hypocaloric diet, no indication of a consistent decline in mood or cognitive function were seen in participants following either KD, despite KD + PL being relatively low in sodium. WK2 scores of “anger” and “depression” were higher in the LFD and KD + PL groups, suggesting that KS may attenuate negative mood parameters during the early intervention stages.

Adults with Down syndrome are an underserved population at high risk for a host of different pathologies from aging and lack of activity.PurposeTo examine the effects of a 10-week resistance training program on measures of motor behavior, cognitive function, mood, and physical fitness.MethodsParticipants (n = 11) were men and women clinically diagnosed with Down syndrome (age: 25.8 ± 6.4 years; height: 151.5 ± 8.3 cm; weight: 67.5 ± 13.0 kg; IQ: 58.3 ± 19.7 units). After familiarization of testing procedures, subjects performed The Arizona Cognitive Test Battery for Down Syndrome, TGMD-2, lower and upper body strength assessments, and body composition via DXA testing, while parental guardians completed cognitive and mood survey assessments (Cognitive Scale for Down Syndrome, Behavioral Rating Inventory of Executive Function, NiSonger Child Behavior Rating Form, Scales of Independent Behavior-Revised, Child Eating Behavior Questionnaire, Social Communication Questionnaire, and Mood and Feelings Questionnaire) at pre and post 10 weeks of periodized resistance training.ResultsSignificant (P ≤ 0.05) improvements in locomotor skills and object control skills were observed post-training. Both locomotor skills (e.g., sprint, gallop, leaping, broad jump) and object control skills (e.g., baseball catch, underhand roll, basketball dribble) were all significantly improved. Facets of cognitive performance significantly improved, specifically executive function and visuospatial working memory capacity, and frontal lobe activity. Mood disturbances significantly decrease. All aspects of physical strength and endurance were improved, i.e., leg press, bench press, sit-ups, push-ups, and chair sit-to-stand post-training. Lean tissue mass was significantly increased post-training.ConclusionThis study dramatically demonstrates that life enhancements for individuals with Down syndrome are achievable with a properly designed resistance training program.

Abstract Background We have previously reported that in patients with type 2 diabetes (T2D) consumption of a very low carbohydrate diet capable of inducing nutritional ketosis over 2 years (continuous care intervention, CCI) resulted in improved body weight, glycemic control, and multiple risk factors for cardiovascular disease (CVD) with the exception of an increase in low density lipoprotein cholesterol (LDL-C). In the present study, we report the impact of this intervention on markers of risk for atherosclerotic cardiovascular disease (CVD), with a focus on lipoprotein subfraction particle concentrations as well as carotid-artery intima-media thickness (CIMT). Methods Analyses were performed in patients with T2D who completed 2 years of this study (CCI; n = 194; usual care (UC): n = 68). Lipoprotein subfraction particle concentrations were measured by ion mobility at baseline, 1, and 2 years and CIMT was measured at baseline and 2 years. Principal component analysis (PCA) was used to assess changes in independent clusters of lipoprotein particles. Results At 2 years, CCI resulted in a 23% decrease of small LDL IIIb and a 29% increase of large LDL I with no change in total LDL particle concentration or ApoB. The change in proportion of smaller and larger LDL was reflected by reversal of the small LDL subclass phenotype B in a high proportion of CCI participants (48.1%) and a shift in the principal component (PC) representing the atherogenic lipoprotein phenotype characteristic of T2D from a major to a secondary component of the total variance. The increase in LDL-C in the CCI group was mainly attributed to larger cholesterol-enriched LDL particles. CIMT showed no change in either the CCI or UC group. Conclusion Consumption of a very low carbohydrate diet with nutritional ketosis for 2 years in patients with type 2 diabetes lowered levels of small LDL particles that are commonly increased in diabetic dyslipidemia and are a marker for heightened CVD risk. A corresponding increase in concentrations of larger LDL particles was responsible for higher levels of plasma LDL-C. The lack of increase in total LDL particles, ApoB, and in progression of CIMT, provide supporting evidence that this dietary intervention did not adversely affect risk of CVD.

Alpelisib is a α-selective phosphatidylinositol 3-kinase (PI3K) inhibitor approved for treatment of postmenopausal women, and men, with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–), PIK3CA-mutated, advanced breast cancer (ABC). Hyperglycemia is a common, on-target adverse effect that impairs treatment efficacy and increases the rate of treatment delays, dose reductions, and discontinuation. Currently, there are no clear guidelines on how to manage hyperglycemia due to alpelisib when metformin is not effective. In this case series, we review 3 subjects with ABC that developed hyperglycemia during alpelisib-fulvestrant therapy and were successfully managed with dietary and pharmacologic interventions. These cases provide anecdotal evidence to support the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i) and very low carbohydrate diets to minimize hyperglycemia during alpelisib therapy.

Brain-Derived Neurotropic Factor (BDNF) expression is decreased in conditions associated with cognitive decline as well as metabolic diseases. One potential strategy to improve metabolic health and elevate BDNF is by increasing circulating ketones. Beta-Hydroxybutyrate (BHB) stimulates BDNF expression, but the association of circulating BHB and plasma BDNF in humans has not been widely studied. Here, we present results from three studies that evaluated how various methods of inducing ketosis influenced plasma BDNF in humans. Study 1 determined BDNF responses to a single bout of high-intensity cycling after ingestion of a dose of ketone salts in a group of healthy adults who were habitually consuming either a mixed diet or a ketogenic diet. Study 2 compared how a ketogenic diet versus a mixed diet impacts BDNF levels during a 12-week resistance training program in healthy adults. Study 3 examined the effects of a controlled hypocaloric ketogenic diet, with and without daily use of a ketone-salt, on BDNF levels in overweight/obese adults. We found that (1) fasting plasma BDNF concentrations were lower in keto-adapted versus non keto-adapted individuals, (2) intense cycling exercise was a strong stimulus to rapidly increase plasma BDNF independent of ketosis, and (3) clinically significant weight loss was a strong stimulus to decrease fasting plasma BDNF independent of diet composition or level of ketosis. These results highlight the plasticity of plasma BDNF in response to lifestyle factors but does not support a strong association with temporally matched BHB concentrations.

Background: Ketogenic diets (KDs) that elevate beta-hydroxybutyrate (BHB) promote weight and fat loss. Exogenous ketones, such as ketone salts (KS), also elevate BHB concentrations with the potential to protect against muscle loss during caloric restriction. Whether augmenting ketosis with KS impacts body composition responses to a well-formulated KD remains unknown.Purpose: To explore the effects of energy-matched, hypocaloric KD feeding (1.0 mM capillary BHB) throughout the study (p < 0.001), with higher fasting concentrations observed in KD + KS than KD + PL for the first 2 weeks (p < 0.05). There were decreases in body mass, whole body fat and lean mass, mid-thigh muscle cross-sectional area, and both visceral and subcutaneous adipose tissues (p < 0.001), but no group differences between the two KDs or with the LFD. Urine nitrogen excretion was significantly higher in KD + PL than LFD (p < 0.01) and trended higher in KD + PL compared to KD + KS (p = 0.076), whereas the nitrogen excretion during KD + KS was similar to LFD (p > 0.05).Conclusion: Energy-matched hypocaloric ketogenic diets favorably affected body composition but were not further impacted by administration of an exogenous BHB-salt that augmented ketosis. The trend for less nitrogen loss with the BHB-salt, if manifested over a longer period of time, may contribute to preserved lean mass.

A growing number of endurance athletes have considered switching from a traditional high-carbohydrate/low-fat (HCLF) to a low-carbohydrate/high-fat (LCHF) eating pattern for health and performance reasons. However, few studies have examined how LCHF diets affect blood lipid profiles in highly-trained runners. In a randomized and counterbalanced, cross-over design, athletes (n = 7 men; VO2max: 61.9 ± 6.1 mL/kg/min) completed six weeks of two, ad libitum, LCHF (6/69/25% en carbohydrate/fat/protein) and HCLF (57/28/15% en carbohydrate/fat/protein) diets, separated by a two-week washout. Plasma was collected on days 4, 14, 28, and 42 during each condition and analyzed for: triglycerides (TG), LDL-C, HDL-C, total cholesterol (TC), VLDL, fasting glucose, and glycated hemoglobin (HbA1c). Capillary blood beta-hydroxybutyrate (BHB) was monitored during LCHF as a measure of ketosis. LCHF lowered plasma TG, VLDL, and TG/HDL-C (all p < 0.01). LCHF increased plasma TC, LDL-C, HDL-C, and TC/HDL-C (all p < 0.05). Plasma glucose and HbA1c were unaffected. Capillary BHB was modestly elevated throughout the LCHF condition (0.5 ± 0.05 mmol/L). Healthy, well-trained, normocholesterolemic runners consuming a LCHF diet demonstrated elevated circulating LDL-C and HDL-C concentrations, while concomitantly decreasing TG, VLDL, and TG/HDL-C ratio. The underlying mechanisms and implications of these adaptive responses in cholesterol should be explored.

Abstract Background Cardiovascular disease (CVD) is a leading cause of death among adults with type 2 diabetes mellitus (T2D). We recently reported that glycemic control in patients with T2D can be significantly improved through a continuous care intervention (CCI) including nutritional ketosis. The purpose of this study was to examine CVD risk factors in this cohort. Methods We investigated CVD risk factors in patients with T2D who participated in a 1 year open label, non-randomized, controlled study. The CCI group (n = 262) received treatment from a health coach and medical provider. A usual care (UC) group (n = 87) was independently recruited to track customary T2D progression. Circulating biomarkers of cholesterol metabolism and inflammation, blood pressure (BP), carotid intima media thickness (cIMT), multi-factorial risk scores and medication use were examined. A significance level of P

The decades-long dietary experiment embodied in the Dietary Guidelines for Americans (DGA) focused on limiting fat, especially saturated fat, and higher carbohydrate intake has coincided with rapidly escalating epidemics of obesity and type 2 diabetes (T2D) that are contributing to the progression of cardiovascular disease (CVD) and other diet-related chronic diseases. Moreover, the lack of flexibility in the DGA as it pertains to low carbohydrate approaches does not align with the contemporary trend toward precision nutrition. We argue that personalizing the level of dietary carbohydrate should be a high priority based on evidence that Americans have a wide spectrum of metabolic variability in their tolerance to high carbohydrate loads. Obesity, metabolic syndrome, and T2D are conditions strongly associated with insulin resistance, a condition exacerbated by increased dietary carbohydrate and improved by restricting carbohydrate. Low-carbohydrate diets are grounded across the time-span of human evolution, have well-established biochemical principles, and are now supported by multiple clinical trials in humans that demonstrate consistent improvements in multiple established risk factors associated with insulin resistance and cardiovascular disease. The American Diabetes Association (ADA) recently recognized a low carbohydrate eating pattern as an effective approach for patients with diabetes. Despite this evidence base, low-carbohydrate diets are not reflected in the DGA. As the DGA Dietary Patterns have not been demonstrated to be universally effective in addressing the needs of many Americans and recognizing the lack of widely available treatments for obesity, metabolic syndrome, and T2D that are safe, effective, and sustainable, the argument for an alternative, low-carbohydrate Dietary Pattern is all the more compelling.

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.

Background. Foods rich in saturated fatty acids (SFAs) have been discouraged by virtue of their cholesterol-raising potential, but this effect is modulated by the food source and background level of carbohydrate. Objective. We aimed to compare the consumption of palm stearin (PS) versus butter on circulating cholesterol responses in the setting of both a low-carbohydrate/high-fat (LC/HF) and high-carbohydrate/low-fat (HC/LF) diet in healthy subjects. We also explored effects on plasma lipoprotein particle distribution and fatty acid composition. Methods. We performed a randomized, controlled-feeding, cross-over study that compared a PS- versus a Butter-based diet in a group of normocholesterolemic, non-obese adults. A controlled canola oil-based ‘Run-In’ diet preceded the experimental PS and Butter diets. All diets were eucaloric, provided for 3-weeks, and had the same macronutrient distribution but varied in primary fat source (40% of the total fat). The same Run-In and cross-over experiments were done in two separate groups who self-selected to either a LC/HF (n = 12) or a HC/LF (n = 12) diet track. The primary outcomes were low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein (HDL)-C, triglycerides, and LDL particle distribution. Results. Compared to PS, Butter resulted in higher LDL-C in both the LC/HF (13.4%, p = 0.003) and HC/LF (10.8%, p = 0.002) groups, which was primarily attributed to large LDL I and LDL IIa particles. There were no differences between PS and Butter in HDL-C, triglycerides, or small LDL particles. Oxidized LDL was lower after PS than Butter in LC/HF (p = 0.011), but not the HC/LF group. Conclusions. These results demonstrate that Butter raises LDL-C relative to PS in healthy normocholesterolemic adults regardless of background variations in carbohydrate and fat, an effect primarily attributed to larger cholesterol-rich LDL particles.

Purpose: Studies on long-term sustainability of low-carbohydrate approaches to treat diabetes are limited. We previously reported the effectiveness of a novel digitally-monitored continuous care intervention (CCI) including nutritional ketosis in improving weight, glycemic outcomes, lipid, and liver marker changes at 1 year. Here, we assess the effects of the CCI at 2 years.Materials and methods: An open label, non-randomized, controlled study with 262 and 87 participants with T2D were enrolled in the CCI and usual care (UC) groups, respectively. Primary outcomes were retention, glycemic control, and weight changes at 2 years. Secondary outcomes included changes in body composition, liver, cardiovascular, kidney, thyroid and inflammatory markers, diabetes medication use and disease status.Results: Reductions from baseline to 2 years in the CCI group resulting from intent-to-treat analyses included: HbA1c, fasting glucose, fasting insulin, weight, systolic blood pressure, diastolic blood pressure, triglycerides, and liver alanine transaminase, and HDL-C increased. Spine bone mineral density in the CCI group was unchanged. Use of any glycemic control medication (excluding metformin) among CCI participants declined (from 55.7 to 26.8%) including insulin (-62%) and sulfonylureas (-100%). The UC group had no changes in these parameters (except uric acid and anion gap) or diabetes medication use. There was also resolution of diabetes (reversal, 53.5%; remission, 17.6%) in the CCI group but not in UC. All the reported improvements had p < 0.00012.Conclusion: The CCI group sustained long-term beneficial effects on multiple clinical markers of diabetes and cardiometabolic health at 2 years while utilizing less medication. The intervention was also effective in the resolution of diabetes and visceral obesity with no adverse effect on bone health.Clinical Trial Registration:Clinicaltrials.gov NCT02519309

Ketogenic diets (KDs) often contain high levels of saturated fat, which may increase liver fat, but the lower carbohydrate intake may have the opposite effect. Using a controlled feeding design, we compared liver fat responses to a hypocaloric KD with a placebo (PL) versus an energy-matched low-fat diet (LFD) in overweight adults. We also examined the added effect of a ketone supplement (KS). Overweight adults were randomized to a 6-week KD (KD + PL) or a KD with KS (KD + KS); an LFD group was recruited separately. All diets were estimated to provide 75% of energy expenditure. Weight loss was similar between groups (p > 0.05). Liver fat assessed by magnetic resonance imaging decreased after 6 week (p = 0.004) with no group differences (p > 0.05). A subset with nonalcoholic fatty liver disease (NAFLD) (liver fat > 5%, n = 12) showed a greater reduction in liver fat, but no group differences. In KD participants with NAFLD, 92% of the variability in change in liver fat was explained by baseline liver fat (p < 0.001). A short-term hypocaloric KD high in saturated fat does not adversely impact liver health and is not impacted by exogenous ketones. Hypocaloric low-fat and KDs can both be used in the short-term to significantly reduce liver fat in individuals with NAFLD.

An amendment to this paper has been published and can be accessed via the original article.

Impaired mitochondrial function often results in excessive production of reactive oxygen species (ROS) and is involved in the etiology of many chronic diseases, including cardiovascular disease, diabetes, neurodegenerative disorders, and cancer. Moderate levels of mitochondrial ROS, however, can protect against chronic disease by inducing upregulation of mitochondrial capacity and endogenous antioxidant defense. This phenomenon, referred to as mitohormesis, is induced through increased reliance on mitochondrial respiration, which can occur through diet or exercise. Nutritional ketosis is a safe and physiological metabolic state induced through a ketogenic diet low in carbohydrate and moderate in protein. Such a diet increases reliance on mitochondrial respiration and may, therefore, induce mitohormesis. Furthermore, the ketone β-hydroxybutyrate (BHB), which is elevated during nutritional ketosis to levels no greater than those resulting from fasting, acts as a signaling molecule in addition to its traditionally known role as an energy substrate. BHB signaling induces adaptations similar to mitohormesis, thereby expanding the potential benefit of nutritional ketosis beyond carbohydrate restriction. This review describes the evidence supporting enhancement of mitochondrial function and endogenous antioxidant defense in response to nutritional ketosis, as well as the potential mechanisms leading to these adaptations.

OBJECTIVE: We tested the reproducibility of changes in the ambulatory blood pressure (BP) from the initial values, an indicator of BP reactivity and cardiovascular health outcomes, in young, healthy adults. METHOD: The subjects wore an ambulatory BP monitor attached by the same investigator at the same time of day until the next morning on two different days (day 1 and day 2) separated by a week. We compared the ambulatory BP change from the initial values at hourly intervals over 24 waking and sleeping hours on days 1 and 2 using linear regression and repeated measures analysis of covariance. RESULTS: The subjects comprised 88 men and 57 women (mean age±SE 22.4±0.3 years) with normal BP (118.3±0.9/69.7±0.6 mmHg). For the total sample, the correlation between the ambulatory BP change on day 1 vs. day 2 over 24, waking, and sleeping hours ranged from 0.37-0.61; among women, the correlation was 0.38-0.71, and among men, it was 0.24-0.52. Among women, the ambulatory systolic/diastolic BP change was greater by 3.1±1.0/2.4±0.8 mmHg over 24 hours and by 3.0±1.1/2.4±0.8 mmHg over waking hours on day 1 than on day 2. The diastolic ambulatory BP change during sleeping hours was greater by 2.2±0.9 mmHg on day 1 than on day 2, but the systolic ambulatory BP change during sleeping hours on days 1 and 2 did not differ. Among men, the ambulatory BP change on days 1 and 2 did not differ. CONCLUSION: Our primary findings were that the ambulatory BP change from the initial values was moderately reproducible; however, it was more reproducible in men than in women. These results suggest that women, but not men, may experience an alerting reaction to initially wearing the ambulatory BP monitor.

Cortical activity is thought to reflect the biomechanical properties of movement (e.g., force or velocity of movement), but fatigue and movement familiarity are important factors that require additional consideration in electrophysiological research. The purpose of this within-group quantitative electroencephalogram (EEG) investigation was to examine changes in cortical activity amplitude and location during four resistance exercise movement protocols emphasizing rate (PWR), magnitude (FOR), or volume (VOL) of force production, while accounting for movement familiarity and fatigue. EEG signals were recorded during each complete repetition and were then grouped by functional region, processed to eliminate artifacts, and averaged to compare overall differences in the magnitude and location of cortical activity between protocols over the course of six sets. Biomechanical, biochemical, and exertional data were collected to contextualize electrophysiological data. The most fatiguing protocols were accompanied by the greatest increases in cortical activity. Furthermore, despite non-incremental loading and lower force levels, VOL displayed the largest increases in cortical activity over time and greatest motor and sensory activity overall. Our findings suggest that cortical activity is strongly related to aspects of fatigue during a high intensity resistance exercise movement.

Metabolic syndrome, which can include weight gain and central obesity, elevated serum insulin and glucose, and insulin resistance, has been strongly associated with breast cancer recurrence and worse outcomes after treatment. Epidemiologic and prospective data do not show conclusive evidence as to which dietary factors may be responsible for these results. Current strategies employ low-fat diets which emphasize supplementing calories with increased intake of fruit, grain, and vegetable carbohydrate sources. Although results thus far have been inconclusive, recent randomized trials employing markedly different dietary strategies in noncancer patients may hold the key to reducing multiple risk factors in metabolic syndrome simultaneously which may prove to increase the long-term outcome of breast cancer patients and decrease recurrences. Since weight gain after breast cancer treatment confers a poor prognosis and may increase recurrence rates, large-scale randomized trials are needed to evaluate appropriate dietary interventions for our breast cancer patients.