Introduction Metabolic syndrome (MetS) has been recognized as one of the most important clinical challenges and global health issues of today. Growing evidence suggests that mechanisms of energy metabolism may also play a key role in mediating aspects of cognitive function. Brain-derived neurotrophic factor (BDNF) is one such factor well known for its critical role in neuronal plasticity, including memory and learning, and more recently metabolic processes. BDNF levels have been shown separately to be dependent on diet and exercise programming. Purpose The purpose of this study was to investigate the effect of diet and exercise on BDNF levels and cognitive functioning with any metabolic association in individuals characterized with MetS. Methods Twelve subjects with MetS followed a randomized crossover design with two four-week interventions, including a carbohydrate (CHO)-restricted Paleolithic-based diet (CRPD; <50gCHO) with sedentary activity (CRPD-Sed) and CRPD with high intensity interval training (HIIT; CRPD-Sed), separated by a four-week washout period. The HIIT exercise consisted of 10 x 60 s cycling intervals interspersed with 60 s of active recovery 3 day/week for four-week. Serum BDNF was detected and quantified via enzyme-linked immunosorbent assay (ELISA). Cognitive executive function (Stroop Test) and self-perceived cognitive symptoms and function (MOS-CFS) were quantified. A two-way analysis of variance with repeated measures was performed with post-hoc analysis using simple effects analysis with a Bonferroni adjustment. The level of statistical significance was established a priori as P < 0.05. Results Compared to baseline, CRPD-Sed and CRPD-Ex improved variables for cognitive function, including increased peripheral serum BDNF levels (20% and 38%), psychomotor speed and cognitive flexibility (-14%, -14%), and self-perceived cognitive symptoms and functioning (+8%, +16%), respectively. BDNF inversely correlated with %body fat (r = -0.35, P < 0.05), fasting glucose (r = -0.64, P < 0.05), triglycerides (r = -0.55, P < 0.05), and insulin sensitivity (r = -0.25, P < 0.05). Conclusion This study shows the short-term beneficial effects of carbohydrate-restricted diet on serum BDNF and executive function in those individuals characterized with MetS. We have shown that the addition of exercise can further improve neuroprotection and cognitive function beyond the results of diet alone.

The optimal nutritional treatment for gestational diabetes (GDM) is still a matter of debate. With increasing rates of GDM and potential negative consequences for the health of mother and child, the best treatment should be established. The Nordic diet with emphasis on plant-based protein show promising health outcomes in other populations but has yet to be investigated in GDM population. The aim of this study, which is part of the "Effect of plant-based Nordic diet versus carbohydrate-restricted diet on glucose levels in gestational diabetes" (eMOM) pilot study was to compare the short-term effects of healthy Nordic diet (HND) and the currently recommended moderate restriction of carbohydrates diet (MCRD) on glucose and lipid metabolism in women with GDM.

Background: Obesity affects ∼20% of children in the United States and reports of successful dietary treatment are lacking. This study aimed to determine the change in body weight in severely obese youth after carbohydrate-restricted dietary intervention. Methods: This single-center study of a carbohydrate-restricted diet (≤30 grams per day), with unlimited calories, fat, and protein for 3-4 months, examined two groups of severely obese youth of ages 5-18 years: Group A, retrospectively reviewed charts of severely obese youth referred to the Pediatric Obesity Clinic at Hoops Family Children's Hospital and the Ambulatory Division of Marshall Pediatrics, Marshall University School of Medicine, in Huntington, WV, between July 1, 2014 and June 30, 2017 (n = 130), and Group B, prospective participants, referred between July 1, 2018 and December 31, 2018, followed with laboratory studies pre- and postdietary intervention (n = 8). Results: In Group A, 310 participants began the diet, 130 (42%) returned after 3-4 months. Group B had 14 enrollees who began the diet, and 8 followed up at 3-4 months (57%). Girls compared with boys were more likely to complete the diet (P = 0.02). Participants <12 years age were almost twice as likely to complete the diet compared with those 12-18 years (64% vs. 36%, P < 0.01); however, the older group subjects who completed the diet had the same percentage of weight loss compared with those <12 years (6.9% vs. 6.9%). Group A had reductions in weight of 5.1 kg (P < 0.001), body mass index (BMI) 2.5 kg/m2 (P < 0.001), and percentage weight loss 6.9% (P < 0.001). Group B had reductions in weight 9.6 kg (P < 0.01), BMI 4 kg/m2 (P < 0.01), and percentage weight loss 9% (P < 0.01). In addition, participants had significant reductions of fasting serum insulin (P < 0.01), triglycerides (P < 0.01), and 20-hydroxyeicosatetraenoic acid (P < 0.01). Conclusions: This study demonstrated a carbohydrate-restricted diet, utilized short term, effectively reduced weight in a large percentage of severely obese youth, and can be replicated in a busy primary care office.

A carbohydrate-restricted diet is a widely recommended intervention for non-alcoholic fatty liver disease (NAFLD), but a systematic perspective on the multiple benefits of this diet is lacking. Here, we performed a short-term intervention with an isocaloric low-carbohydrate diet with increased protein content in obese subjects with NAFLD and characterized the resulting alterations in metabolism and the gut microbiota using a multi-omics approach. We observed rapid and dramatic reductions of liver fat and other cardiometabolic risk factors paralleled by (1) marked decreases in hepatic de novo lipogenesis; (2) large increases in serum β-hydroxybutyrate concentrations, reflecting increased mitochondrial β-oxidation; and (3) rapid increases in folate-producing Streptococcus and serum folate concentrations. Liver transcriptomic analysis on biopsy samples from a second cohort revealed downregulation of the fatty acid synthesis pathway and upregulation of folate-mediated one-carbon metabolism and fatty acid oxidation pathways. Our results highlight the potential of exploring diet-microbiota interactions for treating NAFLD.

Introduction One approach to slow the pandemic of obesity and chronic disease is to look to our evolutionary past for clues of the changing behaviors contributing to the emergence of 'diseases of civilization'. Modern humans have deviated from the lifestyle behaviors of our ancestors that have introduced pressures (i.e. diet and activity changes) quicker than our genetic ability to respond. This caused a 'mismatch' between our biological systems and environment, leading to 'man-made' chronic diseases. Purpose The purpose of the study was to investigate the effects of a short-term evolutionarily informed dietary and lifestyle intervention on inflammatory and cardio-metabolic profiles in individuals characterized as having metabolic syndrome (MetS). Methods Twelve subjects with MetS followed a crossover design with two, four-week interventions, including a carbohydrate (CHO)-restricted Paleolithic-based diet (CRPD; <50g CHO) with sedentary activity (CRPD-Sed) and CRPD with high-intensity interval training (CRPD-Ex), separated by a four-week washout period. The HIIT exercise consisted of 10 X 60 seconds (s) cycling intervals interspersed with 60s of active recovery three d/wk for four weeks. The effects of a diet with sedentary activity as compared to a diet with exercise on body composition, as well as the cardiovascular, inflammatory, and metabolic profiles, were assessed. A two-way analysis of variance (ANOVA) with repeated measures was performed with a post-hoc analysis using a simple effects analysis with a Bonferroni adjustment. The level of statistical significance was established a priori as p < 0.05. Results Compared to baselines, CRPD-Sed and CRPD-Ex improved cardio-metabolic markers, including reductions in waist adiposity (-15%, -18%), body mass (-3%, -5%), body fat % (BF%; -7%, -12%), fasting plasma glucose (GLU; -20%, -27%), triglycerides (TG; -47%, -52%), fasting insulin (-34%, -39%), insulin resistance (-35%, -46%), and increased HDL-C (+22%, +36%) and VO2max (+22% and +29%), respectively. CRPD-Sed and CRPD-Ex also reduced inflammatory markers, including hsCRP (-32% and-36%), TNF-alpha (-35% and -41%), IL-6 (-29% and -40%), and ICAM-1 (-19%, -23%), respectively, when compared to baseline. Conclusion Adopting behaviors from our evolutionary past, including diet and exercise, shows favorable cardio-metabolic and inflammatory profiles in those individuals characterized with MetS.

A carbohydrate-restricted diet aimed at lowering insulin levels has the potential to slow Alzheimer's disease (AD). Restricting carbohydrate consumption reduces insulin resistance, which could improve glucose uptake and neural health. A hallmark feature of AD is widespread cortical thinning; however, no study has demonstrated that lower net carbohydrate (nCHO) intake is linked to attenuated cortical atrophy in patients with AD and confirmed amyloidosis.

Type 2 diabetes mellitus is a chronic progressive disease. During the course of the disease intensive treatment is often necessary resulting in multiple interventions including administration of insulin. Although dietary intervention is highly recommended, the clinical results of the widely prescribed diets with low fat content and high carbohydrates are disappointing. In this proof-of-concept study, we tested the effect of dietary carbohydrate-restriction in conjunction with metformin and liraglutide on metabolic control in patients with type 2 diabetes.

Metabolic syndrome (MetS) is a group of risk factors that increase the risk of death and a variety of chronic diseases. Recent studies have indicated that the imbalance of gut microbiota might contribute to development and progression of metabolic syndrome. Carbohydrate restriction in the diet has been proven to be one of the most effective methods in the management of metabolic syndrome, even in the absence of weight loss. However, no study has examined the effects of a carbohydrate-restricted diet on gut microbiota composition in metabolic syndrome patients. Thus, we will examine the effects of a "moderately restricted carbohydrate (MRC)" diet on gut microbiota, insulin resistance, and components of MetS among Iranian women. In addition, the stability of changes in dependent variables, including gut microbiota, will also be assessed.

Non-alcoholic fatty liver disease (NAFLD) is a hepatic condition that is considerably prevalent across the world. Dietary intakes, in which macronutrient composition is precisely planned, might be able to reduce inflammation, steatosis and fibrosis among patients with NAFLD. A moderately carbohydrate restricted diet with weight loss has been demonstrated to improve liver fat content among overweight or obese patients. However, there is no information about the appropriateness of such a restriction, without weight loss, in normal-weight patients. This randomised clinical trial will be aimed at assessing the effect of moderate carbohydrate restriction on liver enzymes, liver steatosis and fibrosis in normal-weight patients with NAFLD.

We investigated long-term effects of low carbohydrate diets on wild type mice, streptozotocin-injected and KKAy obese diabetic mice. These mice were pair-fed three different types of diets, standard chow (SC, C∶P∶F = 63∶15∶22), a low carbohydrate (LC, C∶P∶F = 38∶25∶37) diet and a severely carbohydrate restricted (SR, C∶P∶F = 18∶45∶37) diet for 16 weeks. Despite comparable body weights and serum lipid profiles, wild type and diabetic mice fed the low carbohydrate diets exhibited lower insulin sensitivity and this reduction was dependent on the amount of carbohydrate in the diet. When serum fatty acid compositions were investigated, monounsaturation capacity, i.e. C16:1/C16:0 and C18:1/C18:0, was impaired in all murine models fed the low carbohydrate diets, consistent with the decreased expression of hepatic stearoyl-CoA desaturase-1 (SCD1). Interestingly, both the hepatic expressions and serum levels of fibroblast growth factor 21 (FGF21), which might be related to longevity, were markedly decreased in both wild type and KKAy mice fed the SR diet. Taking into consideration that fat compositions did not differ between the LC and SR diets, we conclude that low carbohydrate diets have deleterious metabolic effects in both wild type and diabetic mice, which may explain the association between diets relatively low in carbohydrate and the elevated risk of cardiovascular events observed in clinical studies.

Carbohydrate-restricted diets and intermittent fasting (IF) have been rapidly gaining interest among the general population and patients with cardiometabolic disease, such as overweight or obesity, diabetes, and hypertension. However, there are limited expert recommendations for these dietary regimens. This study aimed to evaluate the level of scientific evidence on the benefits and harms of carbohydrate-restricted diets and IF to make responsible recommendations. A meta-analysis and systematic literature review of 66 articles on 50 randomized controlled trials (RCTs) of carbohydrate-restricted diets and 10 articles on eight RCTs of IF was performed. Based on the analysis, the following recommendations are suggested. In adults with overweight or obesity, a moderately-low carbohydrate or low carbohydrate diet (mLCD) can be considered as a dietary regimen for weight reduction. In adults with type 2 diabetes mellitus, mLCD can be considered as a dietary regimen for improving glycemic control and reducing body weight. In contrast, a very-low carbohydrate diet (VLCD) and IF are recommended against in patients with diabetes. Furthermore, no recommendations are suggested for VLCD and IF in adults with overweight or obesity, and carbohydrate-restricted diets and IF in patients with hypertension. Here, we describe the results of our analysis and the evidence for these recommendations.

Carbohydrate-restricted diets and intermittent fasting (IF) have been rapidly gaining interest among the general population and patients with cardiometabolic disease, such as overweight or obesity, diabetes, and hypertension. However, there are limited expert recommendations for these dietary regimens. This study aimed to evaluate the level of scientific evidence on the benefits and harms of carbohydrate-restricted diets and IF to make responsible recommendations. A meta-analysis and systematic literature review of 66 articles on 50 randomized controlled trials (RCTs) of carbohydrate-restricted diets and 10 articles on eight RCTs of IF was performed. Based on the analysis, the following recommendations are suggested. In adults with overweight or obesity, a moderately-low carbohydrate or low carbohydrate diet (mLCD) can be considered as a dietary regimen for weight reduction. In adults with type 2 diabetes mellitus, mLCD can be considered as a dietary regimen for improving glycemic control and reducing body weight. In contrast, a very-low carbohydrate diet (VLCD) and IF are recommended against in patients with diabetes. Furthermore, no recommendations are suggested for VLCD and IF in adults with overweight or obesity, and carbohydrate-restricted diets and IF in patients with hypertension. Here, we describe the results of our analysis and the evidence for these recommendations.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exert their antidiabetic effects by promoting urinary glucose excretion. Nutrition therapy is obviously important, but little is known about the interactions between SGLT2i agents and carbohydrate restriction. Therefore, we studied these interactions using an obese diabetic animal model. KK-Ay mice were pair-fed normal chow [NC; carbohydrate: fat: protein = 65:15:20], low carbohydrate [LC; 43:42:15] or severely carbohydrate restricted diets [SR; 12:45:43] for 12 weeks. Tofogliflozin (Tofo) was administered as the SGLT2i in the NC and LC diet groups. Blood glucose levels were significantly increased in the SR group. Tofo reduced blood glucose levels significantly in the NC group during the experiment and in the LC group at 2-6 weeks. Plasma triglycerides were markedly elevated in the SR group without Tofo, but decreased in response to Tofo administration. Hepatic triglyceride contents were not changed by the LC or the SR diet alone. However, Tofo ameliorated hepatosteatosis in NC-fed animals. Consistent with the downregulation of stearoyl-CoA desaturase 1, the ratio of plasma monounsaturated to saturated fatty acids was significantly reduced in the LC with Tofo and in the SR alone groups, but was not altered in the NC with Tofo group. In summary, metabolism of glucose and lipids was improved by Tofo but not by the SR diet. Furthermore, Tofo improved these parameters more effectively in the NC than in the LC diet group. These data suggest that the effects of SGLT2i are distinct from those of carbohydrate restriction and that a nonrestricted dietary carbohydrate composition is essential for SGLT2i treatment to be effective.

Low-carbohydrate diets (LCDs) often differ in their diet composition, which may lead to conflicting results between randomized controlled trials. Therefore, we aimed to compare the effects of different degrees of carbohydrate (CHO) restriction on cardiometabolic risk markers in humans. The experimental LCDs of 37 human trials were classified as (1) moderate-low CHO diets (<45-40 E%, n = 13), (2) low CHO diets (<40-30 E%, n = 16), and (3) very-low CHO diets (<30-3 E%; n = 8). Summary estimates of weighted mean differences (WMDs) in selected risk markers were calculated using random-effect meta-analyses. Differences between the LCD groups were assessed with univariate meta-regression analyses. Overall, the LCDs resulted in significant weight loss, reduced diastolic blood pressure BP, and increased total cholesterol and high-density lipoprotein cholesterol (HDL-C), without significant differences between the three LCD groups. Higher low-density lipoprotein cholesterol (LDL-C) concentrations were found with the very-low CHO diets compared to the moderate-low CHO diets. Decreases in triacylglycerol (TAG) concentrations were more pronounced with the low and very-low CHO diets, compared to the moderate-low CHO diets. Substitution of CHO by mainly saturated fatty acids (SFAs) increased total cholesterol, LDL-C, and HDL-C concentrations. Except for LDL-C and TAGs, effects were not related to the degree of CHO restriction. Potential effects of nutrient exchanges should be considered when following LCDs.

Very low carbohydrate/ketogenic diets (VLC/KDs) are popular but their role in managing pre-diabetes and type 2 diabetes (T2D) is uncertain. This study uses a systematic review and meta-analysis of randomized controlled trials to estimate the effect of these diets in this population.

Linkages between carbohydrates, obesity and cancer continue to demonstrate conflicting results. Evidence suggests inconclusive direct linkages between carbohydrates and specific cancers. Conversely, obesity has been strongly linked to a wide range of cancers. The purpose of the study is to explore linkages between carbohydrate intake and cancer types using a two-step approach. First the study will evaluate the linkages between carbohydrate intake and obesity, potentially stratified by metabolic syndrome status. Second, the estimated attributable fraction of obesity ascribed to carbohydrate intake will be multiplied against obesity attributable fractions for cancer types to give estimated overall attributable fraction for carbohydrate versus cancer type.

The impact of a ketogenic diet (KD) (<50 g/d carbohydrate, >75% fat) on athletic performance has sparked much interest and self-experimentation in the past 3-4 years. Evidence shows 3-4-week adaptations to a KD in endurance-trained athletes were associated with maintenance of moderate (46-63% VO2max) and vigorous intensity (64-90% VO2max) endurance exercise, while at intensities >70% VO2max, increases in fat oxidation were associated with decreased economy (increased oxygen consumption), and in some cases, increased ratings of perceived exertion and heart rate. Two investigations in recreationally active endurance athletes noted no vigorous intensity exercise decrement following 3- and 12-week adaptations. Moderate (70-85% one repetition maximum) and near-maximal to maximal intensity (>85% 1RM) strength performance experienced no decrement following a 3-12-week KD adaptation. Beneficial effects were noted for 2000 m sprint and critical power test completed for short duration at vigorous intensity, while two additional tests noted no decrement. For sprint, near-maximal exercise (>91% VO2max), benefit of the KD was observed for six-second sprint, while no decrement in performance was noted for two additional maximal tests. When protein is equated (grams per kilogram), one investigation noted no decrement in muscle hypertrophy, while one noted a decrement. One investigation with matched protein noted the KD group lost more body fat. In conclusion, moderate-to-vigorous intensity exercise experiences no decrement following adaptation to a KD. Decreases in exercise economy are observed >70% VO2max in trained endurance athletes which may negate performance within field settings. Beneficial effects of the KD during short duration vigorous, and sprint bouts of exercises are often confounded by greater weight loss in the KD group. With more athletes pursuing carbohydrate-restricted diets (moderate and strict (KD)) for their proposed health benefits, more work is needed in the area to address both performance and health outcomes.

Although several observational and experimental studies have examined the effects of low carbohydrate diets (LCDs) on nonalcoholic fatty liver disease (NAFLD), there are considerable inconsistencies among studies. We summarized the effect of LCDs on liver function tests, including intrahepatic lipid content (IHLC), alanine transaminase (ALT), aspartate aminotransferases (AST), and gamma-glutamyl transferase (GGT) in patients with NAFLD.

The liver is responsible for controlling cholesterol homeostasis in the body. HMG-CoA reductase and the LDL receptor (LDL-r) are involved in this regulation and are also ubiquitously expressed in all major tissues. We have previously shown in guinea pigs that there is a correlation in gene expression of HMG-CoA reductase and the LDL-r between liver and mononuclear cells. The present study evaluated human mononuclear cells as a surrogate for hepatic expression of these genes. The purpose was to evaluate the effect of dietary carbohydrate restriction with low and high cholesterol content on HMG-CoA reductase and LDL-r mRNA expression in mononuclear cells. All subjects were counseled to consume a carbohydrate restricted diet with 10-15% energy from carbohydrate, 30-35% energy from protein and 55-60% energy from fat. Subjects were randomly assigned to either EGG (640 mg/d additional dietary cholesterol) or SUB groups [equivalent amount of egg substitute (0 dietary cholesterol contributions) per day] for 12 weeks. At the end of the intervention, there were no changes in plasma total or LDL cholesterol (LDL-C) compared to baseline (P > 0.10) or differences in plasma total or LDL-C between groups. The mRNA abundance for HMG-CoA reductase and LDL-r were measured in mononuclear cells using real time PCR. The EGG group showed a significant decrease in HMG-CoA reductase mRNA (1.98 +/- 1.26 to 1.32 +/- 0.92 arbitrary units P < 0.05) while an increase was observed for the SUB group (1.13 +/- 0.52 to 1.69 +/- 1.61 arbitrary units P < 0.05). Additionally, the LDL-r mRNA abundance was decreased in the EGG group (1.72 +/- 0.69 to 1.24 +/- 0.55 arbitrary units P < 0.05) and significantly increased in the SUB group (1.00 +/- 0.60 to 1.67 +/- 1.94 arbitrary units P < 0.05). The findings indicate that dietary cholesterol during a weight loss intervention alters the expression of genes regulating cholesterol homeostasis.

Dietary modification is an effective method for preventing and managing hypertension. Therefore, we conducted a systematic review and meta-analysis to assess the effects of different dietary approaches for comparing high- and low-carbohydrate diets on systolic and diastolic blood pressure (SBP and DBP, respectively) in patients with type 2 diabetes mellitus (T2DM). We carried out a comprehensive literature search using PubMed, the Cochrane Library, Web of Science, and Scopus without any language and time restrictions until April, 2019. We carried out a meta-analysis using both fixed and random effects models where appropriate and used the I2 index to evaluate heterogeneity. We identified 16 eligible studies, with a total of 1,610 participants. The overall pooled net effect of different dietary approaches on SBP and DBP were -2.29 mmHg [95% confidence interval (CI): -3.49 to -1.1] and -1.03 mmHg (95% CI: -1.77 to -0.29), respectively, compared with high-carbohydrate diets. Indeed, diets high in monounsaturated fatty acids more effective in reducing both SBP and DBP than high-carbohydrate diets, whereas high-protein diets were not effective. Furthermore, we found that different dietary approaches, such as low-fat diets, did not reduce SBP or DBP to a greater extent than low-carbohydrate diets. Overall, the results of our meta-analysis show that diets high in monounsaturated fatty acids are more effective in reducing both SBP and DBP than diets high in carbohydrate, whereas other dietary approaches were not effective.