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Title:
Benefits of a ketogenic diet on repetitive motor behavior in mice
Authors:
Brady, Molly; Beltramini, Anna; Vaughan, Gavin; Bechard, Allison R.
Abstract:
Repetitive motor behaviors are repetitive and invariant movements with no apparent function, and are common in several neurological and neurodevelopmental disorders, including autism spectrum disorders (ASD). However, the neuropathology associated with the expression of these abnormal stereotypic movements is not well understood, and effective treatments are lacking. The ketogenic diet (KD) has been used for almost a century to treat intractable epilepsy and, more recently, disorders associated with inflexibility of behavioral routines. Here, we show a novel application for KD to reduce an abnormal repetitive circling behavior in a rodent model. We then explore potential mediation through the striatum, as dysregulation of cortico-basal ganglia circuitry has previously been implicated in repetitive motor behavior. In Experiments 1 and 2, adult FVB mice were assessed for levels of repetitive circling across a 3-week baseline period. Mice were then switched to KD and repetitive circling was assessed for an additional 3 weeks. In Experiment 1, time on KD was associated with reduced repetitive behavior. In Experiment 2, we replicated these benefits of KD and assessed dendritic spine density in the striatum as one potential mechanism for reducing repetitive behavior, which yielded no differences. In Experiment 3, adult female circling mice were given a single administration of a dopamine D2 receptor antagonist (L-741,646) that was associated with reduced repetitive behavior over time. Future research will explore the relationship between KD and dopamine within basal ganglia nuclei that may be influencing the benefits of KD on repetitive behavior.
Published:
March 26, 2022
Title:
Animal board invited review: Animal source foods in healthy, sustainable, and ethical diets – An argument against drastic limitation of livestock in the food system
Authors:
Leroy, Frédéric; Abraini, Fabien; Beal, Ty; Dominguez-Salas, Paula; Gregorini, Pablo; Manzano, Pablo; Rowntree, Jason; van Vliet, Stephan
Abstract:
Animal source foods are evolutionarily appropriate foods for humans. It is therefore remarkable that they are now presented by some as unhealthy, unsustainable, and unethical, particularly in the urban West. The benefits of consuming them are nonetheless substantial, as they offer a wide spectrum of nutrients that are needed for cell and tissue development, function, and survival. They play a role in proper physical and cognitive development of infants, children, and adolescents, and help promote maintenance of physical function with ageing. While high-red meat consumption in the West is associated with several forms of chronic disease, these associations remain uncertain in other cultural contexts or when consumption is part of wholesome diets. Besides health concerns, there is also widespread anxiety about the environmental impacts of animal source foods. Although several production methods are detrimental (intensive cropping for feed, overgrazing, deforestation, water pollution, etc.) and require substantial mitigation, damaging impacts are not intrinsic to animal husbandry. When well-managed, livestock farming contributes to ecosystem management and soil health, while delivering high-quality foodstuffs through the upcycling of resources that are otherwise non-suitable for food production, making use of marginal land and inedible materials (forage, by-products, etc.), integrating livestock and crop farming where possible has the potential to benefit plant food production through enhanced nutrient recycling, while minimising external input needs such as fertilisers and pesticides. Moreover, the impacts on land use, water wastage, and greenhouse gas emissions are highly contextual, and their estimation is often erroneous due to a reductionist use of metrics. Similarly, whether animal husbandry is ethical or not depends on practical specificities, not on the fact that animals are involved. Such discussions also need to factor in that animal husbandry plays an important role in culture, societal well-being, food security, and the provision of livelihoods. We seize this opportunity to argue for less preconceived assumptions about alleged effects of animal source foods on the health of the planet and the humans and animals involved, for less top-down planning based on isolated metrics or (Western) technocratic perspectives, and for more holistic and circumstantial approaches to the food system.
Published:
March 1, 2022
Title:
Comparative analysis of ketone body metabolism in BALB/c mice infected with Trypanosoma evansi and Toxoplasma gondii
Authors:
Zhang, Zhaobo; Li, Yifan; Jiang, Ning; Sang, Xiaoyu; Han, Limei
Abstract:
KBs (ketone bodies), i.e., acetoacetate, acetone, and (R)-3-Hydroxybutanoate, constitute the intermediate products of the incomplete oxidative degradation of fatty acids. These KBs are used as a source of energy in the hosts' brain, skeletal muscles, and heart. Additionally, they regulate inflammation and oxidative stress of the host by acting as signaling mediators. Parasitic infection is known to result in abnormal physiological and biochemical metabolism, ketoacidosis, and other damage to the host. In this study, we investigated the effects of Trypanosoma evansi and Toxoplasma gondii on ketone body metabolism in mice, as well as the KB levels in the brain, liver, and peripheral blood. T. gondii was found to significantly increase the KB levels, resulting in ketonemia; T. evansi was found to stabilize KB levels in mice. Further investigations showed that T. evansi downregulated the expression of genes encoding enzymes involved in KBs synthesizing pathway and enhanced KBs synthesizing to eliminate ketonemia. Conversely, T. gondii significantly increased the expression of genes encoding enzymes involved in KBs synthesizing pathway and decreased KBs metabolism pathway ones and resulting in increased KBs levels in peripheral blood, culminating in ketonemia. These findings elucidate the differences in the KBs metabolism resulting from infection with T. evansi and T. gondii.
Published:
March 1, 2022
Title:
Outcomes of parenteral vs enteral ketogenic diet in pediatric super-refractory status epilepticus
Authors:
Chomtho, Sirinuch; Uaariyapanichkul, Jaraspong; Chomtho, Krisnachai
Abstract:
Background Super-refractory status epilepticus (SRSE) is extremely difficult to control and associated with poor outcomes. Ketogenic diet (KD) has been increasingly used for SRSE treatment. Enteral ketosis induction in SRSE is sometimes unfeasible, leading to the use of parenteral KD which has limited data among children. Objectives To assess the effectiveness of KD and compare parenteral and enteral ketosis induction as treatment options in pediatric SRSE patients. Methods This study is a retrospective medical record review of children
Published:
March 1, 2022
Title:
Effect of ketogenic diet on obesity asthma
Authors:
Ludan, Kong; Qiuping, Wu
Abstract:
Recently investigators pay more attention to the relationship between obesity and bronchial asthma (asthma).Obesity is increasingly recognized as a possible risk factor for childhood asthma, and 70% of patients with difficult-to-treat asthma are overweight or obese. In recent years, ketogenic diet, as one of the natural therapies, has been shown to have positive effects on weight loss process; and recent studies showed that ketogenic diet reduced airway inflammation in asthma. This review summarized the mechanisms of associations between obesity and asthma, and described the potential mechanisms of ketogenic diet affecting obese asthma, such as controlling body weight, reducing inflammatory response, regulating intestinal flora and modifying epigenetics, to provide new ideas for the prevention and treatment of obesity asthma.
Published:
February 12, 2022
Title:
Association of Coronary Plaque With Low-Density Lipoprotein Cholesterol Levels and Rates of Cardiovascular Disease Events Among Symptomatic Adults
Authors:
Mortensen, Martin Bødtker; Caínzos-Achirica, Miguel; Steffensen, Flemming Hald; Bøtker, Hans Erik; Jensen, Jesper Møller; Sand, Niels Peter Rønnow; Maeng, Michael; Bruun, Jens Meldgaard; Blaha, Michael J.; Sørensen, Henrik Toft; Pareek, Manan; Nasir, Khurram; Nørgaard, Bjarne L.
Abstract:
Atherosclerosis burden and coronary artery calcium (CAC) are associated with the risk for atherosclerotic cardiovascular disease (ASCVD) events, with absence of plaque and CAC indicating low risk. Whether this is true in patients with elevated levels of low-density lipoprotein cholesterol (LDL-C) is not known. Specifically, a high prevalence of noncalcified plaque might signal high risk.To determine the prevalence of noncalcified and calcified plaque in symptomatic adults and assess its association with cardiovascular events across the LDL-C spectrum.This cohort study included symptomatic patients undergoing coronary computed tomographic angiography from January 1, 2008, to December 31, 2017, from the seminational Western Denmark Heart Registry. Follow-up was completed on July 6, 2018. Data were analyzed from April 2 to December 2, 2021.Prevalence of calcified and noncalcified plaque according to LDL-C strata of less than 77, 77 to 112, 113 to 154, 155 to 189, and at least 190 mg/dL. Severity of coronary artery disease was categorized using CAC scores of 0, 1 to 99, and ≥100, where higher numbers indicate greater CAC burden.Atherosclerotic cardiovascular disease events (myocardial infarction and stroke) and death.A total of 23 143 patients with a median age of 58 (IQR, 50-65) years (12 857 [55.6%] women) were included in the analysis. During median follow-up of 4.2 (IQR, 2.3-6.1) years, 1029 ASCVD and death events occurred. Across all LDL-C strata, absence of CAC was a prevalent finding (ranging from 438 of 948 [46.2%] in patients with LDL-C levels of at least 190 mg/dL to 4370 of 7964 [54.9%] in patients with LDL-C levels of 77-112 mg/dL) and associated with no detectable plaque in most patients, ranging from 338 of 438 (77.2%) in those with LDL-C levels of at least 190 mg/dL to 1067 of 1204 (88.6%) in those with LDL-C levels of less than 77 mg/dL. In all LDL-C groups, absence of CAC was associated with low rates of ASCVD and death (6.3 [95% CI, 5.6-7.0] per 1000 person-years), with increasing rates in patients with CAC scores of 1 to 99 (11.1 [95% CI, 10.0-12.5] per 1000 person-years) and CAC scores of at least 100 (21.9 [95% CI, 19.9-24.4] per 1000 person-years). Among those with CAC scores of 0, the event rate per 1000 person-years was 6.3 (95% CI, 5.6-7.0) in the overall population compared with 6.9 (95% CI, 4.0-11.9) in those with LDL-C levels of at least 190 mg/dL. Across all LDL-C strata, rates were similar and low in those with CAC scores of 0, regardless of whether they had no plaque or purely noncalcified plaque.The findings of this cohort study suggest that in symptomatic patients with severely elevated LDL-C levels of at least 190 mg/dL who are universally considered to be at high risk by guidelines, absence of calcified and noncalcified plaque on coronary computed tomographic angiography was associated with low risk for ASCVD events. These results further suggest that atherosclerosis burden, including CAC, can be used to individualize treatment intensity in patients with severely elevated LDL-C levels.
Published:
February 11, 2022
Title:
Ketogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth
Authors:
Yang, Lifeng; TeSlaa, Tara; Ng, Serina; Nofal, Michel; Wang, Lin; Lan, Taijin; Zeng, Xianfeng; Cowan, Alexis; McBride, Matthew; Lu, Wenyun; Davidson, Shawn; Liang, Gaoyang; Oh, Tae Gyu; Downes, Michael; Evans, Ronald; Hoff, Daniel Von; Guo, Jessie Yanxiang; Han, Haiyong; Rabinowitz, Joshua D.
Abstract:
Published:
February 11, 2022
Title:
Ketogenic diet in pediatric seizures: a randomized controlled trial review and Meta-Analysis
Authors:
Pizzo, Francesco; Collotta, Ausilia Desiree; Di Nora, Alessandra; Costanza, Giuseppe; Ruggieri, Martino; Falsaperla, Raffaele
Abstract:
Background The ketogenic diet is a non-pharmacologic treatment option for children with drug-resistant epilepsy. This systematic review and meta-analysis aimed to assess the efficacy of the ketogenic diet on seizures frequency in children.Methods We reviewed the literature using Cochrane, EMBASE, MEDLINE, and highly qualified journals.Randomized controlled trials were chosen to investigate the seizures-free regime or at least 50% seizures reduction after three months from the starting of the ketogenic diet or earlier. We have selected articles from January 2011 to January 2020.Results Eight articles were eligible. The data show a significant reduction in seizure frequency in the dietary treatment pediatric population. The rate of a seizures-free regime or at least 50% seizures reduction was 48.31% of patients in the intervention group.Our overall meta-analysis underlined the significant efficacy. The KD group is 5.6 times more likely than the control group to have a 50% reduction of seizures after three months of the diet or earlier.QUADAS and AMSTAR assessments showed a low risk of bias and adequate accuracy.Conclusion The results show that the KD reduces seizure frequency in children with drug-refractory epilepsy. KD is an effective treatment option for children and adolescents with refractory epilepsy.
Published:
February 11, 2022
Title:
Low dose 1,3-butanediol reverses age-associated vascular dysfunction independent of ketone body β-hydroxybutyrate
Authors:
McCarthy, Cameron G.; Waigi, Emily W.; Yeoh, Beng San; Mell, Blair; Vijay-Kumar, Matam; Wenceslau, Camilla F.; Joe, Bina
Abstract:
With an aging global population, identifying novel therapeutics are necessary to increase longevity and decrease the deterioration of essential end organs such as the vasculature. Secondary alcohol, 1,3-butanediol (1,3-BD), is commonly administered to stimulate the biosynthesis of the most abundant ketone body β-hydroxybutyrate (βHB), in lieu of nutrient deprivation. However, supra-pharmacological concentrations of 1,3-BD are necessary to significantly increase systemic βHB, and 1,3-BD per se can cause vasodilation at nanomolar concentrations. Therefore, we hypothesized that 1,3-BD could be a novel anti-aging therapeutic, independent of βHB biosynthesis. To test this hypothesis, we administered a low dose (5%) 1,3-BD to young and old Wistar-Kyoto (WKY) rats via drinking water for four weeks and measured indices of vascular function and metabolism post-treatment. We observed that low dose 1,3-BD was sufficient to reverse age-associated endothelial-dependent and -independent dysfunction, and this was not associated with increased βHB bioavailability. Further analysis of the direct vasodilator mechanisms of 1,3-BD revealed that it is predominantly an endothelium-dependent vasodilator through activation of potassium channels and nitric oxide synthase. In summary, we report that 1,3-BD, at a concentration that does not stimulate βHB biosynthesis, could be a nutraceutical that can reverse the age-associated decline in vascular function. These results emphasize that 1,3-BD has multiple, concentration-dependent mechanisms of action. Therefore, we suggest alternative approaches to study the physiological and cardiovascular effects of βHB.
Published:
February 11, 2022
Title:
Mitochondrial and metabolic dysfunction in ageing and age-related diseases
Authors:
Amorim, João A.; Coppotelli, Giuseppe; Rolo, Anabela P.; Palmeira, Carlos M.; Ross, Jaime M.; Sinclair, David A.
Abstract:
Organismal ageing is accompanied by progressive loss of cellular function and systemic deterioration of multiple tissues, leading to impaired function and increased vulnerability to death. Mitochondria have become recognized not merely as being energy suppliers but also as having an essential role in the development of diseases associated with ageing, such as neurodegenerative and cardiovascular diseases. A growing body of evidence suggests that ageing and age-related diseases are tightly related to an energy supply and demand imbalance, which might be alleviated by a variety of interventions, including physical activity and calorie restriction, as well as naturally occurring molecules targeting conserved longevity pathways. Here, we review key historical advances and progress from the past few years in our understanding of the role of mitochondria in ageing and age-related metabolic diseases. We also highlight emerging scientific innovations using mitochondria-targeted therapeutic approaches.
Published:
February 10, 2022
Title:
Probiotics counteract hepatic steatosis caused by ketogenic diet and upregulate AMPK signaling in a model of infantile epilepsy
Authors:
Mu, Chunlong; Nikpoor, Naghmeh; Tompkins, Thomas A.; Rho, Jong M.; Scantlebury, Morris H.; Shearer, Jane
Abstract:
Background Infantile spasms syndrome (IS) is a type of epilepsy affecting 1.6 to 4.5 per 10,000 children in the first year of life, often with severe lifelong neurodevelopmental consequences. Only two first-line pharmacological treatments currently exist for IS and many children are refractory to these therapies. In such cases, children are treated with the ketogenic diet (KD). While effective in reducing seizures, the diet can result in dyslipidemia over time. Methods Employing a neonatal Sprague-Dawley rat model of IS, we investigated how the KD affects hepatic steatosis and its modulation by a defined probiotic blend. A combination of multiple readouts, including malondialdehyde, fatty acid profiles, lipid metabolism-related enzyme mRNA expression, mitochondrial function, histone deacetylase activity, cytokines and chemokines were evaluated using liver homogenates. Findings The KD reduced seizures, but resulted in severe hepatic steatosis, characterized by a white liver, triglyceride accumulation, elevated malondialdehyde, polyunsaturated fatty acids and lower acyl-carnitines compared to animals fed a control diet. The KD-induced metabolic phenotype was prevented by the co-administration of a blend of Streptococcus thermophilus HA-110 and Lactococcus lactis subsp. lactis HA-136. This probiotic blend protected the liver by elevating pAMPK-mediated signaling and promoting lipid oxidation. The strains further upregulated the expression of caspase 1 and interleukin 18, which may contribute to their hepatoprotective effect in this model. Interpretation Our results suggest that early intervention with probiotics could be considered as an approach to reduce the risk of hepatic side effects of the KD in children who are on the diet for medically indicated reasons. Funding This study was funded by the Alberta Children's Hospital Research Institute and Mitacs Accelerate Program (IT16942).
Published:
February 9, 2022
Title:
An integrated model of obesity pathogenesis that revisits causal direction
Authors:
Ludwig, David S.; Sørensen, Thorkild I. A.
Abstract:
Weight gain indicates a positive energy balance, with calorie intake exceeding expenditure. However, this fact of physics cannot inform causality. Potential pathways to obesity include a positive energy balance that drives weight gain or weight gain that drives the positive energy balance. Here, we propose an integrated model of obesity pathogenesis that incorporates both pathways.
Published:
February 8, 2022
Title:
The efficacy of an unrestricted cycling ketogenic diet in preclinical models of IDH wild-type and IDH mutant glioma
Authors:
Javier, Rodrigo; Wang, Wenxia; Drumm, Michael; McCortney, Kathleen; Sarkaria, Jann N.; Horbinski, Craig
Abstract:
Infiltrative gliomas are the most common neoplasms arising in the brain, and remain largely incurable despite decades of research. A subset of these gliomas contains mutations in isocitrate dehydrogenase 1 (IDH1mut) or, less commonly, IDH2 (together called “IDHmut”). These mutations alter cellular biochemistry, and IDHmut gliomas are generally less aggressive than IDH wild-type (IDHwt) gliomas. Some preclinical studies and clinical trials have suggested that various forms of a ketogenic diet (KD), characterized by low-carbohydrate and high-fat content, may be beneficial in slowing glioma progression. However, adherence to a strict KD is difficult, and not all studies have shown promising results. Furthermore, no study has yet addressed whether IDHmut gliomas might be more sensitive to KD. The aim of the current study was to compare the effects of a unrestricted, cycling KD (weekly alternating between KD and standard diet) in preclinical models of IDHwt versus IDHmut gliomas. In vitro, simulating KD by treatment with the ketone body β-hydroxybutyrate had no effect on the proliferation of patient-derived IDHwt or IDHmut glioma cells, either in low or normal glucose conditions. Likewise, an unrestricted, cycling KD had no effect on the in vivo growth of patient-derived IDHwt or IDHmut gliomas, even though the cycling KD did result in persistently elevated circulating ketones. Furthermore, this KD conferred no survival benefit in mice engrafted with Sleeping-Beauty transposase-engineered IDHmut or IDHwt glioma. These data suggest that neither IDHwt nor IDHmut gliomas are particularly responsive to an unrestricted, cycling form of KD.
Published:
February 8, 2022
Title:
β-Hydroxybutyrate Alleviates Low Glucose–Induced Apoptosis via Modulation of ROS-Mediated p38 MAPK Signaling
Authors:
Li, Cixia; Chai, Xuejun; Pan, Jiarong; Huang, Jian; Wu, Yongji; Xue, Yuhuan; Zhou, Wentai; Yang, Jiping; Zhu, Xiaoyan; Zhao, Shanting
Abstract:
Hypoglycemia has emerged as a prominent complication in anti-diabetic drug therapy or negative energy balance of animals, which causes brain damage, cognitive impairment, and even death. Brain injury induced by hypoglycemia is closely related to oxidative stress and the production of reactive oxygen species (ROS). The intracellular accumulation of ROS leads to neuronal damage, even death. Ketone body β-hydroxybutyrate (BHBA) not only serves as alternative energy source for glucose in extrahepatic tissues, but is also involved in cellular signaling transduction. Previous studies showed that BHBA reduces apoptosis by inhibiting the excessive production of ROS and activation of caspase-3. However, the effects of BHBA on apoptosis induced by glucose deprivation and its related molecular mechanisms have been seldom reported. In the present study, PC12 cells and primary cortical neurons were used to establish a low glucose injury model. The effects of BHBA on the survival and apoptosis in a glucose deficient condition and related molecular mechanisms were investigated by using flow cytometry, immunofluorescence, and western blotting. PC12 cells were incubated with 1 mM glucose for 24 h as a low glucose cell model, in which ROS accumulation and cell mortality were significantly increased. After 24 h and 48 h treatment with different concentrations of BHBA (0 mM, 0.05 mM, 0.5 mM, 1 mM, 2 mM), ROS production was significantly inhibited. Moreover, cell apoptosis rate was decreased and survival rate was significantly increased in 1 mM and 2 mM BHBA groups. In primary cortical neurons, at 24 h after treatment with 2 mM BHBA, the injured length and branch of neurites were significantly improved. Meanwhile, the intracellular ROS level, the proportion of c-Fos+ cells, apoptosis rate, and nuclear translocation of NF-κB protein after treatment with BHBA were significantly decreased when compared with that in low glucose cells. Importantly, the expression of p38, p-p38, NF-κB, and caspase-3 were significantly decreased, while the expression of p-ERK was significantly increased in both PC12 cells and primary cortical neurons. Our results demonstrate that BHBA decreased the accumulation of intracellular ROS, and further inhibited cell apoptosis by mediating the p38 MAPK signaling pathway and caspase-3 apoptosis cascade during glucose deprivation. In addition, BHBA inhibited apoptosis by activating ERK phosphorylation and alleviated the damage of low glucose to PC12 cells and primary cortical neurons. These results provide new insight into the anti-apoptotic effect of BHBA in a glucose deficient condition and the related signaling cascade.
Published:
February 7, 2022
Title:
The effects of a primary care low-carbohydrate, high-fat dietary educational intervention on laboratory and anthropometric data of patients with chronic disease: a retrospective cohort chart review
Authors:
Myshak-Davis, Alexandra T; Evans, Janet; Howay, Heidi; Sakakibara, Brodie M
Abstract:
Low-carbohydrate and high-fat (LCHF) diets are shown to have health benefits such as weight loss and improved cardiovascular health. Few studies, however, on LCHF diets have been completed in a real-world primary care setting over an extended period of time.To examine the efficacy of a low-carbohydrate, high-fat dietary educational intervention delivered in a family practice setting on weight, body mass index (BMI), blood pressure, glycated haemoglobin (HbA1c), fasting insulin, estimated glomerular filtration rate (eGFR), and albumin to creatinine ratio (ACR). A secondary objective was to determine whether compliance to the program had an effect on outcomes.In this retrospective chart review, we collected laboratory and anthropometric data from an electronic medical record system for patients (n = 122) at least 19 years of age, who attended at least 2 LCHF educational sessions between January 2018 and May 2020. Pre-post mean differences of outcome were analysed using paired sample t-tests. Independent sample t-tests examined the effect of compliance on the outcomes.Statistically significant reductions in weight (3.96 kg [P < 0.001]) and BMI (1.46 kg/m2 [P = 0.001]) were observed. Compared with patients who participated in ≤5 educational visits, patients who participated in >5 visits showed trends towards more clinically significant changes in weight, BMI, systolic blood pressure, diastolic blood pressure, HbA1c, eGFR, and ACR.Improvements in weight and BMI indicate the utility of providing LCHF health promotion interventions in primary care settings. Greater compliance to LCHF interventions results in greater improvement in laboratory and anthropometric outcomes, including HbA1c.
Published:
February 5, 2022
Title:
Prolonged Glycemic Adaptation Following Transition From a Low- to High-Carbohydrate Diet: A Randomized Controlled Feeding Trial
Authors:
Jansen, Lisa T.; Yang, Nianlan; Wong, Julia M.W.; Mehta, Tapan; Allison, David B.; Ludwig, David S.; Ebbeling, Cara B.
Abstract:
Consuming ≥150 g/day carbohydrate is recommended for 3 days before an oral glucose tolerance test (OGTT) for diabetes diagnosis. For evaluation of this recommendation, time courses of glycemic changes following transition from a very-low-carbohydrate (VLC) to high-carbohydrate diet were assessed with continuous glucose monitoring (CGM).After achieving a weight loss target of 15% (±3%) on the run-in VLC diet, participants (18–50 years old, BMI ≥27 kg/m2) were randomly assigned for 10 weeks to one of three isoenergetic diets: VLC (5% carbohydrate and 77% fat); high carbohydrate, high starch (HC-Starch) (57% carbohydrate and 25% fat, including 20% refined grains); and high carbohydrate, high sugar (HC-Sugar) (57% carbohydrate and 25% fat, including 20% sugar). CGM was done throughout the trial (n = 64) and OGTT at start and end (n = 41). All food was prepared in a metabolic kitchen and consumed under observation.Glucose metrics continued to decline after week 1 in the HC-Starch and HC-Sugar groups (P < 0.05) but not VLC. During weeks 2–5, fasting and 2-h glucose (millimoles per liter per week) decreased in HC-Starch (fasting −0.10, P = 0.001; 2 h −0.10, P = 0.04). During weeks 6–9, 2-h glucose decreased in HC-Starch (−0.07, P = 0.01) and fasting and 2-h glucose decreased in HC-Sugar (fasting −0.09, P = 0.001; 2 h −0.09, P = 0.003). The number of participants with abnormal glucose tolerance by OGTT remained 10 (of 16) in VLC at start and end but decreased from 17 to 9 (of 25) in both high-carbohydrate groups.Physiological adaptation from a low- to high-carbohydrate diet may require many weeks, with implications for the accuracy of diabetes tests, interpretation of macronutrient trials, and risks of periodic planned deviations from a VLC diet.
Published:
February 2, 2022
Title:
Antinutrients: Lectins, goitrogens, phytates and oxalates, friends or foe?
Authors:
López-Moreno, M.; Garcés-Rimón, M.; Miguel, M.
Abstract:
The intake of foods derived from plants has been proposed as an useful strategy in the prevention of several chronic diseases. However, plants also possess a group of substances known as antinutrients, which may be responsible for deleterious effects related to the absorption of nutrients and micronutrients, or exert beneficial health effects. This review compiles scientific evidence regarding the physiological impact of some antinutrients (lectins, goitrogens, phytates and oxalates) in the human health, their negative effects and the culinary and industrial procedures to reduce their presence in foods. It can be concluded that, the effects of antinutrients on human health could change when consumed in their natural food matrix, and after processing or culinary treatment. Accordingly, some of these compounds could have beneficial effects in different pathological conditions. Future research is required to understand the therapeutic potential of these compounds in humans.
Published:
February 1, 2022
Title:
Atlas of exercise metabolism reveals time-dependent signatures of metabolic homeostasis
Authors:
Sato, Shogo; Dyar, Kenneth A.; Treebak, Jonas T.; Jepsen, Sara L.; Ehrlich, Amy M.; Ashcroft, Stephen P.; Trost, Kajetan; Kunzke, Thomas; Prade, Verena M.; Small, Lewin; Basse, Astrid Linde; Schönke, Milena; Chen, Siwei; Samad, Muntaha; Baldi, Pierre; Barrès, Romain; Walch, Axel; Moritz, Thomas; Holst, Jens J.; Lutter, Dominik; Zierath, Juleen R.; Sassone-Corsi, Paolo
Abstract:
Published:
February 1, 2022
Title:
Effects of a Low-Carbohydrate Ketogenic Diet on Reported Pain, Blood Biomarkers and Quality of Life in Patients with Chronic Pain: A Pilot Randomized Clinical Trial
Authors:
Field, Rowena; Pourkazemi, Fereshteh; Rooney, Kieron
Abstract:
A low-carbohydrate ketogenic diet has been reported to improve chronic pain by reducing inflammation, oxidative stress, and sensitivity within the nervous system. The main aim of this trial is to evaluate the effects of a ketogenic diet on reported pain, blood biomarkers and quality of life in patients with chronic pain.Participants with chronic musculoskeletal pain were recruited for a 12-week diet intervention that commenced with a 3-week run-in diet removing ultra-processed foods, followed by randomization to either a whole-food/well-formulated ketogenic diet (WFKD) or to continue with the minimally processed whole-food diet (WFD). Outcome measures included: average pain (visual analogue scale VAS), blood biomarkers, anthropometrics, adherence, depression, anxiety, sleep, ketones, quality of life, diet satisfaction, and macronutrient intake.Average weekly pain improved for both groups. WFKD group VAS reduced by 17.9 ± 5.2 mm (P = .004) and the WFD group VAS reduced 11.0 ± 9.0 mm (P = .006). Both groups also reported improved quality of life (WFKD = 11.5 ± 2.8%, P = .001 and WFD = 11.0 ± 3.5%, P = .014). The WFKD group also demonstrated significant improvements in pain interference (P = 0.013), weight (P < .005), depression (P = .015), anxiety (P = .013), and inflammation (hsCRP) (P = .009). Significant average pain reduction remained at three-month follow-up for both groups (WFKD P = .031, WFD P = .011).The implementation of a whole-food diet that restricts ultra-processed foods is a valid pain management tool; however, a low-carbohydrate ketogenic diets may have potentially greater pain reduction, weight loss and mood improvements.
Published:
February 1, 2022
Title:
No sustained increase in zooarchaeological evidence for carnivory after the appearance of Homo erectus
Authors:
Barr, W. Andrew; Pobiner, Briana; Rowan, John; Du, Andrew; Faith, J. Tyler
Abstract:
The appearance of Homo erectus shortly after 2.0 Ma is widely considered a turning point in human dietary evolution, with increased consumption of animal tissues driving the evolution of larger brain and body size and a reorganization of the gut. An increase in the size and number of zooarchaeological assemblages after the appearance of H. erectus is often offered as a central piece of archaeological evidence for increased carnivory in this species, but this characterization has yet to be subject to detailed scrutiny. Any widespread dietary shift leading to the acquisition of key traits in H. erectus should be persistent in the zooarchaeological record through time and can only be convincingly demonstrated by a broad-scale analysis that transcends individual sites or localities. Here, we present a quantitative synthesis of the zooarchaeological record of eastern Africa from 2.6 to 1.2 Ma. We show that several proxies for the prevalence of hominin carnivory are all strongly related to how well the fossil record has been sampled, which constrains the zooarchaeological visibility of hominin carnivory. When correcting for sampling effort, there is no sustained increase in the amount of evidence for hominin carnivory between 2.6 and 1.2 Ma. Our observations undercut evolutionary narratives linking anatomical and behavioral traits to increased meat consumption in H. erectus, suggesting that other factors are likely responsible for the appearance of its human-like traits.
Published:
February 1, 2022
Title:
Nutritional Deficiencies in Vegetarian, Gluten-Free, and Ketogenic Diets
Authors:
Andrewski, Erik; Cheng, Katherine; Vanderpool, Charles
Abstract:
Previously, medical diets, including the ketogenic and gluten-free diets, were rare outside of their target population. Subspecialists more familiar with risks and benefits often managed nutrition and any associated shortcomings. With more patients electively following a gluten-free or ketogenic diet for nonmedical needs, as well as the increasing prevalence of vegetarian diets, general pediatricians are seeing more followers of restrictive diets with general well-child care. Increasingly, general pediatricians can be the first provider to witness presenting signs or symptoms of associated nutritional deficiencies. This article reviews signs and symptoms of possible nutrient deficiencies seen with the vegetarian, ketogenic, and gluten-free diets.
Published:
February 1, 2022
Title:
Study protocol on the safety and feasibility of a normocaloric ketogenic diet in people with amyotrophic lateral sclerosis
Authors:
De Marchi, Fabiola; Collo, Alessandro; Scognamiglio, Ada; Cavaletto, Maria; Bozzi Cionci, Nicole; Biroli, Giampaolo; Di Gioia, Diana; Riso, Sergio; Mazzini, Letizia
Abstract:
Objectives This study evaluates the safety and feasibility of a normocaloric ketogenic diet (KD) in people with amyotrophic lateral sclerosis (ALS) for reducing hyperexcitability levels and modulating neuroinflammation. Methods This is a prospective, open-label pilot study involving men and women diagnosed with ALS, ages 18 to 75 y. The primary outcome is the safety and reproducibility of the KD in people with ALS. We will monitor secondary clinical outcomes with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale score, forced vital capacity, the Amyotrophic Lateral Sclerosis Assessment Questionnaire, blood parameters, and gut microbiota analyses. All participants will follow the KD for 8 wk. During the diet, the clinical status of all participants will be monitored every 15 d through neurologic and nutritional visits and biochemical markers. The research ethics committee approved the study. Results Safety will be assessed by measuring the number and severity of adverse events, including death, and any changes in blood chemistry, vital signs, and clinical exam results. Tolerability will be assessed to complete the proposed 8 wk of treatment while maintaining adequate nutritional status without inducing malnutrition. Conclusions Adequate caloric intake is essential in ALS, because insufficient intake induces loss of body mass. We hope that the proposed study will provide a positive result in terms of the safety and feasibility of a KD in people ALS, with the purpose of developing a patient-centered diet program to limit disease progression and possibly improve survival.
Published:
February 1, 2022
Title:
The potential pharmacological mechanisms of β-hydroxybutyrate for improving cognitive functions
Authors:
Wang, Jian-Hong; Guo, Lei; Wang, Su; Yu, Neng-Wei; Guo, Fu-Qiang
Abstract:
β-Hydroxybutyl acid (βOHB), the most prevalent type of ketone in the human body, is involved in the pathogenesis of cognitive disorders, especially Alzheimer’s dementia (AD), through a variety of mechanisms, such as enhancing mitochondrial metabolism, regulating signaling molecule, increasing histone acetylation, affecting the metabolism of Aβ and Tau proteins, inhibiting inflammation and lipid metabolism, and regulating intestinal microbes. Based on the above findings, clinical drug development in AD has begun to focus on βOHB.
Published:
February 1, 2022
Title:
Substantial early changes in bone and calcium metabolism among adult pharmacoresistant epilepsy patients on a modified Atkins diet
Authors:
Molteberg, Ellen; Taubøll, Erik; Kverneland, Magnhild; Iversen, Per Ole; Selmer, Kaja Kristine; Nakken, Karl Otto; Hofoss, Dag; Thorsby, Per Medbøe
Abstract:
OBJECTIVE: The aim of this study was to investigate whether the modified Atkins diet (MAD), a variant of the ketogenic diet, has an impact on bone- and calcium (Ca) metabolism. METHODS: Two groups of adult patients with pharmacoresistant epilepsy were investigated. One, the diet group (n = 53), was treated with MAD for 12 weeks, whereas the other, the reference group (n = 28), stayed on their habitual diet in the same period. All measurements were performed before and after the 12 weeks in both groups. We assessed bone health by measuring parathyroid hormone (PTH), Ca, 25-OH vitamin D (25-OH vit D), 1,25-OH vitamin D (1,25-OH vit D), phosphate, alkaline phosphatase (ALP), and the bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide collagen type 1 (CTX-1). In addition, we examined the changes of sex hormones (estradiol, testosterone, luteinizing hormone, follicle-stimulating hormone), sex hormone-binding globulin, and leptin. RESULTS: After 12 weeks of MAD, we found a significant reduction in PTH, Ca, CTX-1, P1NP, 1,25-OH vit D, and leptin. There was a significant increase in 25-OH vit D. These changes were most pronounced among patients
Published:
January 28, 2022
Title:
Depressive symptoms improve over 2 years of type 2 diabetes treatment via a digital continuous remote care intervention focused on carbohydrate restriction
Authors:
Adams, Rebecca N.; Athinarayanan, Shaminie J.; McKenzie, Amy L.; Hallberg, Sarah J.; McCarter, James P.; Phinney, Stephen D.; Gonzalez, Jeffrey S.
Abstract:
Depressive symptoms are prevalent among people with type 2 diabetes (T2D) and, even at low severity levels, are associated with worse diabetes outcomes. Carbohydrate restriction is an effective treatment for T2D but its long-term impacts on depressive symptoms are unclear. In the current study we explored changes in depressive symptoms over 2 years among 262 primarily non-depressed T2D patients participating in a continuous remote care intervention emphasizing carbohydrate restriction. Subclinical depressive symptoms decreased over the first 10 weeks and reductions were maintained out to 2 years. Increased frequency of blood ketone levels indicative of adherence to low carbohydrate eating predicted decreases in depressive symptoms. Concerns have been raised with recommending restrictive diets due to potential negative impacts on quality-of-life factors such as mood; however, results of the current study support positive rather than negative long-term impacts of closely monitored carbohydrate restriction on depressive symptoms.
Published:
January 27, 2022
Title:
Gut bacterial nutrient preferences quantified in vivo
Authors:
Zeng, Xianfeng; Xing, Xi; Gupta, Meera; Keber, Felix C.; Lopez, Jaime G.; Roichman, Asael; Wang, Lin; Neinast, Michael D.; Donia, Mohamed S.; Wühr, Martin; Jang, Cholsoon; Rabinowitz, Joshua D.
Abstract:
Great progress has been made in understanding gut microbiome’s products and their effects on health and disease. Less attention, however, has been given to the inputs that gut bacteria consume. Here we quantitatively examine inputs and outputs of the mouse gut microbiome, using isotope tracing. The main input to microbial carbohydrate fermentation is dietary fiber, and to branched-chain fatty acids and aromatic metabolites is dietary protein. In addition, circulating host lactate, 3-hydroxybutyrate and urea (but not glucose or amino acids) feed the gut microbiome. To determine nutrient preferences across bacteria, we traced into genus-specific bacterial protein sequences. We find systematic differences in nutrient use: Most genera in the phylum Firmicutes prefer dietary protein, Bacteroides dietary fiber, and Akkermansia circulating host lactate. Such preferences correlate with microbiome composition changes in response to dietary modifications. Thus, diet shapes the microbiome by promoting the growth of bacteria that preferentially use the ingested nutrients.
Published:
January 26, 2022
Title:
Urinary metabolic biomarkers of diet quality in European children are associated with metabolic health
Authors:
Stratakis, Nikos; Siskos, Alexandros P.; Papadopoulou, Eleni; Nguyen, Anh N.; Zhao, Yinqi; Margetaki, Katerina; Lau, Chung-Ho E.; Coen, Muireann; Maitre, Lea; Fernández-Barrés, Silvia; Agier, Lydiane; Andrusaityte, Sandra; Basagaña, Xavier; Brantsaeter, Anne Lise; Casas, Maribel; Fossati, Serena; Grazuleviciene, Regina; Heude, Barbara; McEachan, Rosemary Rc; Meltzer, Helle Margrete; Millett, Christopher; Rauber, Fernanda; Robinson, Oliver; Roumeliotaki, Theano; Borras, Eva; Sabidó, Eduard; Urquiza, Jose; Vafeiadi, Marina; Vineis, Paolo; Voortman, Trudy; Wright, John; Conti, David V.; Vrijheid, Martine; Keun, Hector C.; Chatzi, Leda
Abstract:
Urinary metabolic profiling is a promising powerful tool to reflect dietary intake and can help understand metabolic alterations in response to diet quality. Here, we used 1H NMR spectroscopy in a multicountry study in European children (1147 children from 6 different cohorts) and identified a common panel of 4 urinary metabolites (hippurate, N-methylnicotinic acid, urea, and sucrose) that was predictive of Mediterranean diet adherence (KIDMED) and ultra-processed food consumption and also had higher capacity in discriminating children's diet quality than that of established sociodemographic determinants. Further, we showed that the identified metabolite panel also reflected the associations of these diet quality indicators with C-peptide, a stable and accurate marker of insulin resistance and future risk of metabolic disease. This methodology enables objective assessment of dietary patterns in European child populations, complementary to traditional questionary methods, and can be used in future studies to evaluate diet quality. Moreover, this knowledge can provide mechanistic evidence of common biological pathways that characterize healthy and unhealthy dietary patterns, and diet-related molecular alterations that could associate to metabolic disease.
Published:
January 25, 2022
Title:
A combination of ketogenic diet and voluntary exercise ameliorates anxiety and depression-like behaviors in Balb/c mice
Authors:
Gumus, Hikmet; Ilgin, Rabia; Koc, Basar; Yuksel, Oguz; Kizildag, Servet; Guvendi, Guven; Karakilic, Asli; Kandis, Sevim; Hosgorler, Ferda; Ates, Mehmet; Alacam, Hasan; Uysal, Nazan
Abstract:
The positive effects of both ketogenic diet (KD) and regular voluntary exercise on anxiety and depression behavior have been recently reported in rodent animals, but the effects of pairing a KD with exercise on depression and anxiety are unknown. In this study, we aimed to investigate the effects of combination of KD and regular voluntary exercise on anxiety and depression-like behavior in Balb/c mice. We’ve demostrated that anxiety and depression levels decreased in KD-exercised (KD-Ex) mice. β-hydroxybutyrate (BHB) levels increased while glucose, insulin levels and LDL/HDL ratio decreased in KD-Ex mice. There was a negative correlation between BHB and the time spent in the closed arms of elevated plus maze (EPM) or the time spent in periphery walls of open field test (OFT) and the immobility time in forced swim test (FST) which all of them are indicators of low depression and anxiety levels. There was a positive correlation between LDL/HDL ratio and the time spent in the closed arms of EPM or the immobility time in FST. The immobility time in FST was positively correlated with insulin while the mobility time in FST was negatively correlated with glucose. In conclusion, these results suggest that decline in anxiety and depression-like behaviors resulted from KD with regular voluntary exercise may be associated with increased BHB levels and decreased LDL/HDL ratio and insulin or glucose levels. Further research is necessary for our understanding of the mechanisms by which pairing a KD with voluntary exercise influences brain and behavior.
Published:
January 23, 2022
Title:
Feasibility of an MI-CBT ketogenic adherence program for older adults with mild cognitive impairment
Authors:
Sheffler, Julia L.; Arjmandi, Bahram; Quinn, Jamie; Hajcak, Greg; Vied, Cynthia; Akhavan, Neda; Naar, Sylvie
Abstract:
The National Institutes of Health Obesity-Related Behavioral Intervention Trials model for intervention development was used to establish the feasibility and proof of concept of a motivational ketogenic nutrition adherence program for older adults with mild cognitive impairment.
Published:
January 22, 2022
Title:
Feasibility of an MI-CBT ketogenic adherence program for older adults with mild cognitive impairment
Authors:
Sheffler, Julia L.; Arjmandi, Bahram; Quinn, Jamie; Hajcak, Greg; Vied, Cynthia; Akhavan, Neda; Naar, Sylvie
Abstract:
BACKGROUND: The National Institutes of Health Obesity-Related Behavioral Intervention Trials model for intervention development was used to establish the feasibility and proof of concept of a motivational ketogenic nutrition adherence program for older adults with mild cognitive impairment. METHODS: This was a single-arm, single-center feasibility trial. A comprehensive assessment protocol, including a clinical interview, neuropsychological testing, and genetic sequencing was used as an initial screening. Nine participants (aged 64-75) with possible amnestic mild cognitive impairment were consented for the intervention. Participants completed pre- and post-intervention neuropsychological assessments using the updated Repeatable Battery for Assessment of Neuropsychological Status. Participants tracked their macronutrient consumption using food diaries and ketone levels using urinalysis test strips daily. Mood and other psychosocial variables were collected through surveys, and qualitative exit interviews were completed. RESULTS: 100% of participants who began the trial completed the 6-week ketogenic nutrition adherence program, including completion of the pre- and post-assessments. Eight participants achieved measurable levels of ketones during the program. The average self-rated adherence across the program was 8.7 out of 10. A Wilcoxon Signed-Rank test demonstrated significant improvement in cognitive performance from baseline (median = 88) to follow up (median = 96, Z = - 2.26, p = .024). The average difference in cognitive performance from baseline to follow-up was - 7.33 (95% CI - 12.85, - 1.82). CONCLUSIONS: Results supported the feasibility for moving to the next phase and demonstrated proof of concept for the intervention. The next step is a randomized pilot trial to test clinical signals of effect compared to a control condition. TRIAL REGISTRATION: This trial was retrospectively registered with clinicaltrials.gov on July 13, 2021. The trial number is NCT04968041.
Published:
January 22, 2022
Title:
Isonitrogenous low-carbohydrate diet elicits specific changes in metabolic gene expression in the skeletal muscle of exercise-trained mice
Authors:
Saito, Hazuki; Wada, Naoko; Iida, Kaoruko
Abstract:
With the renewed interest in low-carbohydrate diets (LCDs) in the sports field, a few animal studies have investigated their potential. However, most rodent studies have used an LCD containing low protein, which does not recapitulate a human LCD, and the muscle-specific adaptation in response to an LCD remains unclear. Therefore, we investigated the effects of two types of LCDs, both containing the same proportion of protein as a regular diet (isonitrogenous LCD; INLCD), on body composition, exercise performance, and metabolic fuel selection at the genetic level in the skeletal muscles of exercise-trained mice. Three groups of mice (n = 8 in each group), one fed a regular AIN-93G diet served as the control, and the others fed either of the two INLCDs containing 20% protein and 10% carbohydrate (INLCD-10%) or 20% protein and 1% carbohydrate (INLCD-1%) had a regular exercise load (5 times/week) for 12 weeks. Body weight and muscle mass did not decrease in either of the INLCD-fed groups, and the muscle glycogen levels and endurance capacity did not differ among the three groups. Only in the mice fed INLCD-1% did the plasma ketone concentration significantly increase, and gene expression related to glucose utilization significantly declined in the muscles. Both INLCD-1% and INLCD-10% consumption increased gene expression related to lipid utilization. These results suggest that, although INLCD treatment did not affect endurance capacity, it helped maintain muscle mass and glycogen content regardless of the glucose intake restrictions in trained mice. Moreover, an INLCD containing a low carbohydrate content might present an advantage by increasing lipid oxidation without ketosis and suppressing muscle glucose utilization.
Published:
January 21, 2022
Title:
Vegans and vegetarians living in Nottingham (UK) continue to be at risk of iodine deficiency
Authors:
Eveleigh, Elizabeth; Coneyworth, Lisa; Zhou, Mi; Burdett, Hannah; Malla, Jhama; Nguyen, Van Hoang; Welham, Simon
Abstract:
Iodine is essential for thyroid hormone synthesis. Individuals adhering to vegan and vegetarian diets have been found to be vulnerable to iodine deficiency. Yet, iodine has not been monitored in these groups across time. This study aims to investigate iodine status, intake and knowledge in vegans, vegetarians, and omnivores and determine changes between 2016-17 and 2019. Dietary intake (µg day-1) was estimated by three-day food diaries (FD), and iodine food frequency questionnaires (FFQ). Urinary iodine concentration (UIC), analysed by ICP-MS, assessed iodine status according to World Health Organisation (WHO) criteria. Iodine knowledge was scored by an adapted questionnaire. IBM SPSS was used for statistical analysis.
Published:
January 21, 2022
Title:
Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis
Authors:
Murphy, Neil; Song, Mingyang; Papadimitriou, Nikos; Carreras-Torres, Robert; Langenberg, Claudia; Martin, Richard M; Tsilidis, Konstantinos K; Barroso, Inês; Chen, Ji; Frayling, Tim; Bull, Caroline J; Vincent, Emma E; Cotterchio, Michelle; Gruber, Stephen B; Pai, Rish K; Newcomb, Polly A; Perez-Cornago, Aurora; van Duijnhoven, Franzel J B; Van Guelpen, Bethany; Vodicka, Pavel; Wolk, Alicja; Wu, Anna H; Peters, Ulrike; Chan, Andrew T; Gunter, Marc J
Abstract:
Glycemic traits—such as hyperinsulinemia, hyperglycemia, and type-2 diabetes—have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type-2 diabetes with colorectal cancer.Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type-2 diabetes (n = 268). Using two-sample MR, we examined these variants in relation to colorectal cancer risk (48,214 cases and 64,159 controls).In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-standard deviation [SD]=1.65, 95% CI = 1.15–2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86–1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88–1.23) concentrations on colorectal cancer risk. Genetic liability to type-2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01–1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00–1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05–1.40), but not in women.Our results support a causal effect of higher fasting insulin, but not glucose traits or type-2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis.
Published:
January 20, 2022
Title:
Re-routing metabolism by the mitochondrial pyruvate carrier inhibitor MSDC-0160 attenuates neurodegeneration in a rat model of Parkinson’s disease
Authors:
Mallet, David; Goutaudier, Raphael; Barbier, Emmanuel L.; Carnicella, Sebastien; Colca, Jerry R.; Fauvelle, Florence; Boulet, Sabrina
Abstract:
Background A growing body of evidence supports the idea that mitochondrial dysfunction might represent a key feature of Parkinson’s disease (PD). Central regulators of energy production, mitochondria are also involved in several other essential functions such as cell death pathways and neuroinflammation which make them a potential therapeutic target for PD management. Interestingly, recent studies related to PD have reported a neuroprotective effect of targeting mitochondrial pyruvate carrier (MPC) by the insulin sensitizer MSDC-0160. As the sole point of entry of pyruvate into the mitochondrial matrix, MPC plays a crucial role in energetic metabolism which is impacted in PD. This study therefore aimed at providing insights into the mechanisms underlying the neuroprotective effect of MSDC-0160. Methods We investigated behavioral, cellular and metabolic impact of chronic MSDC-0160 treatment in unilateral 6-OHDA PD rats. We evaluated mitochondrial related processes through the expression of pivotal mitochondrial enzymes in dorsal striatal biopsies and the level of metabolites in serum samples using nuclear magnetic resonance spectroscopy (NMR)-based metabolomics. Results MSDC-0160 treatment in unilateral 6-OHDA rats improved motor behavior, decreased dopaminergic denervation and reduced mTOR activity and neuroinflammation. Concomitantly, MSDC-0160 administration strongly modified energy metabolism as revealed by increased ketogenesis, beta oxidation and glutamate oxidation to satisfy energy needs and maintain energy homeostasis. Conclusion MSDC-0160 exerts its neuroprotective effect through reorganization of multiple pathways connected to energy metabolism.
Published:
January 20, 2022
Title:
Ketogenic diet, African American women, and cardiovascular health: A systematic review
Authors:
Hanners, Audra; Melnyk, Bernadette; Volek, Jeff; Kelley, Marjorie M.
Abstract:
BACKGROUND: Cardiovascular disease (CVD) is the number one cause of death in the United States of America and across the world. The high prevalence of obesity (56.9%) in African American women contributes to high rates of CVD. Ketogenic nutritional therapy has been shown to be a safe and effective therapy for weight loss and reduction in other CVD risk factors (e.g., HgbA1C and blood pressure). However, the evidence investigating ketogenic nutritional therapy among African American women to improve CVD risk factors has not yet been synthesized. AIMS: To conduct a systematic review of the evidence on CVD risk reduction and ketogenic nutrition therapy among African American women. METHODS: CINAHL Plus, Cochrane, EMBASE, MEDLINE/PubMed, SCOPUS, and Web of Science were searched for quantitative studies focused on ketogenic nutritional therapy and CVD risk factors among African American women. Included studies measured beta-hydroxybutyrate as an indicator of dietary adherence. RESULTS: Of 4,799 articles identified, six articles representing five studies were included in this review. The majority of participants were female, with very few identified as African American women. Primary outcomes included weight, body mass index (BMI), blood pressure, and lipids. Dietary adherence was difficult to assess. Significant reductions in weight and BMI were noted. Heterogeneity in study design, intervention length, and measurement of dietary adherence made generalizations difficult. Few studies continually monitored dietary adherence using beta-hydroxybutyrate levels, thus threatening the internal validity of the studies. A gap in our understanding remains concerning CVD risk and ketogenic nutritional therapy among African American women specifically. LINKING EVIDENCE TO ACTION: Ketogenic nutritional therapy is effective in women to reduce weight and BMI. Ketogenic nutritional therapy may be beneficial in reducing CVD risk factors. Monitoring dietary adherence using beta-hydroxybutyrate levels with commercially available monitors is key to intervention success.
Published:
January 19, 2022
Title:
The mitochondrial β-oxidation enzyme HADHA restrains hepatic glucagon response by promoting β-hydroxybutyrate production
Authors:
Pan, An; Sun, Xiao-Meng; Huang, Feng-Qing; Liu, Jin-Feng; Cai, Yuan-Yuan; Wu, Xin; Alolga, Raphael N.; Li, Ping; Liu, Bao-Lin; Liu, Qun; Qi, Lian-Wen
Abstract:
Disordered hepatic glucagon response contributes to hyperglycemia in diabetes. The regulators involved in glucagon response are less understood. This work aims to investigate the roles of mitochondrial β-oxidation enzyme HADHA and its downstream ketone bodies in hepatic glucagon response. Here we show that glucagon challenge impairs expression of HADHA. Liver-specific HADHA overexpression reversed hepatic gluconeogenesis in mice, while HADHA knockdown augmented glucagon response. Stable isotope tracing shows that HADHA promotes ketone body production via β-oxidation. The ketone body β-hydroxybutyrate (BHB) but not acetoacetate suppresses gluconeogenesis by selectively inhibiting HDAC7 activity via interaction with Glu543 site to facilitate FOXO1 nuclear exclusion. In HFD-fed mice, HADHA overexpression improved metabolic disorders, and these effects are abrogated by knockdown of BHB-producing enzyme. In conclusion, BHB is responsible for the inhibitory effect of HADHA on hepatic glucagon response, suggesting that HADHA activation or BHB elevation by pharmacological intervention hold promise in treating diabetes.
Published:
January 19, 2022
Title:
A Compared Study of Gentle Ketogenic Diet Containing Medium-Chain Triglycerides or Long-Chain Triglycerides on Chronic Sleep Deprivation-Induced Cognitive Deficiency in Mice
Authors:
Wang, Xueyan; Yang, Yueqi; Xiao, Aiai; Zhang, Ning; Miao, Mingyong; Wang, Zhengping; Han, Jun; Wen, Min
Abstract:
Ketogenic diet (KD) is well known for its neuroprotective effect, but little is known about its prophylactic efficacy against chronic sleep deprivation (SD) induced cognitive deficiency. Emerging study indicated that ferroptosis plays an important role in neurologic diseases but has been rarely reported in SD. Here, we investigated the prophylactic effects of medium-chain triglycerides enriched KD (MKD) and long-chain triglycerides enriched KD (LKD) on cognitive deficiency and revealed the underlying mechanism focus on the ferroptosis in chronic SD model mice. Results showed that MKD exhibited stronger effects than LKD on improving cognitive deficiency via suppressing ferroptosis and improving synaptic plasticity. Further mechanism results indicated that MKD produced higher Sirt3 protein levels than LKD, which probably contributed to the synergistic effect of beta hydroxybutyric acid and decanoic acid. Our finds provide novel evidence for KD as a safe and feasible dietary intervention to prevent chronic SD induced cognitive deficiency, and suggested a better choice of medium-chain fatty acid enriched KD.
Published:
January 17, 2022
Title:
A comparative study of the effect of a gentle ketogenic diet containing medium-chain or long-chain triglycerides on chronic sleep deprivation-induced cognitive deficiency
Authors:
Wang, Xueyan; Yang, Yueqi; Xiao, Aiai; Zhang, Ning; Miao, Mingyong; Wang, Zhengping; Han, Jun; Wen, Min
Abstract:
The ketogenic diet (KD) is well known for its neuroprotective effect, but little is known about its prophylactic efficacy against chronic sleep deprivation (SD) induced cognitive deficiency. An emerging study indicated that ferroptosis plays an important role in neurologic diseases but has been rarely reported in chronic SD. Here, we investigated the prophylactic effects of a medium-chain triglyceride-enriched KD (MKD) and a long-chain triglyceride-enriched KD (LKD) on cognitive deficiency and revealed the underlying mechanism focused on ferroptosis in chronic SD model mice. The results showed that the MKD exhibited stronger effects than the LKD on improving cognitive deficiency via suppressing ferroptosis and improving synaptic plasticity. Further mechanism results indicated that MKD produced higher Sirt3 protein levels than LKD, which probably contributed to the synergistic effect of beta hydroxybutyric acid and decanoic acid. Our finds provide novel evidence for the KD as a safe and feasible dietary intervention to prevent chronic SD-induced cognitive deficiency, and suggest a better choice of medium-chain fatty acid-enriched KD.
Published:
January 17, 2022
Title:
Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations
Authors:
Zhu, Huiyuan; Bi, Dexi; Zhang, Youhua; Kong, Cheng; Du, Jiahao; Wu, Xiawei; Wei, Qing; Qin, Huanlong
Abstract:
The ketogenic diet (KD) is a high-fat, adequate-protein, and very-low-carbohydrate diet regimen that mimics the metabolism of the fasting state to induce the production of ketone bodies. The KD has long been established as a remarkably successful dietary approach for the treatment of intractable epilepsy and has increasingly garnered research attention rapidly in the past decade, subject to emerging evidence of the promising therapeutic potential of the KD for various diseases, besides epilepsy, from obesity to malignancies. In this review, we summarize the experimental and/or clinical evidence of the efficacy and safety of the KD in different diseases, and discuss the possible mechanisms of action based on recent advances in understanding the influence of the KD at the cellular and molecular levels. We emphasize that the KD may function through multiple mechanisms, which remain to be further elucidated. The challenges and future directions for the clinical implementation of the KD in the treatment of a spectrum of diseases have been discussed. We suggest that, with encouraging evidence of therapeutic effects and increasing insights into the mechanisms of action, randomized controlled trials should be conducted to elucidate a foundation for the clinical use of the KD.
Published:
January 17, 2022
Title:
“The Bitter Truth of Sugar”—Euglycemic Diabetic Ketoacidosis due to Sodium-glucose Cotransporter-2 Inhibitors: A Case Series
Authors:
Bhagwat, Nikhil M; Pathrose, Edwin; Shah, Mehul; Chandy, David
Abstract:
Diabetic ketoacidosis (DKA) is an acute and major complication of diabetes mellitus (DM), both type I and type II. Biochemically, DKA consists of a triad of blood sugar levels greater than 250 mg/dL, ketonemia of greater than 3 mmol/L and/or significant ketonuria, and a blood pH less than 7.3 with an increased anion gap. Currently, the sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are widely used in management of type II diabetes. There have been several reports of an association between euglycemic diabetic ketoacidosis (EuDKA) and SGLT-2i agents. We present three different patients who were on SGLT-2i therapy who developed recurrent EuDKA postprocedure or sepsis. We believe that prolonged treatment (5–6 days) with intravenous (IV) insulin with glucose until resolution of glycosuria can be considered as an inexpensive marker of resolution of EuDKA. Moreover, the recommended duration for discontinuation of these drugs prior to elective procedures should be longer than 3 days.
Published:
January 17, 2022
Title:
Levantine overkill: 1.5 million years of hunting down the body size distribution
Authors:
Dembitzer, Jacob; Barkai, Ran; Ben-Dor, Miki; Meiri, Shai
Abstract:
Multiple large-bodied species went extinct during the Pleistocene. Changing climates and/or human hunting are the main hypotheses used to explain these extinctions. We studied the causes of Pleistocene extinctions in the Southern Levant, and their subsequent effect on local hominin food spectra, by examining faunal remains in archaeological sites across the last 1.5 million years. We examined whether climate and climate changes, and/or human cultures, are associated with these declines. We recorded animal abundances published in the literature from 133 stratigraphic layers, across 58 Pleistocene and Early Holocene archaeological sites, in the Southern Levant. We used linear regressions and mixed models to assess the weighted mean mass of faunal assemblages through time and whether it was associated with temperature, paleorainfall, or paleoenvironment (C3 vs. C4 vegetation). We found that weighted mean body mass declined log-linearly through time. Mean hunted animal masses 10,500 years ago, were only 1.7% of those 1.5 million years ago. Neither body size at any period, nor size change from one layer to the next, were related to global temperature or to temperature changes. Throughout the Pleistocene, new human lineages hunted significantly smaller prey than the preceding ones. This suggests that humans extirpated megafauna throughout the Pleistocene, and when the largest species were depleted the next-largest were targeted. Technological advancements likely enabled subsequent human lineages to effectively hunt smaller prey replacing larger species that were hunted to extinction or until they became exceedingly rare.
Published:
January 15, 2022
Title:
Role of nutritional ketosis in the improvement of metabolic parameters following bariatric surgery
Authors:
Pindozzi, Fioralba; Socci, Carlo; Bissolati, Massimiliano; Marchi, Monica; Devecchi, Elisabetta; Saibene, Alessandro; Conte, Caterina
Abstract:
BACKGROUND: Ketone bodies (KB) might act as potential metabolic modulators besides serving as energy substrates. Bariatric metabolic surgery (BMS) offers a unique opportunity to study nutritional ketosis, as acute postoperative caloric restriction leads to increased lipolysis and circulating free fatty acids. AIM: To characterize the relationship between KB production, weight loss (WL) and metabolic changes following BMS. METHODS: For this retrospective study we enrolled male and female subjects aged 18-65 years who underwent BMS at a single Institution. Data on demographics, anthropometrics, body composition, laboratory values and urinary KB were collected. RESULTS: Thirty-nine patients had data available for analyses [74.4% women, mean age 46.5 ± 9.0 years, median body mass index 41.0 (38.5; 45.4) kg/m2, fat mass 45.2% ± 6.2%, 23.1% had diabetes, 43.6% arterial hypertension and 74.4% liver steatosis]. At 46.0 ± 13.6 d post-surgery, subjects had lost 12.0% ± 3.6% of pre-operative weight. Sixty-nine percent developed ketonuria. Those with nutritional ketosis were significantly younger [42.9 (37.6; 50.7) years vs 51.9 (48.3; 59.9) years, P = 0.018], and had significantly lower fasting glucose [89.5 (82.5; 96.3) mg/dL vs 96.0 (91.0; 105.3) mg/dL, P = 0.025] and triglyceride levels [108.0 (84.5; 152.5) mg/dL vs 152.0 (124.0; 186.0) mg/dL, P = 0.045] vs those with ketosis. At 6 mo, percent WL was greater in those with postoperative ketosis (-27.5% ± 5.1% vs 23.8% ± 4.3%, P = 0.035). Urinary KBs correlated with percent WL at 6 and 12 mo. Other metabolic changes were similar. CONCLUSION: Our data support the hypothesis that subjects with worse metabolic status have reduced ketogenic capacity and, thereby, exhibit a lower WL following BMS.
Published:
January 15, 2022
Title:
Ketogenic diet for epilepsy: an overview of systematic review and meta-analysis
Authors:
Ruan, Yue; Chen, Lian; She, Dongli; Chung, Yuehuan; Ge, Long; Han, Lin
Abstract:
Ketogenic diet therapy (KDT) is an established nonpharmacologic treatment in various types of epilepsy. We aim to evaluate the quality of the systematic reviews and meta-analyses (SRMAs) of KDT for epilepsy and summarize the evidence on their effects. We conducted an overview on MEDLINE, EMBASE, Cochrane Database of Systematic Review, and Web of Science from database inception to 3 September 2020. Two investigators independently performed study selection to include SRMAs, extracted data and assessed the quality of SRMAs with the AMSTAR-2 and PRISMA statement. Twenty-four SRMAs were selected which encompassed a total of 255 original studies. Four reviews assessed the effects of KDT on infant patients; thirteen reviews reported on children and adolescent patients; eight reviews focused on adults or all patients; four assessed cognitive and behavior outcomes; three assessed quality of life; two assessed growth and development outcomes; seventeen reported on adverse effects; seven reported on retention; ten reported on attrition and reasons; and four reported on death outcomes. Overall, positive effects of KDT for epilepsy on seizure frequency reduction, as well as cognition and behavior were observed. In contrast, the effects of KDT on quality of life, growth and development were more controversial. The present overview indicates that KDT is safe. The most prevalent adverse events were GI, weight loss, and metabolic disorders, while the most common reasons for discontinuance were the lack of observed efficacy and dietary intolerance.
Published:
January 13, 2022
Title:
Global spread of autoimmune disease blamed on western diet
Authors:
McKie, Robin; editor, Robin McKie Observer science
Abstract:
New DNA research by London-based scientists hopes to find cure for rapidly spreading conditions
Published:
January 9, 2022
Title:
Metabolically unhealthy and overweight phenotypes are associated with increased levels of inflammatory cytokines, in a population-based study
Authors:
Ferreira, Fabrícia Geralda; Reitz, Luiza Kuhnen; Valmorbida, Aline; Gabiatti, Mariana Papini; Hansen, Fernanda; Pietro, Patrícia Faria Di; de Oliveira, Leandro Licursi; Trindade, Erasmo Benício Santos de Moraes; Longo, Giana Zarbato
Abstract:
Objective The aim of this study is to determine the association between cytokine levels in metabolic phenotypes. Our hypothesis is that an unhealthy metabolic profile is associated to higher levels of proinflammatory cytokines. Research Methods & Procedures The sample is composed of 743 Brazilian adult individuals classified in four phenotypes: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight (MHOW) and metabolically unhealthy overweight (MUOW). Sociodemographic, anthropometric, clinical and biochemical parameters were collected. Six different cytokines were analyzed from blood samples using the CBA Human Inflammatory cytokines kit and the values divided in quartiles for analysis. Logistic regression models were constructed to assess the association between metabolic phenotypes and cytokines concentrations, adjusted for potential confounders and p
Published:
January 8, 2022
Title:
VLCKD: a real time safety study in obesity
Authors:
Barrea, Luigi; Verde, Ludovica; Vetrani, Claudia; Marino, Francesca; Aprano, Sara; Savastano, Silvia; Colao, Annamaria; Muscogiuri, Giovanna
Abstract:
Very Low-Calorie Ketogenic Diet (VLCKD) is currently a promising approach for the treatment of obesity. However, little is known about the side effects since most of the studies reporting them were carried out in normal weight subjects following Ketogenic Diet for other purposes than obesity. Thus, the aims of the study were: (1) to investigate the safety of VLCKD in subjects with obesity; (2) if VLCKD-related side effects could have an impact on its efficacy.
Published:
January 8, 2022
Title:
VLCKD: a real time safety study in obesity
Authors:
Barrea, Luigi; Verde, Ludovica; Vetrani, Claudia; Marino, Francesca; Aprano, Sara; Savastano, Silvia; Colao, Annamaria; Muscogiuri, Giovanna
Abstract:
Very Low-Calorie Ketogenic Diet (VLCKD) is currently a promising approach for the treatment of obesity. However, little is known about the side effects since most of the studies reporting them were carried out in normal weight subjects following Ketogenic Diet for other purposes than obesity. Thus, the aims of the study were: (1) to investigate the safety of VLCKD in subjects with obesity; (2) if VLCKD-related side effects could have an impact on its efficacy.
Published:
January 8, 2022
Title:
Dietary carbohydrate restriction augments weight loss-induced improvements in glycaemic control and liver fat in individuals with type 2 diabetes: a randomised controlled trial
Authors:
Thomsen, Mads N.; Skytte, Mads J.; Samkani, Amirsalar; Carl, Martin H.; Weber, Philip; Astrup, Arne; Chabanova, Elizaveta; Fenger, Mogens; Frystyk, Jan; Hartmann, Bolette; Holst, Jens J.; Larsen, Thomas M.; Madsbad, Sten; Magkos, Faidon; Thomsen, Henrik S.; Haugaard, Steen B.; Krarup, Thure
Abstract:
Lifestyle modification and weight loss are cornerstones of type 2 diabetes management. However, carbohydrate restriction may have weight-independent beneficial effects on glycaemic control. This has been difficult to demonstrate because low-carbohydrate diets readily decrease body weight. We hypothesised that carbohydrate restriction enhances the beneficial metabolic effects of weight loss in type 2 diabetes.
Published:
January 7, 2022
Title:
Dietary choline is inversely associated with depressive symptoms: a cross-sectional study of the National Health and Nutrition Examination Survey (NHANES) 2011 to 2018
Authors:
Li, Jingxian; Kang, Xiao; Zhang, Liming; Luo, Jia; Zhang, Dongfeng
Abstract:
Background Dietary choline has neuroprotective actions. However, the relationship between dietary choline and depression has been little studied. Methods We conducted a cross-sectional study to explore the association between dietary choline and depressive symptoms in US adults, using data from the 2011 to 2018 National Health and Nutrition Examination Survey (NHANES). 12,906 individuals age ≥20 who had valid information on dietary choline and depressive symptoms were chosen. Depressive symptoms were defined as the score ≥10 of the Patient Health Questionnaire-9 (PHQ-9). Multivariable logistic regression and the restricted cubic splines were used in analyses. Results In three models, compared with the bottom quintile, each quintile of dietary choline was significantly associated with a lower risk of depressive symptoms. After adjusted all selected confounding factors and covariates, the odds ratio with the 95% confidence interval of depressive symptoms was 0.57 (95% CI:0.38-0.85) for the highest quintile versus the lowest quintile of dietary choline intake. Statistical significance was also maintained in gender and age stratification studies. In the study of the dose-response relationship, an L-shaped relationship between dietary choline and depressive symptoms was found. Limitations Causality cannot be inferred in a cross-sectional study. Conclusion In this analysis of US adults, dietary choline intake is inversely associated with the risk of depressive symptoms. An L-shape dose-response relationship between those two was found. Further studies are needed to confirm our results.
Published:
January 7, 2022
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