ß Cell function after Roux-en-Y gastric bypass surgery or reduced energy intake alone in people with obesity.

BackgroundThe effects of diet-induced weight loss (WL) and WL after Roux-en-Y gastric bypass (RYGB) surgery on ß cell function (BCF) are unclear because of conflicting results from different studies, presumably because of differences in the methods used to measure BCF, the amount of WL between treatment groups, and baseline BCF. We evaluated the effect of WL after RYGB surgery or reduced energy intake alone on BCF in people with obesity with and without type 2 diabetes.MethodsBCF (insulin secretion in relationship to plasma glucose) was assessed before and after glucose or mixed-meal ingestion before and after (a) progressive amounts (6%, 11%, 16%) of WL induced by a low-calorie diet (LCD) in people with obesity without diabetes, (b) ~20% WL after RYGB surgery or laparoscopic adjustable gastric banding (LAGB) in people with obesity without diabetes, and (c) ~20% WL after RYGB surgery or LCD alone in people with obesity and diabetes.ResultsDiet-induced progressive WL in people without diabetes progressively decreased BCF. Marked WL after LAGB or RYGB in people without diabetes did not alter BCF. Marked WL after LCD or RYGB in people with diabetes markedly increased BCF, without a difference between groups.ConclusionMarked WL increases BCF in people with obesity and diabetes but not in people with obesity without diabetes. The effect of RYGB-induced WL on BCF is not different from the effect of matched WL after LAGB or LCD alone.trial registrationNCT00981500, NCT02207777, NCT01299519.FundingNIH grants R01 DK037948, P30 DK056341, P30 DK020579, UL1 TR002345.

Monomethyl branched-chain fatty acids: Health effects and biological mechanisms.

Branched-chain fatty acids (BCFA) are a group of lipids that are widely present in various organisms; they take part in numerous biochemical processes and affect multiple signaling pathways. However, BCFA are not well explored in terms of their effects on human health. Recently, they have been gaining interest, especially in relation to various human diseases. This review describes the occurrence of BCFA, their dietary sources, their potential health effects, and the current state of knowledge concerning their mechanism(s) of action. Many studies have been conducted so far in cellular and animal models, which reveal potent anti-cancer, lipid lowering, anti-inflammatory and neuroprotective actions. Research in humans is scarce. Therefore, further studies on animals and humans should be performed to confirm and expand these findings, and improve our understanding of the potential relevance of BCFA to human health and disease.

The role of exercise in obesity-related cancers: Current evidence and biological mechanisms.

Cancer ranks among the five leading causes of death in almost all countries and has important repercussions for individual and public health, the healthcare system, and society in general. Obesity increases the incidence of many types of cancer, but growing evidence suggests that physical activity may decrease risk for developing a variety of obesity-related cancer types, and, in some cases, may improve cancer prognosis and mortality rates. This review summarizes recent evidence on the effect of physical activity on obesity-related cancer prevention and survival. For some cancers, including breast, colorectal, and endometrial cancer, there is strong evidence for a preventative effect of exercise, but for many others, including gallbladder and kidney cancer, and multiple myeloma, evidence is inconsistent or largely lacking. Though many potential mechanisms have been proposed to explain the onco-protective effect of exercise, including improved insulin sensitivity, alterations in sex hormone availability, improved immune function and inflammation, myokine secretion, and modulation of intracellular signaling at the level of AMP kinase, the exact mechanism(s) of action within each cancer subtype remains poorly defined. Overall, a deeper understanding of how exercise can help against cancer and of the exercise parameters that can be altered to optimize exercise prescription is necessary and should be the subject of future investigation.

Compensatory Responses to Exercise Training As Barriers to Weight Loss: Changes in Energy Intake and Non-exercise Physical Activity.

PURPOSE OF REVIEW: Exercise can increase total energy expenditure to very high levels and therefore induce sizable energy deficits that, under carefully controlled conditions, elicit clinically significant weight loss. In real life, however, this is seldom the case among people with overweight or obesity, suggesting the existence of compensatory mechanisms that mitigate exercise-induced negative energy balance. Most studies have focused on possible compensatory changes in energy intake, and comparably little attention has been paid to compensatory changes in the physical activity patterns outside of the prescribed exercise, i.e., non-exercise physical activity (NEPA). The purpose of this paper is to review studies that have assessed changes in NEPA in response to an increase in exercise-induced energy expenditure. RECENT FINDINGS: The available studies examining changes in NEPA in response to exercise training are methodologically heterogeneous, conducted in participants with different age, gender, and body adiposity, and examined responses to varying exercise regimens over a varying duration. About 67% of all studies-80% of short-term (≤ 11 wks, n = 5) and 63% of long-term (> 3 months, n = 19) studies-demonstrate a compensatory decrease in NEPA upon starting a structured exercise training program. A compensatory decrease in other physical activities of daily life upon starting exercise training is a relatively common compensatory response-and probably more common than an increase in energy intake-that may be instrumental in attenuating the energy deficit caused by exercise, and thus preventing weight loss.

Obesity and main urologic cancers: Current systematic evidence, novel biological mechanisms, perspectives and challenges.

Urologic cancers (UC) account for 13.1% of all new cancer cases and 7.9% of all cancer-related deaths. A growing body of evidence has indicated a potential causal link between obesity and UC. The aim of the present review is to appraise in a critical and integrative manner evidence from meta-analyses and mechanistic studies on the role of obesity in four prevalent UC (kidney-KC, prostate-PC, urinary bladder-UBC, and testicular cancer-TC). Special emphasis is given on Mendelian Randomization Studies (MRS) corroborating a genetic causal association between obesity and UC, as well as on the role of classical and novel adipocytokines. Furthermore, the molecular pathways that link obesity to the development and progression of these cancers are reviewed. Available evidence indicates that obesity confers increased risk for KC, UBC, and advanced PC (20-82%, 10-19%, and 6-14%, respectively), whereas for TC adult height (5-cm increase) may increase the risk by 13%. Obese females tend to be more susceptible to UBC and KC than obese males. MRS have shown that a higher genetic-predicted BMI may be causally linked to KC and UBC but not PC and TC. Biological mechanisms that are involved in the association between excess body weight and UC include the Insulin-like Growth Factor axis, altered availability of sex hormones, chronic inflammation and oxidative stress, abnormal secretion of adipocytokines, ectopic fat deposition, dysbiosis of the gastrointestinal and urinary tract microbiomes and circadian rhythm dysregulation. Anti-hyperglycemic and non-steroidal anti-inflammatory drugs, statins, and adipokine receptor agonists/antagonists show potential as adjuvant cancer therapies. Identifying obesity as a modifiable risk factor for UC may have significant public health implications, allowing clinicians to tailor individualized prevention strategies for patients with excess body weight.

Use of Antihyperglycemic Drugs and Risk of Cancer in Patients with Diabetes.

PURPOSE OF REVIEW: Diabetes is associated with an increased risk for several types of cancer. Therefore, use of antihyperglycemic medications to lower blood glucose may modify cancer risk. Here we review available data on the link between the most common classes of antihyperglycemic agents and cancer risk among patients with diabetes. RECENT FINDINGS: A database search was conducted between February 2022 and June 2022 on PubMed and Embase for systematic reviews and meta-analyses investigating the association between antihyperglycemic agents and risk of cancer. Use of biguanides such as metformin is associated with 20-30% lower risk for all cancer incidence, and somewhat greater benefit for cancer-related mortality. Alpha-glucosidase inhibitors, e.g., acarbose, have not been consistently associated with cancer. Similarly, no consistent effects have been reported for thiazolidinediones, but the relationship with cancer seems to depend on the type of drug, dose, and duration of treatment. Exposure to various types of incretin-based therapies (glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors) has not been found to significantly modify cancer risk. Inhibitors of sodium glucose cotransporter-2 may raise risk for bladder cancer and reduce risk for gastrointestinal cancer. Use of insulin and insulin analogs is associated with a significant increase in total cancer risk by almost 50% compared to other antihyperglycemic drugs. Likewise, insulin secretagogues like sulfonylureas have generally been linked to greater risk for cancer by ~ 20%, although these associations may be agent-specific and dose-dependent. Current evidence suggests that the risk of cancer associated with the use of antihyperglycemic medications among patients with diabetes depends on the class of drug and type of agent, dosage, and duration of treatment. More research is needed to delineate the mechanisms by which these agents affect the process of carcinogenesis.

Weight loss improves ß-cell function independently of dietary carbohydrate restriction in people with type 2 diabetes: A 6-week randomized controlled trial.

Background: Carbohydrate restriction may benefit ß-cell function and glucose metabolism in type 2 diabetes (T2D) but also leads to weight loss which in itself is beneficial. Methods: In order to determine the additional effect of carbohydrate restriction in addition to a fixed body weight loss, we randomly assigned 72 adults with T2D and obesity (mean ± SD HbA1c 7.4 ± 0.7%, BMI 33 ± 5 kg/m2) to a carbohydrate-reduced high-protein diet (CRHP; energy percent from carbohydrate/protein/fat: 30/30/40) or an isocaloric conventional diabetes diet (CD; 50/17/33) for 6 weeks. All foods were provided free of charge and total energy intake was tailored individually, so both groups lost 6% of baseline body weight. Results: Despite significantly greater reductions in HbA1c (mean [95% CI] -1.9 [-3.5, -0.3] mmol/mol) after 6 weeks, the CRHP diet neither improved glucose tolerance, ß-cell response to glucose, insulin sensitivity, during a 4-h oral glucose tolerance test, nor basal proinsulin secretion when compared to the CD diet, but increased C-peptide concentration and insulin secretion rate (area under the curve [AUC] and peak) significantly more (~10%, P ≤ 0.03 for all). Furthermore, compared with the CD diet, the CRHP diet borderline increased basal glucagon concentration (16 [-0.1, 34]%, P = 0.05), but decreased glucagon net AUC (-2.0 [-3.4, -0.6] mmol/L ×240 min, P < 0.01), decreased basal triglyceride and total AUC (~20%, P < 0.01 for both), and increased gastric inhibitory polypeptide total AUC (14%, P = 0.01). Conclusion: A moderately carbohydrate-restricted diet for 6 weeks decreased HbA1c but did not improve ß-cell function or glucose tolerance beyond the effects of weight loss when compared with a conventional diabetes diet in people with T2D. Clinical trials registration: www.Clinicaltrials.gov, Identifier: NCT02472951.

Physiological interindividual variability in endogenous estradiol concentration does not influence adipose tissue and hepatic lipid kinetics in women.

Objective: Increased triglyceride (TG) and apolipoprotein B-100 (apoB-100) concentrations in plasma are important risk factors for cardiovascular disease in women. Administration of some estrogen preparations raises plasma TG and apoB-100 concentrations by increasing hepatic very low-density lipoprotein (VLDL) TG and apoB-100 secretion rates. However, the influence of physiological variation in endogenous estradiol on VLDL-TG and VLDL-apoB-100 metabolism and on free fatty acid (FFA) release into plasma (the major source of fatty acids for VLDL-TG production) is not known. Design and methods: We measured basal VLDL-TG, VLDL-apoB-100, and plasma FFA kinetics by using stable isotopically labeled tracers in 36 eumenorrheic, premenopausal women (age: 33 ± 2 years, BMI: 31 ± 1 kg/m2; mean ± s.e.m.) during the follicular phase of the menstrual cycle; participants were divided into two groups based on low (n = 18) or high (n = 18) plasma estradiol concentrations (defined as below or above the median value of 140 pmol/L in the whole group). Results: Mean plasma estradiol concentration was >3-fold higher in the high-estradiol than in the low-estradiol group (299 ± 37 and 96 ± 7 pmol/L, P < 0.001); there was no difference in plasma progesterone concentrations between the two groups (P = 0.976). There were no significant differences in plasma FFA concentration, FFA rate of appearance in plasma, VLDL-TG and VLDL-apoB-100 concentrations, hepatic VLDL-TG and VLDL-apoB-100 secretion rates, VLDL-TG and VLDL-apoB-100 plasma clearance rates, and mean residence times (all P ≥ 0.45). No significant associations were found between plasma estradiol concentration and FFA, VLDL-TG, and VLDL-apoB-100 concentrations and kinetics (all P > 0.19). Conclusions: Plasma estradiol concentration is not an important correlate of basal plasma FFA, VLDL-TG, and VLDL-apoB-100 kinetics in premenopausal women.

Management of Hematologic Malignancies in the Era of COVID-19 Pandemic: Pathogenetic Mechanisms, Impact of Obesity, Perspectives, and Challenges.

The COVID-19 pandemic brought about an unprecedented societal and healthcare system crisis, considerably affecting healthcare workers and patients, particularly those with chronic diseases. Patients with hematologic malignancies faced a variety of challenges, pertinent to the nature of an underlying hematologic disorder itself as well as its therapy as a risk factor for severe SARS-CoV-2 infection, suboptimal vaccine efficacy and the need for uninterrupted medical observation and continued therapy. Obesity constitutes another factor which was acknowledged since the early days of the pandemic that predisposed people to severe COVID-19, and shares a likely causal link with the pathogenesis of a broad spectrum of hematologic cancers. We review here the epidemiologic and pathogenetic features that obesity and hematologic malignancies share, as well as potential mutual pathophysiological links predisposing people to a more severe SARS-CoV-2 course. Additionally, we attempt to present the existing evidence on the multi-faceted crucial challenges that had to be overcome in this diverse patient group and discuss further unresolved questions and future challenges for the management of hematologic malignancies in the era of COVID-19.

Randomized controlled trial of Tesomet for weight loss in hypothalamic obesity.

Context: Hypothalamic injury often leads to rapid, intractable weight gain causing hypothalamic obesity, which is associated with increased risk of cardiovascular and metabolic morbidity and mortality. There are no approved or effective pharmacological treatments for hypothalamic obesity, and conventional lifestyle management remains ineffective. Objective: To investigate the safety and efficacy of Tesomet (0.5 mg tesofensine/50 mg metoprolol) in adults with hypothalamic obesity. Methods: Twenty-one adults with hypothalamic obesity (16 females) were randomized to Tesomet (0.5 mg/50 mg) or placebo for 24 weeks. Patients also received diet/lifestyle counselling. The primary endpoint was safety; secondary endpoints included measures of body weight, appetite scores, quality of life, and metabolic profile. Results: Eighteen patients completed 24 weeks. Consent withdrawal, eligibility, and serious adverse events (SAE) unrelated to treatment resulted in dropouts. One patient experienced a Tesomet-related SAE of exacerbated pre-existing anxiety leading to treatment discontinuation. Tesomet-related adverse events were otherwise mostly mild and included sleep disturbances (Tesomet 50%, placebo 13%), dry mouth (Tesomet 43%, placebo 0%), and headache (Tesomet 36%, placebo 0%). No significant differences in heart rate or blood pressure were observed between groups. Compared to placebo, Tesomet resulted in additional mean (95% CI) weight change of -6.3% ((-11.3; -1.3); P = 0.017), increased the number of patients achieving ≥5% weight loss (Tesomet 8/13, placebo 1/8; P = 0.046), and tended to augment the reduction in waist circumference by 5.7 cm ((-0.1; 11.5); P = 0.054). Conclusion: Tesomet was welltolerated, did not affect heart rate or blood pressure, and resulted in significant reductions in body weight compared to placebo in adults with hypothalamic obesity.

The Impact of the Rate of Weight Loss on Body Composition and Metabolism.

PURPOSE OF REVIEW: Weight loss has multiple beneficial effects on body composition and metabolism, but whether these depend on the rate at which body weight is lost is not clear. We analyzed data from studies in which the same amount of weight loss was induced rapidly or gradually. RECENT FINDINGS: Thirteen studies were included in which the same percentage weight loss was achieved at slow or fast rates (range: 0.2 to 3.2 kg/week) by means of dietary calorie restriction, exercise, and bariatric surgery. Faster rates of weight loss may result in more fat-free mass and less fat mass being lost during the dynamic phase of weight reduction compared with slower rates of weight loss, in conjunction with greater declines in resting energy expenditure. However, these differences are attenuated after 2-4 weeks of stabilization at the new, lower body weight, and do not affect the rate and amount of weight regain 9-33 months later (nor the tissue composition of regained weight). Differences in waist circumference, visceral and liver fat contents, resting blood pressure, fasting blood lipid profile, and insulin and adipokine concentrations in response to different rates of weight loss are trivial. The decline in fasting glucose concentration and the improvement in insulin sensitivity after 6-11% weight loss are both greater with rapid than gradual weight loss, but not different after 18-20% weight loss. Changes in body composition and metabolism after losing the same amount of body weight at different rates are largely similar, and occasional differences are likely not meaningful clinically for the long-term management of obesity and cardiometabolic diseases.

A Narrative Review of the Safety of Anti-COVID-19 Nutraceuticals for Patients with Cancer.

Interest in dietary supplements and their efficacy in treating and preventing disease has increased greatly since the outbreak of the COVID-19 pandemic. Due to the risk of severe COVID-19 in patients with cancer, we conducted a narrative review aiming to better understand the data on the safety of the most efficacious "anti-COVID-19" nutraceuticals for patients with cancer. We conducted a PubMed database search aimed at identifying the most effective nutrients for use against COVID-19. For the identified nutraceuticals, we searched PubMed again regarding their safety for patients with cancer. Fifty-four total records (52 independent studies) were retrieved, pertaining to vitamin D, vitamin C, selenium, omega-3 fatty acids, and zinc. Vitamin D results from 23 articles indicated safe use, but two articles indicated potential harm. All 14 articles for vitamin C and five out of six articles for selenium indicated the safety of use (one study for selenium suggested harm with high-dose supplementation). Results for omega-3 fatty acids (seven articles) and zinc (one article), however, were rather mixed regarding safety. We conclude that vitamin D, vitamin C, and selenium supplements are likely safe or even beneficial at typically recommended doses; however, caution is urged with omega-3 fatty acid supplements, and zinc supplements should likely be avoided. More experimental research is needed, and nutraceutical use by patients with cancer should always be under the supervision of a healthcare team.

Clinical- and omics-based models of subclinical atherosclerosis in healthy Chinese adults: a cross-sectional exploratory study.

BACKGROUND: Classical risk factors, such as fasting cholesterol, blood pressure (BP), and diabetes status are used today to predict the risk of developing cardiovascular disease (CVD). However, accurate prediction remains limited, particularly in low-risk groups such as women and younger individuals. Growing evidence suggests that biomarker concentrations following consumption of a meal challenge are better and earlier predictors of disease development than biomarker concentrations. OBJECTIVE: To test the hypothesis that postprandial responses of circulating biomarkers differ between healthy subjects with and without subclinical atherosclerosis (SA) in an Asian population at low risk of coronary artery disease (CAD). METHODS: One hundred healthy Chinese subjects (46 women, 54 men) completed the study. Subjects consumed a mixed-meal test and 164 blood biomarkers were analyzed over 6 h by using a combination of chemical and NMR techniques. Models were trained using different methodologies (including logistic regression, elastic net, random forest, sparse partial least square) on a random 75% subset of the data, and their performance was evaluated on the remaining 25%. RESULTS: We found that models based on baseline clinical parameters or fasting biomarkers could not reliably predict SA. By contrast, an omics model based on magnitude and timing of postprandial biomarkers achieved high performance [receiving operating characteristic (ROC) AUC: 91%; 95% CI: 77, 100). Investigation of key features of this model enabled derivation of a considerably simpler model, solely based on postprandial BP and age, with excellent performance (AUC: 91%; 95% CI: 78, 100). CONCLUSION: We report a novel model to detect SA based on postprandial BP and age in a population of Asian subjects at low risk of CAD. The use of this model in large-scale CVD prevention programs should be explored. This trial was registered at ClinicalTrials.gov as NCT03531879.

Effects of a Self-Prepared Carbohydrate-Reduced High-Protein Diet on Cardiovascular Disease Risk Markers in Patients with Type 2 Diabetes.

We previously observed beneficial effects of a carbohydrate-reduced, high-protein (CRHP) diet on cardiovascular risk markers in patients with type 2 diabetes mellitus (T2DM) in a crossover 2 × 6-week trial, when all food was provided to subjects as ready-to-eat meals. Here, we report the results from a 6-month open label extension: 28 patients with T2DM were instructed to self-prepare the CRHP diet with dietetic guidance. At weeks 0, 6, 12, and 36, fasting and postprandial (4-h meal test) blood samples were collected for measurements of total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triacylglycerol (TG), apolipoproteins A1 and B, non-esterified fatty acids (NEFA), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6. Diurnal blood pressure and heart rate were also assessed. At the end of the study (week 36), concentrations of fasting total and LDL-cholesterol, fasting and postprandial NEFA and TG, and fasting apolipoprotein-B, CRP and TNF-α concentrations were significantly lower compared with week 0 (p < 0.05). A significant decrease in diurnal heart rate was also observed. From week 12 to 36, an increase in HDL-cholesterol and apolipoprotein-A1 concentrations and a further reduction in fasting and postprandial NEFA (p < 0.05) were found. These changes were independent of minor fluctuations in body weight. We conclude that the substitution of dietary carbohydrate for protein and fat has beneficial effects on several cardiovascular risk markers in patients with T2DM, which are maintained or augmented over the next 6 months when patients select and prepare the CRHP diet on their own in a dietitian-supported setting.

Vitamin D and Obesity: Current Evidence and Controversies.

PURPOSE OF REVIEW: Evidence from observational studies suggests that obesity is associated with low vitamin D. As both obesity and hypovitaminosis D present an alarmingly increased prevalence worldwide, there is an intense research interest to clarify all aspects of this association. This review summarizes current evidence from meta-analyses investigating vitamin D status in obesity, including the effects of weight loss and bariatric surgery on vitamin D status and the outcomes of vitamin D supplementation on body weight. We also discuss potential pathophysiologic mechanisms and important controversies. RECENT FINDINGS: Data from meta-analyses consistently support an inverse association of vitamin D levels with body weight. However, the impact of weight loss on improving vitamin D status is small, while studies on the supplementation with vitamin D after bariatric surgery have shown conflicting results regarding vitamin D status. Moreover, interventional studies do not support a beneficial effect of vitamin D supplementation on body weight. These findings warrant a cautious interpretation due to important methodological limitations and confounding factors, such as high heterogeneity of studies, variable methods of determination of vitamin D and definition of deficiency/insufficiency, use of various adiposity measures and definitions of obesity, and inadequate adjustment for confounding variables influencing vitamin D levels. The underlying pathogenetic mechanisms associating low vitamin D in obesity include volumetric dilution, sequestration into adipose tissue, limited sunlight exposure, and decreased vitamin D synthesis in the adipose tissue and liver. Experimental studies have demonstrated that low vitamin D may be implicated in adipose tissue differentiation and growth leading to obesity either by regulation of gene expression or through modulation of parathyroid hormone, calcium, and leptin. Obesity is associated with low vitamin D status but weight loss has little effect on improving this; vitamin D supplementation is also not associated with weight loss. Evidence regarding vitamin D status after bariatric surgery is contradicting. The link between vitamin D and obesity remains controversial due to important limitations and confounding of studies. More research is needed to clarify the complex interplay between vitamin D and adiposity.

Understanding the Role of the Gut Microbiome and Microbial Metabolites in Non-Alcoholic Fatty Liver Disease: Current Evidence and Perspectives.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD begins as a relatively benign hepatic steatosis which can evolve to non-alcoholic steatohepatitis (NASH); the risk of cirrhosis and hepatocellular carcinoma (HCC) increases when fibrosis is present. NAFLD represents a complex process implicating numerous factors-genetic, metabolic, and dietary-intertwined in a multi-hit etiopathogenetic model. Recent data have highlighted the role of gut dysbiosis, which may render the bowel more permeable, leading to increased free fatty acid absorption, bacterial migration, and a parallel release of toxic bacterial products, lipopolysaccharide (LPS), and proinflammatory cytokines that initiate and sustain inflammation. Although gut dysbiosis is present in each disease stage, there is currently no single microbial signature to distinguish or predict which patients will evolve from NAFLD to NASH and HCC. Using 16S rRNA sequencing, the majority of patients with NAFLD/NASH exhibit increased numbers of Bacteroidetes and differences in the presence of Firmicutes, resulting in a decreased F/B ratio in most studies. They also present an increased proportion of species belonging to Clostridium, Anaerobacter, Streptococcus, Escherichia, and Lactobacillus, whereas Oscillibacter, Flavonifaractor, Odoribacter, and Alistipes spp. are less prominent. In comparison to healthy controls, patients with NASH show a higher abundance of Proteobacteria, Enterobacteriaceae, and Escherichia spp., while Faecalibacterium prausnitzii and Akkermansia muciniphila are diminished. Children with NAFLD/NASH have a decreased proportion of Oscillospira spp. accompanied by an elevated proportion of Dorea, Blautia, Prevotella copri, and Ruminococcus spp. Gut microbiota composition may vary between population groups and different stages of NAFLD, making any conclusive or causative claims about gut microbiota profiles in NAFLD patients challenging. Moreover, various metabolites may be involved in the pathogenesis of NAFLD, such as short-chain fatty acids, lipopolysaccharide, bile acids, choline and trimethylamine-N-oxide, and ammonia. In this review, we summarize the role of the gut microbiome and metabolites in NAFLD pathogenesis, and we discuss potential preventive and therapeutic interventions related to the gut microbiome, such as the administration of probiotics, prebiotics, synbiotics, antibiotics, and bacteriophages, as well as the contribution of bariatric surgery and fecal microbiota transplantation in the therapeutic armamentarium against NAFLD. Larger and longer-term prospective studies, including well-defined cohorts as well as a multi-omics approach, are required to better identify the associations between the gut microbiome, microbial metabolites, and NAFLD occurrence and progression.

Cohort profile: Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO).

The Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO) is a preconception, longitudinal cohort study that aims to study the effects of nutrition, lifestyle, and maternal mood prior to and during pregnancy on the epigenome of the offspring and clinically important outcomes including duration of gestation, fetal growth, metabolic and neural phenotypes in the offspring. Between February 2015 and October 2017, the S-PRESTO study recruited 1039 Chinese, Malay or Indian (or any combinations thereof) women aged 18-45 years and who intended to get pregnant and deliver in Singapore, resulting in 1032 unique participants and 373 children born in the cohort. The participants were followed up for 3 visits during the preconception phase and censored at 12 months of follow up if pregnancy was not achieved (N = 557 censored). Women who successfully conceived (N = 475) were characterised at gestational weeks 6-8, 11-13, 18-21, 24-26, 27-28 and 34-36. Follow up of their index offspring (N = 373 singletons) is on-going at birth, 1, 3 and 6 weeks, 3, 6, 12, 18, 24 and 36 months and beyond. Women are also being followed up post-delivery. Data is collected via interviewer-administered questionnaires, metabolic imaging (magnetic resonance imaging), standardized anthropometric measurements and collection of diverse specimens, i.e. blood, urine, buccal smear, stool, skin tapes, epithelial swabs at numerous timepoints. S-PRESTO has extensive repeated data collected which include genetic and epigenetic sampling from preconception which is unique in mother-offspring epidemiological cohorts. This enables prospective assessment of a wide array of potential determinants of future health outcomes in women from preconception to post-delivery and in their offspring across the earliest development from embryonic stages into early childhood. In addition, the S-PRESTO study draws from the three major Asian ethnic groups that represent 50% of the global population, increasing the relevance of its findings to global efforts to address non-communicable diseases.

Heredity of type 2 diabetes confers increased susceptibility to oxidative stress and inflammation.

INTRODUCTION AND OBJECTIVE: Heredity of type 2 diabetes mellitus (T2DM) is associated with greater risk for developing T2DM. Thus, individuals who have a first-degree relative with T2DM (FDRT) provide a natural model to study factors of susceptibility towards development of T2DM, which are poorly understood. Emerging key players in T2DM pathophysiology such as adverse oxidative stress and inflammatory responses could be among possible mechanisms that predispose FDRTs to develop T2DM. Here, we aimed to examine the role of oxidative stress and inflammatory responses as mediators of this excess risk by studying dynamic postprandial responses in FDRTs. RESEARCH DESIGN AND METHODS: In this open-label case-control study, we recruited normoglycemic men with (n=9) or without (n=9) a family history of T2DM. We assessed plasma glucose, insulin, lipid profile, cytokines and F2-isoprostanes, expression levels of oxidative and inflammatory genes/proteins in circulating mononuclear cells (MNC), myotubes and adipocytes at baseline (fasting state), and after consumption of a carbohydrate-rich liquid meal or insulin stimulation. RESULTS: Postprandial glucose and insulin responses were not different between groups. Expression of oxidant transcription factor NRF2 protein (p<0.05 for myotubes) and gene (pgroup=0.002, ptime×group=0.016), along with its target genes TXNRD1 (pgroup=0.004, ptime×group=0.007), GPX3 (pgroup=0.011, ptime×group=0.019) and SOD-1 (pgroup=0.046 and ptime×group=0.191) was upregulated in FDRT-derived MNC after meal ingestion or insulin stimulation. Synergistically, expression of target genes of inflammatory transcription factor nuclear factor kappa B such as tumor necrosis factor alpha (pgroup=0.001, ptime×group=0.007) was greater in FDRT-derived MNC than in non-FDRT-derived MNC after meal ingestion or insulin stimulation. CONCLUSIONS: Our findings shed light on how heredity of T2DM confers increased susceptibility to oxidative stress and inflammation. This could provide early insights into the underlying mechanisms and future risk of FDRTs for developing T2DM and its associated complications.