Context Insulin resistance (IR) can develop in multiple organs, representing distinct etiologies toward cardiometabolic disease.Objective This study aimed to investigate which proteins and pathways are specific for liver IR or muscle IR in individuals with overweight or obesity of the Diet, Obesity, and Genes cohort (n = 535) (NCT00390637, ClinicalTrials.gov).Methods First, independent associations between muscle and liver IR and protein abundance levels were assessed. In the analysis, we corrected for study center, sex, body mass index, and age, whereby the analyses on liver IR were adjusted for muscle IR and vice versa. Differentially abundant proteins were then subjected to pathway enrichment analysis.Results Muscle IR was associated with 160 proteins, and liver IR was associated with 81 proteins. Of these, 12 were shared between both forms of IR. Pathway enrichment analysis identified 51 enriched pathways for muscle IR, characterized by a strong inflammatory profile, including chemokine signaling, interleukin-6 signaling, and complement system-related pathways. In contrast, liver IR was associated with 11 enriched pathways, primarily related to the complement system.Conclusion Understanding the processes underlying these distinct IR phenotypes could inform the development of personalized prevention strategies.

The worldwide prevalence of overweight and obesity has increased rapidly in the last decades. This rise has led to a surge in comorbidities such as type 2 diabetes (T2D), cardiometabolic diseases, and mental health issues. While general population-based nutrition guidelines have proven effective in reducing T2D incidence by 50%, a significant 30% of participants do not respond to these interventions. Precision nutrition (PN), tailored towards the metabolic phenotype (metabotype), genotype, or microbial characteristics, has shown promise in improving blood glucose control and cardiometabolic health compared with standard nutritional guidelines. This scoping review aims to discuss advancements in PN over the past decade, focusing on heterogeneity in response to dietary interventions aiming to prevent T2D and related cardiometabolic disease in overweight and obese individuals. A semi-systematic PubMed search with defined criteria was conducted to identify precision nutrition (PN) randomized clinical trials and related post-hoc analyses reporting cardiometabolic health outcomes. Numerous studies have shown actionable diet-host interactions, with intervention stratification based on genotype, gut microbiome, metabolome, lipidome, fasting glucose and insulin, postprandial glycemic response, tissue-specific insulin resistance, or combinations thereof. Many of these metabotypes, genotypes, and microbial signatures allow for accurate cardiometabolic outcome predictions and are actionable targets for future PN research. More recently, machine-learning methodologies in the form of postprandial response prediction models have increasingly been used in PN research. However, prospective evidence on effective PN strategies that may prevent the onset of T2D is currently limited. A mechanistic understanding of response and nonresponse in cardiometabolic outcome improvement is crucial in the development of novel phenotyping methodologies and prediction models in PN. These advancements could lead to more inclusive and effective PN strategies to prevent T2D and related conditions.

Obesity is a complex chronic disease requiring lifelong comprehensive treatment. In addition to lifestyle counseling that improves nutrition and physical activity, a promising new generation of obesity medications has been added to bariatric procedures as therapeutic options to achieve weight reduction and improve health outcomes. With the promise of effective and safe treatments comes the need to emphasize maximal reduction of body fat and minimal loss of vital body components, including skeletal muscle and bone. Nutrition is a critical aspect of obesity care and is leveraged to support preservation of lean tissues, such as skeletal muscle, through adequate, daily, high-quality protein intake and intake of key micronutrients. More targeted nutrition approaches that promote muscle protein synthesis include amino acid supplementation with leucine and its metabolite β-hydroxy β-methylbutyrate. Another potential target for support is the gut microbiome, as its adequate function is increasingly seen as playing a role in human health and metabolism. Obesity is a heterogenous disease, and there is considerable interest in specific metabolic phenotypes that might be used to tailor nutrition strategies. As research advances on these and other fronts, there is the potential to identify precision nutrition strategies for individualized, more effective approaches to lifelong obesity management.

AIMS:Individuals with liver insulin-resistant (LIR) or muscle insulin-resistant (MIR) phenotypes may respond differently to dietary interventions. Given the interaction between insulin resistance and cardiovascular risk, this sub-analysis of the PERSON study examined whether a personalized diet according to MIR or LIR phenotypes improves vascular function and cardiovascular disease risk factors. MATERIALS AND METHODS:We randomized 119 participants to a 12-week low-fat, high-protein, high-fibre diet (LFHP; may be optimal for LIR) or Mediterranean diet (high in monounsaturated fat, HMUFA; may be optimal for MIR). Randomization linked the insulin-resistant (IR) phenotype to the proposed optimal diet, leading to PhenoDiet A (MIR-HMUFA and LIR-LFHP) and PhenoDiet B (MIR-LFHP and LIR-HMUFA). Before and after the intervention, vascular function (carotid artery reactivity) and cardiovascular risk factors (blood pressure, total cholesterol, HDL-cholesterol and Framingham risk score) were examined. A 7-point oral glucose tolerance test was performed to determine insulin resistance (Matsuda index and HOMA-IR) and disposition index. RESULTS:Following drop-out (n = 18), 101 participants finished the intervention (54 women, 61 ± 7 years, 27.6 [26.4;30.0] kg/m2), with n = 80 available for the primary outcome of vascular function. Overall, the dietary interventions significantly decreased blood pressure, total cholesterol, HDL-cholesterol and the Framingham risk score (all p < 0.05), while vascular function was not affected (p = 0.485). Insulin resistance (p ≤ 0.001), but not disposition index (p = 0.362), was significantly improved after intervention. The Matsuda index (p = 0.078) tended to increase more and total cholesterol (p = 0.052) tended to decrease more in PhenoDiet group B than A, but other changes in outcome parameters were not significantly different between PhenoDiet groups. The LFHP diet resulted in more pronounced improvements in cholesterol, diastolic blood pressure (DBP) and insulin resistance compared with the HMUFA diet (all p < 0.05). CONCLUSION:A 12-week diet improves metabolic and cardiovascular outcomes, but not vascular function in insulin-resistant adults with overweight or obesity. Whilst the LFHP diet resulted in greater improvements in cardiometabolic risk markers than the HMUFA diet, we found no significant differences between the PhenoDiet groups.

Consumption of sweeteners and sweetness enhancers (S SEs) is a popular strategy to reduce sugar intake, but the role of S SEs in body weight regulation and gut microbiota composition remains debated. Here, we show that S SEs in a healthy diet support weight loss maintenance and beneficial gut microbiota shifts in adults with overweight or obesity. In this multi-centre, randomized, controlled trial, we included 341 adults and 38 children with overweight or obesity. Adults followed a 2-month low-energy diet for ≥5 NCT04226911 . The SWEET project is a multicenter, randomized, controlled trial that shows that long-term consumption of sweeteners and sweetness enhancers improves body weight control and elicits beneficial gut microbiota changes in adults with overweight or obesity.

Precision nutrition is a vibrant and rapidly evolving field of scientific research and innovation with the potential to deliver health, societal and economic benefits by improving healthcare delivery and policies. Advances in deep phenotyping technologies, digital tools and artificial intelligence have made possible early proof-of-concept research that expands the understanding of within- and between-person variability in responses to diet. These studies illustrate the promise of precision nutrition to complement the traditional 'one size fits all' dietary guidelines, which, while considering broad life-stage and disease-specific nutritional requirements, often lack the granularity to account fully for individual variations in nutritional needs and dietary responses. Despite these developments, however, considerable challenges remain before precision nutrition can be implemented on a broader scale. This Review examines the current state of precision nutrition research, with a focus on its application to reducing the incidence and burden of cardiometabolic diseases. We critically examine the evidence base, explore the potential benefits and discuss the challenges and opportunities ahead.

CONTEXT:Fetuin B is a steatosis-responsive hepatokine that induces glucose intolerance in mice. Recently, we found that fetuin B in white adipose tissue was positively associated with peripheral insulin resistance in mice and a small study population, possibly through a fetuin B-induced inflammatory response in adipocytes. OBJECTIVE:This translational study aimed to investigate the link between plasma fetuin B and the adipose tissue transcriptome and plasma proteome in a large cohort of humans. METHODS:Continuous linear regression analysis in R was applied to investigate the link between plasma fetuin B and the adipose tissue transcriptome (n = 207) and plasma proteome (n = 558) in humans, after adjustment for sex, age, and study center (model 1); model 1 + BMI (model 2); and model 2 + insulin sensitivity (Matsuda index) (model 3). RESULTS:Plasma fetuin B was associated with more than 100 genes in white adipose tissue, belonging to pathways related to cytokine/chemokine signaling (models 1 and 2) and insulin signaling (all models), and with more than 146 plasma proteins involved in pathways related to metabolic processes and insulin signaling (all models). CONCLUSION:Plasma fetuin B is related to adipose tissue genes and plasma proteins involved in metabolic processes and insulin signaling. Our findings provide evidence for the involvement of white adipose tissue in fetuin B-induced insulin resistance.

Background Evidence suggests that increased distal short-chain fatty acid (SCFA) production beneficially impacts metabolic health. However, indigestible carbohydrate availability is limited in the distal colon; consequently, microbes shift toward protein fermentation, often linked to adverse metabolic health effects. We aimed to identify specific fiber(s) that promote saccharolytic fermentation in the distal colon and thereby may (partially) inhibit proteolytic fermentation. Methods Potato-fiber, pectin, and inulin were studied individually and in combination against a high (predigested) protein background using an in vitro model of the colon (TIM-2) inoculated with pooled, standardized fecal microbiota from individuals with overweight/obesity. Microbiota composition and activity were assessed at different timepoints to simulate the travel throughout the colon (proximal: 0-8 h, distal: 8-24 h) and compared to a high protein (HP)_control, receiving only proteins. Results Fiber addition increased total SCFA production compared to HP_control (52.11 ± 1.49 vs 27.07 ± 0.26 mmol) whereas total branched-chain fatty acids (BCFA; a marker for protein fermentation) production only slightly decreased (3.31 ± 0.10 vs 4.18 ± 0.40 mmol). Combining potato-fiber and pectin led to the highest total and distal SCFA production and distal SCFA:BCFA. Fiber addition attenuated HP-induced increases in several bacterial taxa including Mogibacterium and Coprococcus, independent of fiber type. Additionally, time- and fiber-specific microbial signatures were identified: inulin increased Bifidobacterium (proximal) relative abundance and pectin and/or potato-fiber increased Prevotella 9 (distal) relative abundance. Conclusion The most marked increase in distal colonic SCFA production was induced by combining potato-fiber and pectin. Further research should elucidate whether this switch toward saccharolytic fermentation translates into beneficial metabolic health effects in humans.

Type 2 diabetes and obesity have become major public health concerns. Growing evidence suggests that increased dietary fiber intake, through its interaction with the gut microbiota, may help prevent these diseases. Here, we demonstrate in a 12-week randomized, placebo-controlled trial in individuals at risk for type 2 diabetes that intake of an intrinsic fiber product, consisting of entire plant cells, tended to improve peripheral insulin sensitivity (p = 0.085), increased whole-body insulin sensitivity (p = 0.032), reduced circulating triglycerides (p = 0.049), and tended to reduce intrahepatic lipid content (p = 0.063), along with an increased proportion of small adipocytes (p = 0.008). Phylogenetic and metagenomic analysis revealed that these outcomes coincided with increased levels of fiber-degrading Bifidobacterium spp. and butyrate-producing Anaerostipes spp. and a functional shift toward a distal butyrogenic trophic chain while the best responding individuals had increased levels of pectin degraders that may produce propionate. Our findings demonstrate the pivotal role of slowly fermented, intrinsic plant cell fibers in improving cardiometabolic health. This study was registered at ClinicalTrials.gov (NCT04714944).

Nutritional epidemiology aims to link dietary exposures to chronic disease, but the instruments for evaluating dietary intake are inaccurate. One way to identify unreliable data and the sources of errors is to compare estimated intakes with the total energy expenditure (TEE). In this study, we used the International Atomic Energy Agency Doubly Labeled Water Database to derive a predictive equation for TEE using 6,497 measures of TEE in individuals aged 4 to 96years. The resultant regression equation predicts expected TEE from easily acquired variables, such as body weight, age and sex, with 95% predictive limits that can be used to screen for misreporting by participants in dietary studies. We applied the equation to two large datasets (National Diet and Nutrition Survey and National Health and Nutrition Examination Survey) and found that the level of misreporting was >50%. The macronutrient composition from dietary reports in these studies was systematically biased as the level of misreporting increased, leading to potentially spurious associations between diet components and body mass index.

Insulin resistance (IR) is an early marker of cardiometabolic deterioration which may develop heterogeneously in key metabolic organs, including the liver (LIR) and skeletal muscle (MIR). This tissue-specific IR is characterized by distinct metabolic signatures, but the role of the gut microbiota in its etiology remains unclear. Here, we profiled the gut microbiota, its metabolites and the plasma metabolome in individuals with either a LIR or MIR phenotype (n = 233). We observed distinct microbial community structures LIR and MIR, and higher short-chain fatty acid (SCFA) producing bacteria, fecal SCFAs and branched-chain fatty acids and a higher postprandial plasma glucagon-like-peptide-1 response in LIR. In addition, we found variations in metabolome profiles and phenotype-specific associations between microbial taxa and functional metabolite groups. Overall, our study highlights association between gut microbiota and its metabolites composition with IR heterogeneity that can be targeted in precision-based strategies to improve cardiometabolic health. Clinicaltrials.gov registration: NCT03708419.

The gut microbiome has been identified as a significant factor in host metabolism, playing a key role in the etiology of obesity, type 2 diabetes and cardiometabolic risk. Butyrate, produced by the gut microbiome from indigestible carbohydrates, has been shown to have beneficial effects on body weight control, inflammation, and insulin resistance, primarily evidenced by animal studies and in vitro experiments. However, translating these benefits to humans remains challenging due to variability in mode of butyrate administration or production upon fermentation of dietary fibers, as well as in butyrate absorption, and its metabolism. For instance, oral butyrate supplementation can directly increase circulating butyrate levels, thereby targeting peripheral tissues. In contrast, butyrate produced by the gut microbiome may also influence metabolism through local signaling mechanisms affecting peripheral tissues. Additionally, there may be large heterogeneity in the response of the individuals to butyrate interventions. Future research should aim to better understand butyrate kinetics and dynamics and its mechanisms in regulating intestinal and metabolic health. In human studies, longer-term, placebo-controlled trials are needed to establish the efficacy of either targeting butyrate production or supplementation in individuals with obesity and/or metabolic disturbances. Personalized dietary interventions based on individual microbiota composition and/or function and metabolic profiles may optimize butyrate production and its metabolic benefits. This could pave the way for effective butyrate-based interventions to improve metabolic health and prevent obesity-related complications.

The intestinal microbiota, consisting of an estimated 10<^>10-10<^>11 organisms, regulate physiological processes involved in digestion, metabolism, and immunity. Surprisingly, these intestinal microorganisms have been found to influence tissues that are not directly in contact with the gut, such as adipose tissue, the liver, skeletal muscle, and the brain. This interaction takes place even when intestinal barrier function is uncompromised. An increasing body of evidence suggests that bacterial membrane vesicles (bMVs), in addition to bacterial metabolites such as short-chain fatty acids, are able to mediate effects of the microbiota on these host tissues. The ability of bMVs to dissipate from the intestinal lumen into systemic circulation hereby facilitates the transport and presentation of bacterial components and metabolites to host organs. Importantly, there are indications that the interaction between bMVs and tissues or immune cells may play a role in the etiology of (chronic metabolic) disease. For example, the gut-derived bMV-mediated induction of insulin resistance in skeletal muscle cells and pro-inflammatory signaling by adipocytes possibly underlies diseases such as type 2 diabetes and obesity. Here, we review the current knowledge on bMVs in the microbiota's effects on host energy/substrate metabolism with a focus on etiological roles in the onset and progression of metabolic disease. We furthermore illustrate that vesicle production by bacterial microbiota could potentially be modulated through lifestyle intervention to improve host metabolism.

Antibiotic use disrupts microbial composition and activity in humans, but whether this disruption in turn affects host metabolic health is unclear. Cohort studies show associations between antibiotic use and an increased risk of developing obesity and type 2 diabetes mellitus. Here, we review available clinical trials and show the disruptive effect of antibiotic use on the gut microbiome in humans, as well as its impact on bile acid metabolism and microbial metabolites such as short-chain fatty acids. Placebo-controlled human studies do not show a consistent effect of antibiotic use on body weight and insulin sensitivity at a population level, but rather an individual-specific or subgroup-specific response. This response to antibiotic use is affected by the resistance and resilience of the gut microbiome, factors that determine the extent of disruption and the speed of recovery afterwards. Nutritional strategies to improve the composition and functionality of the gut microbiome, as well as its recovery after antibiotic use (for instance, with prebiotics), require a personalized approach to increase their efficacy. Improved insights into key factors that influence the individual-specific response to antibiotics and dietary intervention may lead to better efficacy in reversing or preventing antibiotic-induced microbial dysbiosis as well as strategies for preventing cardiometabolic diseases.

Background Doubly labeled water is gold standard for measuring total energy expenditure (TEE). Measurements using the method are sensitive to the isotope dilution space ratio (DSR). Accuracy and precision of the method might be improved if we could identify factors influencing DSR. Objectives We evaluated the potential associations of age, sex, ethnicity, anthropometry, body composition, turnover rates of the isotopes, and geographical elevation with DSR. Methods We used univariate regression analysis to explore the relationships between the continuous variables and analysis of variance to test the relationships between the categorical variables with DSR. Subsequently, we used general linear model (GLM) and 1-way analysis of variance to evaluate the simultaneous associations of age, sex, ethnicity, fat-free mass (FFM) and fat mass (FM) on DSR. Results From 5678 measurements complied from studies around the world with diverse ethnicity and living at various elevations, the mean DSR was 1.0364 ± 0.0141. No meaningful physiologic effect of any of the continuous and categorical variable on DSR was detected. General linear model analysis revealed no effect of FFM and FM (P > 0.33) on DSR, but DSR decreased with age (P < 0.001) among those aged 60 y and older regardless of sex. Among the Whites who were younger than 60 y, DSR was not related to FFM and FM (P = 0.73) but was affected by both age and sex (P < 0.001). Conclusions Previous estimates of age-related decline in TEE may have overestimated TEE at age 90 y. Validation studies on older participants are required to confirm this finding.

Continuous glucose monitoring (CGM) is a promising, minimally invasive alternative to plasma glucose measurements for calibrating physiology-based mathematical models of insulin-regulated glucose metabolism, reducing the reliance on in-clinic measurements. However, the use of CGM glucose, particularly in combination with insulin measurements, to develop personalized models of glucose regulation remains unexplored. Here, we simultaneously measured interstitial glucose concentrations using CGM as well as plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT) in individuals with overweight or obesity to calibrate personalized models of glucose-insulin dynamics. We compared the use of interstitial glucose with plasma glucose in model calibration, and evaluated the effects on model fit, identifiability, and model parameters’ association with clinically relevant metabolic indicators. Models calibrated on both plasma and interstitial glucose resulted in good model fit, and the parameter estimates associated with metabolic indicators such as insulin sensitivity measures in both cases. Moreover, practical identifiability of model parameters was improved in models estimated on CGM glucose compared to plasma glucose. Together these results suggest that CGM glucose may be considered as a minimally invasive alternative to plasma glucose measurements in model calibration to quantify the dynamics of glucose regulation.

Background/Objective Insulin resistance is more prominent in men than women. If this involves adipose tissue is unknown and was presently examined. Subjects/Methods AdipoIR (in vivo adipose insulin resistance index) was measured in 2344 women and 787 men. In 259 of the women and 54 of the men, insulin induced inhibition of lipolysis (acylglycerol breakdown) and stimulation of lipogenesis (glucose conversion to acylglycerols) were determined in subcutaneous adipocytes; in addition, basal (spontaneous) lipolysis was also determined in the fat cells. In 234 women and 115 men, RNAseq expression of canonical insulin signal genes were measured in subcutaneous adipose tissue. Messenger RNA transcripts of the most discriminant genes were quantified in 175 women and 109 men. Results Men had higher AdipoIR values than women but only when obesity (body mass index 30 kg/m 2 or more) was present ( p < 0.0001). The latter sex dimorphism was found among physically active and sedentary people, in those with and without cardiometabolic disease and in people using nicotine or not ( p = 0.0003 or less). In obesity, adipocyte insulin sensitivity (half maximum effective hormone concentration) and maximal antilipolytic effect were tenfold and 10% lower, respectively, in men than women ( p = 0.005 or less). Basal rate of lipolysis was two times higher in men than women ( p > 0.0001). Sensitivity and maximum effect of insulin on lipogenesis were similar in both sexes ( p = 0.26 and p = 0.18, respectively). When corrected for multiple comparison only RNAseq expression of insulin receptor substrate 1 ( IRS1 ) was lower in men than women ( p < 0.0001). The mRNA transcript for IRS1 was 60% higher in women than men ( p < 0.0001). Conclusions In obesity, adipose tissue insulin resistance is more pronounced in men than in women. The mechanism involves less efficient insulin-mediated inhibition of adipocyte lipolysis, increased basal rate of lipolysis and decreased adipose expression of a key element of insulin signaling, IRS1 .

Abstract Background Body composition and body fat distribution are important predictors of cardiometabolic diseases. The etiology of cardiometabolic diseases is heterogenous, and partly driven by inter-individual differences in tissue-specific insulin sensitivity. Objectives To investigate (1) the associations between body composition and whole-body, liver and muscle insulin sensitivity, and (2) changes in body composition and insulin sensitivity and their relationship after a 12-week isocaloric diet high in mono-unsaturated fatty acids (HMUFA) or a low-fat, high-protein, high-fiber (LFHP) diet. Methods This subcohort analysis of the PERSON study includes 93 individuals (53% women, BMI 25–40 kg/m2, 40–75 years) who participated in this randomized intervention study. At baseline and after 12 weeks of following the LFHP, or HMUFA diet, we performed a 7-point oral glucose tolerance test to assess whole-body, liver, and muscle insulin sensitivity, and whole-body magnetic resonance imaging to determine body composition and body fat distribution. Both diets are within the guidelines of healthy nutrition. Results At baseline, liver fat content was associated with worse liver insulin sensitivity (β [95%CI]; 0.12 [0.01; 0.22]). Only in women, thigh muscle fat content was inversely related to muscle insulin sensitivity (-0.27 [-0.48; -0.05]). Visceral adipose tissue (VAT) was inversely associated with whole-body, liver, and muscle insulin sensitivity. Both diets decreased VAT, abdominal subcutaneous adipose tissue (aSAT), and liver fat, but not whole-body and tissue-specific insulin sensitivity with no differences between diets. Waist circumference, however, decreased more following the LFHP diet as compared to the HMUFA diet (-3.0 vs. -0.5 cm, respectively). After the LFHP but not HMUFA diet, improvements in body composition were positively associated with improvements in whole-body and liver insulin sensitivity. Conclusions Liver and muscle insulin sensitivity are distinctly associated with liver and muscle fat accumulation. Although both LFHP and HMUFA diets improved in body fat, VAT, aSAT, and liver fat, only LFHP-induced improvements in body composition are associated with improved insulin sensitivity. Trial registration NCT03708419 (clinicaltrials.gov).