A new framework for exploratory network mediator analysis in omics data.

Omics methods are widely used in basic biology and translational medicine research. More and more omics data are collected to explain the impact of certain risk factors on clinical outcomes. To explain the mechanism of the risk factors, a core question is how to find the genes/proteins/metabolites that mediate their effects on the clinical outcome. Mediation analysis is a modeling framework to study the relationship between risk factors and pathological outcomes, via mediator variables. However, high-dimensional omics data are far more challenging than traditional data: (1) From tens of thousands of genes, can we overcome the curse of dimensionality to reliably select a set of mediators? (2) How do we ensure that the selected mediators are functionally consistent? (3) Many biological mechanisms contain nonlinear effects. How do we include nonlinear effects in the high-dimensional mediation analysis? (4) How do we consider multiple risk factors at the same time? To meet these challenges, we propose a new exploratory mediation analysis framework, medNet, which focuses on finding mediators through predictive modeling. We propose new definitions for predictive exposure, predictive mediator, and predictive network mediator, using a statistical hypothesis testing framework to identify predictive exposures and mediators. Additionally, two heuristic search algorithms are proposed to identify network mediators, essentially subnetworks in the genome-scale biological network that mediate the effects of single or multiple exposures. We applied medNet on a breast cancer data set and a metabolomics data set combined with food intake questionnaire data. It identified functionally consistent network mediators for the exposures' impact on the outcome, facilitating data interpretation.

Linoleic acid blunts early osteoblast differentiation and impairs oxidative phosphorylation in vitro.

BACKGROUND: Linoleic acid (LNA), an essential polyunsaturated fatty acid (PUFA), plays a crucial role in cellular functions. However, excessive intake of LNA, characteristic of Western diets, can have detrimental effects on cells and organs. Human observational studies have shown an inverse relationship between plasma LNA concentrations and bone mineral density. The mechanism by which LNA impairs the skeleton is unclear, and there is a paucity of research on the effects of LNA on bone-forming osteoblasts. METHODS: The effect of LNA on osteoblast differentiation, cellular bioenergetics, and production of oxidized PUFA metabolites in vitro, was studied using primary mouse bone marrow stromal cells (BMSC) and MC3T3-E1 osteoblast precursors. RESULTS: LNA treatment decreased alkaline phosphatase activity, an early marker of osteoblast differentiation, but had no effect on committed osteoblasts or on mineralization by differentiated osteoblasts. LNA suppressed osteoblast commitment by blunting the expression of Runx2 and Osterix, key transcription factors involved in osteoblast differentiation, and other key osteoblast-related factors involved in bone formation. LNA treatment was associated with increased production of oxidized LNA- and arachidonic acid-derived metabolites and blunted oxidative phosphorylation, resulting in decreased ATP production. CONCLUSION: Our results show that LNA inhibited early differentiation of osteoblasts and this inhibitory effect was associated with increased production of oxidized PUFA metabolites that likely impaired energy production via oxidative phosphorylation.

Vitamin D and prebiotics for intestinal health in cystic fibrosis: Rationale and design for a randomized, placebo-controlled, double-blind, 2 x 2 trial of administration of prebiotics and cholecalciferol (vitamin D3) (Pre-D trial) in adults with cystic fibrosis.

Individuals with cystic fibrosis (CF) have dysfunctional intestinal microbiota and increased gastrointestinal (GI) inflammation also known as GI dysbiosis. It is hypothesized that administration of high-dose cholecalciferol (vitamin D3) together with a prebiotic (inulin) will be effective, and possibly additive or synergistic, in reducing CF-related GI and airway dysbiosis. Thus, a 2 x 2 factorial design, placebo-controlled, double-blinded, pilot and feasibility, clinical trial was proposed to test this hypothesis. Forty adult participants with CF were block-randomized into one of four groups: 1) high-dose oral vitamin D3 (50,000 IU weekly) plus oral prebiotic placebo daily; 2) oral prebiotic (12 g inulin daily) plus oral placebo vitamin D3 weekly; 3) combined oral vitamin D3 weekly and oral prebiotic inulin daily; and 4) oral vitamin D3 placebo weekly and oral prebiotic placebo. The primary endpoints included 12-week changes in the microbial bacterial communities, gut and airway microbiota richness and diversity before and after the intervention. This pilot study examined whether vitamin D3 with or without prebiotics supplementation was feasible, changed airway and gut microbiota, and reduced dysbiosis, which in turn, may improve health outcomes and quality of life of patients with CF.

Maternal and Offspring Fatty Acid Desaturase Variants, Prenatal DHA Supplementation, and Dietary n-6:n-3 Fatty Acid Ratio in Relation to Cardiometabolic Health in Mexican Children.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in fatty acid desaturase (FADS) genes may modify dietary fatty acid requirements and influence cardiometabolic health (CMH). OBJECTIVES: We evaluated the role of selected variants in maternal and offspring FADS genes on offspring CMH at the age of 11 y and assessed interactions of genotype with diet quality and prenatal docosahexaenoic acid (DHA) supplementation. METHODS: We used data from offspring (n = 203) born to females who participated in a randomized controlled trial of DHA supplementation (400 mg/d) from midgestation to delivery. We generated a metabolic syndrome (MetS) score from body mass index, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and fasting glucose and identified 6 distinct haplotypes from 5 offspring FADS SNPs. Dietary n-6 (ω-6):n-3 fatty acid ratios were derived from 24-h recall data (n = 141). We used generalized linear models to test associations of offspring diet and FADS haplotypes with MetS score and interactions of maternal and offspring FADS SNP rs174602 with prenatal treatment group and dietary n-6:n-3 ratio on MetS score. RESULTS: Associations between FADS haplotypes and MetS score were null. Offspring SNP rs174602 did not modify the association of prenatal DHA supplementation with MetS score. Among children with TT or TC genotype for SNP rs174602 (n = 88), those in the highest n-6:n-3 ratio tertile (>8.61) had higher MetS score relative to the lowest tertile [<6.67) (Δ= 0.36; 95% confidence interval (CI): 0.03, 0.69]. Among children with CC genotype (n = 53), those in the highest n-6:n-3 ratio tertile had a lower MetS score relative to the lowest tertile (Δ= -0.23; 95% CI: -0.61, 0.16). CONCLUSIONS: There was evidence of an interaction of offspring FADS SNP rs174602 with current dietary polyunsaturated fatty acid intake, but not with prenatal DHA supplementation, on MetS score. Further studies may help to determine the utility of targeted supplementation strategies and dietary recommendations based on genetic profile.

Vitamin D and Prebiotics for Intestinal Health in Cystic Fibrosis: Rationale and design for a randomized, placebo-controlled, double-blind, 2 × 2 trial of administration of prebiotics and cholecalciferol (vitamin D3) (Pre-D Trial) in adults with cystic fibrosis.

Individuals with cystic fibrosis (CF) have dysfunctional intestinal microbiota and increased gastrointestinal (GI) inflammation also known as GI dysbiosis. It is hypothesized that administration of high-dose cholecalciferol (vitamin D3) together with a prebiotic (inulin) will be effective, and possibly additive or synergistic, in reducing CF-related GI dysbiosis and improving intestinal functions. Thus, a 2 × 2 factorial design, placebo-controlled, double-blind, clinical trial was proposed to test this hypothesis. Forty adult participants with CF will be block-randomized into one of four groups: 1) high-dose oral vitamin D3 (50,000 IU weekly) plus oral prebiotic placebo daily; 2) oral prebiotic (12 g inulin daily) plus oral placebo vitamin D3 weekly; 3) combined oral vitamin D3 weekly and oral prebiotic inulin daily; and 4) oral vitamin D3 placebo weekly and oral prebiotic placebo. The primary endpoints will include 12-week changes in the reduced relative abundance of gammaproteobacteria, and gut microbiota richness and diversity before and after the intervention. This clinical study will examine whether vitamin D3 with or without prebiotics will improve intestinal health and reduce GI dysbiosis, which in turn, should improve health outcomes and quality of life of patients with CF.

Vitamin D for glycemic control following an acute pulmonary exacerbation: A secondary analysis of a multicenter, double-blind, randomized, placebo-controlled trial in adults with cystic fibrosis.

Individuals with cystic fibrosis (CF) often incur damage to pancreatic tissue due to a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein, leading to altered chloride transport on epithelial surfaces and subsequent development of cystic fibrosis-related diabetes (CFRD). Vitamin D deficiency has been associated with the development of CFRD. This was a secondary analysis of a multicenter, double-blind, randomized, placebo-controlled study in adults with CF hospitalized for an acute pulmonary exacerbation (APE), known as the Vitamin D for the Immune System in Cystic Fibrosis (DISC) trial (NCT01426256). This was a pre-planned secondary analysis to examine if a high-dose bolus of cholecalciferol (vitamin D3) can mitigate declined glucose tolerance commonly associated with an acute pulmonary exacerbation (APE). Glycemic control was assessed by hemoglobin A1c (HbA1c) and fasting blood glucose levels before and 12 months after the study intervention. Within 72 hours of hospital admission, participants were randomly assigned to a single dose of oral vitamin D3 (250,000 IU) or placebo, and subsequently, received 50,000 IU of vitamin D3 or placebo every other week, beginning at month 3 and ending on month 12. Forty-nine of the 91 participants in the parent study were eligible for the secondary analysis. There were no differences in 12-month changes in HbA1c or fasting blood glucose in participants randomized to vitamin D or placebo. A high-dose bolus of vitamin D3 followed by maintenance vitamin D3 supplementation did not improve glycemic control in patients with CF after an APE.

Feasibility of Multiparametric Perfusion Assessment in Diabetic Foot Ulcer Using Intravoxel Incoherent Motion and Blood Oxygenation-Level Dependent MRI.

BACKGROUND: Patients with type-2 diabetes (T2DM) are at increased risk of developing diabetic foot ulcers (DFU) and experiencing impaired wound healing related to underlying microvascular disease. PURPOSE: To evaluate the sensitivity of intra-voxel incoherent motion (IVIM) and blood oxygen level dependent (BOLD) MRI to microvascular changes in patients with DFUs. STUDY TYPE: Case-control. POPULATION: 20 volunteers who were age and body mass index matched, including T2DM patients with DFUs (N = 10, mean age = 57.5 years), T2DM patients with controlled glycemia and without DFUs (DC, N = 5, mean age = 57.4 years) and healthy controls (HC, N = 5, mean age = 52.8 years). FIELD STRENGTH/SEQUENCE: 3T/multi-b-value IVIM and dynamic BOLD. ASSESSMENT: Resting IVIM parameters were obtained using a multi-b-value diffusion-weighted imaging sequence and two IVIM models were fit to obtain diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f) and microvascular volume fraction (MVF) parameters. Microvascular reactivity was evaluated by inducing an ischemic state in the foot with a blood pressure cuff during dynamic BOLD imaging. Perfusion indices were assessed in two regions of the foot: the medial plantar (MP) and lateral plantar (LP) regions. STATISTICAL TESTS: Effect sizes of group mean differences were assessed using Hedge's g adjusted for small sample sizes. RESULTS: DFU participants exhibited elevated D*, f, and MVF values in both regions (g ≥ 1.10) and increased D (g = 1.07) in the MP region compared to DC participants. DC participants showed reduced f and MVF compared to HC participants in the MP region (g ≥ 1.06). Finally, the DFU group showed reduced tolerance for ischemia in the LP region (g = -1.51) and blunted reperfusion response in both regions (g < -2.32) compared to the DC group during the cuff-occlusion challenge. DATA CONCLUSION: The combined use of IVIM and BOLD MRI shows promise in differentiating perfusion abnormalities in the feet of diabetic patients and suggests hyperperfusion in DFU patients. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 1.

High-Resolution Plasma Metabolomics and Thiamine Status in Critically Ill Adult Patients.

Background and Aim: Thiamine (Vitamin B1) is an essential micronutrient and a co-factor for metabolic functions related to energy metabolism. We determined the association between whole blood thiamine pyrophosphate (TPP) concentrations and plasma metabolites using high resolution metabolomics in critically ill patients. Methods: Cross-sectional study performed in Erciyes University Hospital, Kayseri, Turkey and Emory University, Atlanta, GA, USA. Participants were ≥ 18 years of age, with an expected length of ICU stay longer than 48 hours, receiving furosemide therapy for at least 6 months before ICU admission. Results: Blood for TPP and metabolomics was obtained on the day of ICU admission. Whole blood TPP concentrations were measured using high-performance liquid chromatography (HPLC). Liquid chromatography/mass spectrometry was used for plasma high-resolution metabolomics. Data was analyzed using regression analysis of TPP levels against all plasma metabolomic features in metabolome-wide association studies. We also compared metabolomic features from patients in the highest TPP concentration tertile to patients in the lowest TPP tertile as a secondary analysis. We enrolled 76 participants with a median age of 69 (range, 62.5-79.5) years. Specific metabolic pathways associated with whole blood TPP levels, using both regression and tertile analysis, included pentose phosphate, fructose and mannose, branched chain amino acid, arginine and proline, linoleate, and butanoate pathways. Conclusions: Plasma high-resolution metabolomics analysis showed that whole blood TPP concentrations are significantly associated with metabolites and metabolic pathways linked to the metabolism of energy, amino acids, lipids, and the gut microbiome in adult critically ill patients.

Quality of dietary macronutrients is associated with glycemic outcomes in adults with cystic fibrosis.

Objective: Poor diet quality contributes to metabolic dysfunction. This study aimed to gain a greater understanding of the relationship between dietary macronutrient quality and glucose homeostasis in adults with cystic fibrosis (CF). Design: This was a cross-sectional study of N = 27 adults with CF with glucose tolerance ranging from normal (n = 9) to prediabetes (n = 6) to being classified as having cystic fibrosis-related diabetes (CFRD, n = 12). Fasted blood was collected for analysis of glucose, insulin, and C-peptide. Insulin resistance was assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA2-IR). Subjects without known CFRD also underwent a 2-h oral glucose tolerance test. Three-day food records were used to assess macronutrient sources. Dietary variables were adjusted for energy intake. Statistical analyses included ANOVA, Spearman correlations, and multiple linear regression. Results: Individuals with CFRD consumed less total fat and monounsaturated fatty acids (MUFA) compared to those with normal glucose tolerance (p < 0.05). In Spearman correlation analyses, dietary glycemic load was inversely associated with C-peptide (rho = -0.28, p = 0.05). Total dietary fat, MUFA, and polyunsaturated fatty acids (PUFA) were positively associated with C-peptide (rho = 0.39-0.41, all p < 0.05). Plant protein intake was inversely related to HOMA2-IR (rho = -0.28, p = 0.048). Associations remained significant after adjustment for age and sex. Discussion: Improvements in diet quality are needed in people with CF. This study suggests that higher unsaturated dietary fat, higher plant protein, and higher carbohydrate quality were associated with better glucose tolerance indicators in adults with CF. Larger, prospective studies in individuals with CF are needed to determine the impact of diet quality on the development of CFRD.

Characterizing substrate utilization during the fasted state using plasma high-resolution metabolomics.

OBJECTIVES: High-resolution metabolomics enables global assessment of metabolites and molecular pathways underlying physiologic processes, including substrate utilization during the fasted state. The clinical index for substrate utilization, respiratory exchange ratio (RER), is measured via indirect calorimetry. The aim of this pilot study was to use metabolomics to identify metabolic pathways and plasma metabolites associated with substrate utilization in healthy, fasted adults. METHODS: This cross-sectional study included 33 adults (mean age 27.7 ± 4.9 y, mean body mass index 24.8 ± 4 kg/m2). Participants underwent indirect calorimetry to determine resting RER after an overnight fast. Untargeted metabolomics was performed on fasted plasma samples using dual-column liquid chromatography and ultra-high-resolution mass spectrometry. Linear regression and pathway enrichment analyses identified pathways and metabolites associated with substrate utilization measured with indirect calorimetry. RESULTS: RER was significantly associated with 1389 metabolites enriched within 13 metabolic pathways (P < 0.05). Lipid-related findings included general pathways, such as fatty acid activation, and specific pathways, such as C21-steroid hormone biosynthesis and metabolism, butyrate metabolism, and carnitine shuttle. Amino acid pathways included those central to metabolism, such as glucogenic amino acids, and pathways needed to maintain reduction-oxidation reactions, such as methionine and cysteine metabolism. Galactose and pyrimidine metabolism were also associated with RER (all P < 0.05). CONCLUSIONS: The fasting plasma metabolome reflects the diverse macronutrient pathways involved in carbohydrate, amino acid, and lipid metabolism during the fasted state in healthy adults. Future studies should consider the utility of metabolomics to profile individual nutrient requirements and compare findings reported here to clinical populations.

Total choline intake and working memory performance in adults with phenylketonuria.

BACKGROUND: Despite early diagnosis and compliance with phenylalanine (Phe)-restricted diets, many individuals with phenylketonuria (PKU) still exhibit neurological changes and experience deficits in working memory and other executive functions. Suboptimal choline intake may contribute to these impairments, but this relationship has not been previously investigated in PKU. The objective of this study was to determine if choline intake is correlated with working memory performance, and if this relationship is modified by diagnosis and metabolic control. METHODS: This was a cross-sectional study that included 40 adults with PKU and 40 demographically matched healthy adults. Web-based neurocognitive tests were used to assess working memory performance and 3-day dietary records were collected to evaluate nutrient intake. Recent and historical blood Phe concentrations were collected as measures of metabolic control. RESULTS: Working memory performance was 0.32 z-scores (95% CI 0.06, 0.58) lower, on average, in participants with PKU compared to participants without PKU, and this difference was not modified by total choline intake (F[1,75] = 0.85, p = 0.36). However, in a subgroup with complete historical blood Phe data, increased total choline intake was related to improved working memory outcomes among participants with well controlled PKU (Phe = 360 µmol/L) after adjusting for intellectual ability and mid-childhood Phe concentrations (average change in working memory per 100 mg change in choline = 0.11; 95% CI 0.02, 0.20; p = 0.02). There also was a trend, albeit nonsignificant (p = 0.10), for this association to be attenuated with increased Phe concentrations. CONCLUSIONS: Clinical monitoring of choline intake is essential for all individuals with PKU but may have important implications for working memory functioning among patients with good metabolic control. Results from this study should be confirmed in a larger controlled trial in people living with PKU.

Changes in bone turnover after high-dose vitamin D supplementation during acute pulmonary exacerbation in cystic fibrosis.

In people with cystic fibrosis (CF), chronic inflammation and infection increase the risk for low bone mineral density and CF-related bone disease. During acute pulmonary exacerbations (APE), people with CF have increases in markers of bone resorption. Vitamin D has been proposed as a potential nutrient to lower inflammation. In this ancillary analysis of the Vitamin D for the Immune System in CF study, we hypothesized that vitamin D administered at the time of APE would have favorable changes on bone turnover markers compared to placebo. Participants with CF were randomized to receive a single dose of 250,000 IU of vitamin D or placebo during an APE and followed for 1 year for the primary outcome of APE or death after randomization. Bone turnover markers: C-terminal telopeptide (CTX-1) and procollagen type 1 intact N-terminal propetide (P1NP) were assessed at randomization (during APE) and after recovery from the APE in 45 participants. Participants randomized to vitamin D had significant decreases in markers of bone turnover; participants who received placebo had non-significant increases in markers of bone turnover. Vitamin D supplementation during an APE may help reduce the risk for CF-related bone disease.

Antiracist Structural Intervention at the Emory University Institutional Review Board.

Although racial and ethnic categories are social constructs without inherent biologic or genetic meaning, race and ethnicity impact health outcomes through racism. The use of racial categories in biomedical research often misattributes the cause of health inequities to genetic and inherent biological differences rather than to racism. Improving research practices around race and ethnicity is an urgent priority and requires education as well as structural change. We describe an evidence-based intervention for an institutional review board (IRB). Our IRB now requires all biomedical study protocols to define racial and ethnic classifications they plan to use, to state whether they are describing or explaining differences between groups, and to provide justification for any use of racial or ethnic group variables as covariates. This antiracist IRB intervention is an example of how research institutions can help ensure the scientific validity of studies and avoid the unscientific reification of race and ethnicity as inherently biological or genetic concepts.

Obesogens and Obesity: State-of-the-Science and Future Directions Summary from a Healthy Environment and Endocrine Disruptors Strategies Workshop.

On September 7 and 8, 2022, Healthy Environment and Endocrine Disruptors Strategies, an Environmental Health Sciences program, convened a scientific workshop of relevant stakeholders involved in obesity, toxicology, or obesogen research to review the state of the science regarding the role of obesogenic chemicals that might be contributing to the obesity pandemic. The workshop's objectives were to examine the evidence supporting the hypothesis that obesogens contribute to the etiology of human obesity; to discuss opportunities for improved understanding, acceptance, and dissemination of obesogens as contributors to the obesity pandemic; and to consider the need for future research and potential mitigation strategies. This report details the discussions, key areas of agreement, and future opportunities to prevent obesity. The attendees agreed that environmental obesogens are real, significant, and a contributor at some degree to weight gain at the individual level and to the global obesity and metabolic disease pandemic at a societal level; moreover, it is at least, in theory, remediable.

Obesity Modifies the Relationship Between Raltegravir and Dolutegravir Hair Concentrations and Body Weight Gain in Women Living with HIV.

Integrase strand-transfer inhibitors (INSTIs) are associated with weight gain in women living with HIV (WLH). Relationships between drug exposure, baseline obesity, and INSTI-associated weight gain remain unclear. Data from 2006 to 2016 were analyzed from virally suppressed WLH enrolled in the Women's Interagency HIV Study, who switched/added an INSTI to antiretroviral therapy: [raltegravir (RAL), dolutegravir (DTG), or elvitegravir (EVG)]. Percent body weight change was calculated from weights obtained a median 6 months pre-INSTI and 14 months post-INSTI initiation. Hair concentrations were measured with validated liquid chromatography-mass spectrometry (MS)/MS assays. Baseline (preswitch) weight status evaluated obese (body mass index, BMI, ≥30 kg/m2) versus nonobese (BMI <30 kg/m2). Mixed models examined the drug hair concentration*baseline obesity status interaction for each INSTI. There were 169 WLH included: 53 (31%) switched to RAL, 72 (43%) to DTG, and 44 (26%) to EVG. Women were median age 47-52 years, predominantly Non-Hispanic Black, median CD4 counts >500 cells/mm3, >75% with undetectable HIV-1 RNA. Over ∼1 year, women experienced median increases in body weight: 1.71% (-1.78, 5.00) with RAL; 2.40% (-2.82, 6.50) with EVG; and 2.48% (-3.60, 7.88) with DTG. Baseline obesity status modified the relationship between hair concentrations and percent weight change for DTG and RAL (p's < 0.05): higher DTG, yet lower RAL concentrations were associated with greater weight gain among nonobese women. Additional pharmacologic assessments are needed to understand the role of drug exposure in INSTI-associated weight gain.

Cystic Fibrosis-Related Diabetes Workshop: Research Priorities Spanning Disease Pathophysiology, Diagnosis, and Outcomes.

Cystic fibrosis (CF) is a recessive disorder arising from mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is expressed in numerous tissues, with high expression in the airways, small and large intestine, pancreatic and hepatobiliary ducts, and male reproductive tract. CFTR loss in these tissues disrupts regulation of salt, bicarbonate, and water balance across their epithelia, resulting in a systemic disorder with progressive organ dysfunction and damage. Pancreatic exocrine damage ultimately manifests as pancreatic exocrine insufficiency that begins as early as infancy. Pancreatic remodeling accompanies this early damage, during which abnormal glucose tolerance can be observed in toddlers. With increasing age, however, insulin secretion defects progress such that CF-related diabetes (CFRD) occurs in 20% of teens and up to half of adults with CF. The relevance of CFRD is highlighted by its association with increased morbidity, mortality, and patient burden. While clinical research on CFRD has greatly assisted in the care of individuals with CFRD, key knowledge gaps on CFRD pathogenesis remain. Furthermore, the wide use of CFTR modulators to restore CFTR activity is changing the CFRD clinical landscape and the field's understanding of CFRD pathogenesis. For these reasons, the National Institute of Diabetes and Digestive and Kidney Diseases and the Cystic Fibrosis Foundation sponsored a CFRD Scientific Workshop, 23-25 June 2021, to define knowledge gaps and needed research areas. This article describes the findings from this workshop and plots a path for CFRD research that is needed over the next decade.

Cystic Fibrosis-Related Diabetes Workshop: Research Priorities Spanning Disease Pathophysiology, Diagnosis, and Outcomes.

Cystic fibrosis (CF) is a recessive disorder arising from mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is expressed in numerous tissues, with high expression in the airways, small and large intestine, pancreatic and hepatobiliary ducts, and male reproductive tract. CFTR loss in these tissues disrupts regulation of salt, bicarbonate, and water balance across their epithelia, resulting in a systemic disorder with progressive organ dysfunction and damage. Pancreatic exocrine damage ultimately manifests as pancreatic exocrine insufficiency that begins as early as infancy. Pancreatic remodeling accompanies this early damage, during which abnormal glucose tolerance can be observed in toddlers. With increasing age, however, insulin secretion defects progress such that CF-related diabetes (CFRD) occurs in 20% of teens and up to half of adults with CF. The relevance of CFRD is highlighted by its association with increased morbidity, mortality, and patient burden. While clinical research on CFRD has greatly assisted in the care of individuals with CFRD, key knowledge gaps on CFRD pathogenesis remain. Furthermore, the wide use of CFTR modulators to restore CFTR activity is changing the CFRD clinical landscape and the field's understanding of CFRD pathogenesis. For these reasons, the National Institute of Diabetes and Digestive and Kidney Diseases and the Cystic Fibrosis Foundation sponsored a CFRD Scientific Workshop, 23-25 June 2021, to define knowledge gaps and needed research areas. This article describes the findings from this workshop and plots a path for CFRD research that is needed over the next decade.

Increased adiposity is associated with altered skeletal muscle energetics.

The objective of this pilot study was to characterize relationships between skeletal muscle energy metabolism and body composition in healthy adults with varied amounts and distribution of adipose tissue. In vivo muscle energetics were quantified using dynamic 31P magnetic resonance spectroscopy with knee extension exercise standardized to subject lean body mass. Spearman's correlation analysis examined relationships between muscle metabolism indices and measures of adiposity including body mass index (BMI), total body fat, and quadriceps intermuscular adipose tissue (IMAT). Post hoc partial correlations were examined controlling for additional body composition measures. Kruskal-Wallis tests with Dunn-Sidak post hoc comparisons evaluated group differences in energy metabolism based on body composition profiles (i.e., lean, normal-weight obese, and overweight-obese) and IMAT tertiles. BMI negatively correlated with end-exercise muscle pH after correcting for IMAT and total body fat (r = -0.46, P = 0.034). Total adiposity negatively correlated with maximum oxidative capacity after correcting for IMAT (r = -0.54, P = 0.013). IMAT positively correlated with muscle proton buffering capacity after correcting for total body fat (r = 0.53, P = 0.023). Body composition groups showed differences in end-exercise fall in [PCr] with normalized workload (P = 0.036; post hoc: overweight-obese < lean, P = 0.029) and maximum oxidative capacity (P = 0.021; post hoc: normal-weight obese < lean, P = 0.016). IMAT tertiles showed differences in end-exercise fall in [PCr] with normalized workload (P = 0.035; post hoc: 3rd < 1st, P = 0.047). Taken together, these results support increased adiposity is associated with reduced muscle energetic efficiency with more reliance on glycolysis, and when accompanied with reduced lean mass, is associated with reduced maximum oxidative capacity.NEW & NOTEWORTHY Skeletal muscle energy production is influenced by both lean body mass and adipose tissue but the effect of their distribution on energy metabolism is unclear. This study examined variations in quadriceps muscle energy metabolism in healthy adults with varied relative amounts of lean and adipose tissue. Results suggest increased adiposity is associated with reduced muscle energetic efficiency with more reliance on glycolysis, and when accompanied with reduced lean mass, is associated with reduced maximum oxidative capacity.

Untargeted, High-Resolution Metabolomics in Pediatric Eosinophilic Esophagitis.

BACKGROUND/OBJECTIVES: Eosinophilic esophagitis (EoE) is an inflammatory disease of unclear etiology. The aim of this study was to use untargeted plasma metabolomics to identify metabolic pathway alterations associated with EoE to better understand the pathophysiology. METHODS: This prospective, case-control study included 72 children, aged 1-17 years, undergoing clinically indicated upper endoscopy (14 diagnosed with EoE and 58 controls). Fasting plasma samples were analyzed for metabolomics by high-resolution dual-chromatography mass spectrometry. Analysis was performed on sex-matched groups at a 2:1 ratio. Significant differences among the plasma metabolite features between children with and without EoE were determined using multivariate regression analysis and were annotated with a network-based algorithm. Subsequent pathway enrichment analysis was performed. RESULTS: Patients with EoE had a higher proportion of atopic disease (85.7% vs 50%, P = 0.019) and any allergies (100% vs 57.1%, P = 0.0005). Analysis of the dual chromatography features resulted in a total of 918 metabolites that differentiated EoE and controls. Glycerophospholipid metabolism was significantly enriched with the greatest number of differentiating metabolites and overall pathway enrichment ( P < 0.01). Multiple amino and fatty acid pathways including linoleic acid were also enriched, as well as pyridoxine metabolism ( P < 0.01). CONCLUSIONS: In this pilot study, we found differences in metabolites involved in glycerophospholipid and inflammation pathways in pediatric patients with EoE using untargeted metabolomics, as well as overlap with amino acid metabolome alterations found in atopic disease.