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Background Observational reports suggest that supplementation that increases citric acid cycle intermediates via anaplerosis may have therapeutic advantages over traditional medium-chain triglyceride (MCT) treatment of long-chain fatty acid oxidation disorders (LC-FAODs) but controlled trials have not been reported. The goal of our study was to compare the effects of triheptanoin (C7), an anaplerotic seven-carbon fatty acid triglyceride, to trioctanoin (C8), an eight-carbon fatty acid triglyceride, in patients with LC-FAODs. Methods A double blinded, randomized controlled trial of 32 subjects with LC-FAODs (carnitine palmitoyltransferase-2, very long-chain acylCoA dehydrogenase, trifunctional protein or long-chain 3-hydroxy acylCoA dehydrogenase deficiencies) who were randomly assigned a diet containing 20% of their total daily energy from either C7 or C8 for 4 months was conducted. Primary outcomes included changes in total energy expenditure (TEE), cardiac function by echocardiogram, exercise tolerance, and phosphocreatine recovery following acute exercise. Secondary outcomes included body composition, blood biomarkers, and adverse events, including incidence of rhabdomyolysis. Results Patients in the C7 group increased left ventricular (LV) ejection fraction by 7.4% ( p  = 0.046) while experiencing a 20% ( p  = 0.041) decrease in LV wall mass on their resting echocardiogram. They also required a lower heart rate for the same amount of work during a moderate-intensity exercise stress test when compared to patients taking C8. There was no difference in TEE, phosphocreatine recovery, body composition, incidence of rhabdomyolysis, or any secondary outcome measures between the groups. Conclusions C7 improved LV ejection fraction and reduced LV mass at rest, as well as lowering heart rate during exercise among patients with LC-FAODs. Clinical Trial Registration: Clinicaltrials.gov NCT01379625.

•Validated dietary methods are key to reducing biomarker bias in IEM-related clinical trials.•Dietary methods vary widely across PKU, FAOD, and MMA/PA studies.•Most studies relied on self-reported diet records, not validated methods.•Small trial sizes make diet stability critical for valid conclusions.•More precision and validity are needed for reliable dietary assessments. Inborn errors of metabolism (IEMs) are rare genetic conditions that often require strict dietary management to prevent serious health complications. With the rise of pharmaceutical therapies for IEMs, clinical trials now use diet-sensitive biomarkers to assess drug efficacy. However, uncontrolled dietary variation can confound biomarker outcomes. This review evaluates how diet is managed and monitored in pharmaceutical clinical trials for IEMs and compares those practices against FDA guidance and validated nutrition assessment standards. An analytic narrative review was conducted from November 2023 to March 2024 using Cochrane Library searches. Seventeen clinical trials met inclusion criteria, involving phenylketonuria (PKU), fatty-acid oxidation disorders, and methylmalonic/propionic acidemia. Each trial was evaluated against 14 dietary study design elements based on the 2023 FDA guidance document and principles of precision, reproducibility, and validity from nutrition science literature. Dietary methodologies varied widely across trials. Fatty-acid oxidation disorder and methylmalonic/propionic acidemia studies used more structured dietary controls and multiple biomarkers/clinical assessments. In contrast, PKU trials relied heavily on blood phenylalanine levels, with limited assessment of dietary variability or adherence. Only a few of the included studies used validated dietary assessment methods, defined the range of acceptable dietary intake, or statistically assessed adherence to the dietary plan. Most failed to use objective tools to confirm compliance and instead relied on self-reported diet records. Newer trials showed improved adherence to FDA recommendations, but no study met all 14 elements. Dietary assessments remain inconsistently addressed in IEM clinical trials, particularly in PKU. Failure to account for dietary variability reduces confidence in biomarker interpretation. Adopting validated dietary assessment methods and statistical modeling of intake variation can improve reproducibility and reduce confounding. Future trials should quantify acceptable dietary fluctuations and incorporate validated tools to ensure dietary rigor in biomarker-based drug efficacy studies.

Clinical trials play a vital role in developing new medications for nutrition-related diseases, such as phenylketonuria (PKU), obesity, and diabetes. Dietary management is often a critical component of these trials, as consistency in diet can significantly influence outcomes and the evaluation of drug efficacy. While the Federal Drug Administration (FDA) provides guidance on managing and monitoring diets in clinical trials, the extent to which these practices are implemented remains unclear. This review examines diet management practices in phase 2 and 3 clinical trials for weight loss, type 2 diabetes, and PKU. A systematic review methodology was employed, with PubMed and Cochrane searches identifying 14 articles for weight loss and diabetes trials and 5 articles for PKU trials that met inclusion criteria. Key practices include the use of inclusion/exclusion criteria, study endpoints incorporating multiple biomarkers, and the implementation of specific dietary protocols. Weight loss and PKU trials were more likely to employ detailed dietary guidelines than diabetes trials. However, all the reviewed studies lacked critical elements outlined in published nutrition research guidelines. This review underscores the variability and deficiencies in diet management practices in clinical trials for nutrition-related disorders. These gaps highlight the need for more standardized and transparent approaches to dietary monitoring and reporting in order to improve the reliability and reproducibility of trial outcomes. •Diet control is key to reducing biomarker bias in nutrition-related trials.•Diet management methods differ across weight loss, diabetes, and PKU trials.•PKU trials use stricter diets but do not fully meet FDA guidance.•Small PKU trial sizes make consistent diets even more critical.•More precision and validity are needed for reliable drug outcomes.

To begin to understand the contributions of maternal obesity and over-nutrition to human development and the early origins of obesity, we utilized a non-human primate model to investigate the effects of maternal high-fat feeding and obesity on breast milk, maternal and fetal plasma fatty acid composition and fetal hepatic development. While the high-fat diet (HFD) contained equivalent levels of n-3 fatty acids (FA's) and higher levels of n-6 FA's than the control diet (CTR), we found significant decreases in docosahexaenoic acid (DHA) and total n-3 FA's in HFD maternal and fetal plasma. Furthermore, the HFD fetal plasma n-6:n-3 ratio was elevated and was significantly correlated to the maternal plasma n-6:n-3 ratio and maternal hyperinsulinemia. Hepatic apoptosis was also increased in the HFD fetal liver. Switching HFD females to a CTR diet during a subsequent pregnancy normalized fetal DHA, n-3 FA's and fetal hepatic apoptosis to CTR levels. Breast milk from HFD dams contained lower levels of eicosopentanoic acid (EPA) and DHA and lower levels of total protein than CTR breast milk. This study links chronic maternal consumption of a HFD with fetal hepatic apoptosis and suggests that a potentially pathological maternal fatty acid milieu is replicated in the developing fetal circulation in the nonhuman primate.

Aims/hypothesis Adults with type 1 diabetes should perform daily physical activity to help maintain health and fitness, but the influence of daily step counts on continuous glucose monitoring (CGM) metrics are unclear. This analysis used the Type 1 Diabetes Exercise Initiative (T1DEXI) dataset to investigate the effect of daily step count on CGM-based metrics. Methods In a 4 week free-living observational study of adults with type 1 diabetes, with available CGM and step count data, we categorised participants into three groups—below (<7000), meeting (7000–10,000) or exceeding (>10,000) the daily step count goal—to determine if step count category influenced CGM metrics, including per cent time in range (TIR: 3.9–10.0 mmol/l), time below range (TBR: <3.9 mmol/l) and time above range (TAR: >10.0 mmol/l). Results A total of 464 adults with type 1 diabetes (mean±SD age 37±14 years; HbA 1c 48.8±8.1 mmol/mol [6.6±0.7%]; 73% female; 45% hybrid closed-loop system, 38% standard insulin pump, 17% multiple daily insulin injections) were included in the study. Between-participant analyses showed that individuals who exceeded the mean daily step count goal over the 4 week period had a similar TIR (75±14%) to those meeting (74±14%) or below (75±16%) the step count goal ( p >0.05). In the within-participant comparisons, TIR was higher on days when the step count goal was exceeded or met (both 75±15%) than on days below the step count goal (73±16%; both p <0.001). The TBR was also higher when individuals exceeded the step count goals (3.1%±3.2%) than on days when they met or were below step count goals (difference in means −0.3% [ p =0.006] and −0.4% [ p =0.001], respectively). The total daily insulin dose was lower on days when step count goals were exceeded (0.52±0.18 U/kg; p <0.001) or were met (0.53±0.18 U/kg; p <0.001) than on days when step counts were below the current recommendation (0.55±0.18 U/kg). Step count had a larger effect on CGM-based metrics in participants with a baseline HbA 1c ≥53 mmol/mol (≥7.0%). Conclusions/interpretation Our results suggest that, compared with days with low step counts, days with higher step counts are associated with slight increases in both TIR and TBR, along with small reductions in total daily insulin requirements, in adults living with type 1 diabetes. Data availability The data that support the findings reported here are available on the Vivli Platform (ID: T1-DEXI; https://doi.org/10.25934/PR00008428 ). Graphical Abstract

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a fatty acid oxidation disorder (FAOD) caused by a pathogenic variant, c.1528 G > C, in HADHA encoding the alpha subunit of trifunctional protein (TFPα). Individuals with LCHADD develop chorioretinopathy and peripheral neuropathy not observed in other FAODs in addition to the more ubiquitous symptoms of hypoketotic hypoglycemia, rhabdomyolysis and cardiomyopathy. We report a CRISPR/Cas9 generated knock-in murine model of G1528C in Hadha that recapitulates aspects of the human LCHADD phenotype. Homozygous pups are less numerous than expected from Mendelian probability, but survivors exhibit similar viability with wildtype (WT) littermates. Tissues of LCHADD homozygotes express TFPα protein, but LCHADD mice oxidize less fat and accumulate plasma 3-hydroxyacylcarnitines compared to WT mice. LCHADD mice exhibit lower ketones with fasting, exhaust earlier during treadmill exercise and develop a dilated cardiomyopathy compared to WT mice. In addition, LCHADD mice exhibit decreased visual performance, decreased cone function, and disruption of retinal pigment epithelium. Neurological function is affected, with impaired motor function during wire hang test and reduced open field activity. The G1528C knock-in mouse exhibits a phenotype similar to that observed in human patients; this model will be useful to explore pathophysiology and treatments for LCHADD in the future. A mouse model of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) recapitulates specific aspects of human LCHADD and may serve as a useful resource to probe disease pathophysiology in the future.

Treatment recommendations in mitochondrial fatty acid oxidation (FAO) defects are diverse. With implementation of newborn screening and identification of asymptomatic patients, it is necessary to define whom to treat and how strictly. We here discuss critical questions that are currently under debate. For some asymptomatic long-chain defects, long-chain fat restriction plays a minor role, and a normal diet may be introduced. For patients presenting only with myopathic symptoms, e.g., during exercise, treatment may be adapted to energy demand. As a consequence, patients with exercise-induced myopathy may be able to return to normal activity when provided with medium-chain triglycerides (MCT) prior to exercise. There is no need to limit participation in sports. Progression of retinopathy in disorders of the mitochondrial trifunctional protein complex is closely associated with hydroxyacylcarnitine accumulation. A strict low-fat diet with MCT supplementation is recommended to slow or prevent progression of chorioretinopathy. Additional docosahexanoic acid does not prevent the decline in retinal function but does promote nonspecific improvement in visual acuity and is recommended. There is no evidence that L-carnitine supplementation is beneficial. Thus, supplementation with L-carnitine in a newborn identified by screening with either a medium-chain or long-chain defect is not supported. With respect to the use of the odd-chain medium-chain triglyceride triheptanoin in myopathic phenotypes, randomized trials are needed to establish whether triheptanoin is more effective than even-chain MCT. With increasing pathophysiological knowledge, new treatment options have been identified and are being clinically evaluated. These include the use of bezafibrates in myopathic long-chain defects.

ObjectiveIncreased infant birth weight and adiposity are associated with an altered risk of adult chronic diseases. The objective was to investigate the association between maternal dietary fat intake during pregnancy and newborn adiposity.Study designThe study included 79 singleton pregnancies. Associations between maternal dietary fat intake during each trimester and infant adiposity at birth were assessed.ResultAverage total grams of maternal total dietary fat and unsaturated fat intake during pregnancy correlated with infant percent body fat after adjusting for potential confounding variables (r = 0.23, p = 0.045; r = 0.24, p = 0.037). Maternal average daily intake of total fat, saturated fat, and unsaturated fat during the second trimester of pregnancy were each associated with infant percent body fat (r = 0.25, p = 0.029; r = 0.23, p = 0.046; r = 0.25, p = 0.031; respectively).ConclusionsThe second trimester of pregnancy is a key time period for fetal adipose tissue metabolic programming and therefore a target for nutritional intervention.

Blood and urine acylcarnitine profiles are commonly used to diagnose long-chain fatty acid oxidation disorders (FAOD: i.e., long-chain hydroxy-acyl-CoA dehydrogenase [LCHAD] and carnitine palmitoyltransferase 2 [CPT2] deficiency), but the global metabolic impact of long-chain FAOD has not been reported. We utilized untargeted metabolomics to characterize plasma metabolites in 12 overnight-fasted individuals with FAOD (10 LCHAD, two CPT2) and 11 healthy age-, sex-, and body mass index (BMI)-matched controls, with the caveat that individuals with FAOD consume a low-fat diet supplemented with medium-chain triglycerides (MCT) while matched controls consume a typical American diet. In plasma 832 metabolites were identified, and partial least squared-discriminant analysis (PLS-DA) identified 114 non-acylcarnitine variables that discriminated FAOD subjects and controls. FAOD individuals had significantly higher triglycerides and lower specific phosphatidylethanolamines, ceramides, and sphingomyelins. Differences in phosphatidylcholines were also found but the directionality differed by metabolite species. Further, there were few differences in non-lipid metabolites, indicating the metabolic impact of FAOD specifically on lipid pathways. This analysis provides evidence that LCHAD/CPT2 deficiency significantly alters complex lipid pathway flux. This metabolic signature may provide new clinical tools capable of confirming or diagnosing FAOD, even in subjects with a mild phenotype, and may provide clues regarding the biochemical and metabolic impact of FAOD that is relevant to the etiology of FAOD symptoms.