A ketogenic diet lowers myocardial fatty acid oxidation but does not affect oxygen consumption: a study in overweight humans.

OBJECTIVE: A ketogenic diet (KD) characterized by very low carbohydrate intake and high fat consumption may simultaneously induce weight loss and be cardioprotective. The "thrifty substrate hypothesis" posits that ketone bodies are more energy efficient compared with other cardiac oxidative substrates such as fatty acids. This work aimed to study whether a KD with presumed increased myocardial ketone body utilization reduces cardiac fatty acid uptake and oxidation, resulting in decreased myocardial oxygen consumption (MVO2 ). METHODS: This randomized controlled crossover trial examined 11 individuals with overweight or obesity on two occasions: (1) after a KD and (2) after a standard diet. Myocardial free fatty acid (FFA) oxidation, uptake, and esterification rate were measured using dynamic [11 C]palmitate positron emission tomography (PET)/computed tomography, whereas MVO2 and myocardial external efficiency (MEE) were measured using dynamic [11 C]acetate PET. RESULTS: The KD increased plasma ß-hydroxybutyrate, reduced myocardial FFA oxidation (p < 0.01) and uptake (p = 0.03), and increased FFA esterification (p = 0.03). No changes were observed in MVO2 (p = 0.2) or MEE (p = 0.87). CONCLUSIONS: A KD significantly reduced myocardial FFA uptake and oxidation, presumably by increasing ketone body oxidation. However, this change in cardiac substrate utilization did not improve MVO2 , speaking against the thrifty substrate hypothesis.

Nutrient sensing: LEAP2 concentration in response to fasting, glucose, lactate, and ß-hydroxybutyrate in healthy young males.

BACKGROUND: The appetite-suppressing potential of liver-expressed antimicrobial peptide 2 (LEAP2), and its antagonistic effects on the hunger-inducing hormone ghrelin have attracted scientific interest. It is unclear how LEAP2 is influenced by fasting and how it responds to specific nutrients. OBJECTIVES: The purpose of this investigation was to assess whether LEAP2 concentration 1) decreases after fasting, 2) increases postprandially, and 3) is regulated by nutrient sensing in the splanchnic bed. METHODS: Plasma LEAP2 concentration was measured in blood samples from 5 clinical cross-over trials, following 1) 36 h of fasting (n = 8), 2) 10 h of fasting (n = 37, baseline data pooled from 4 of the clinical trials), 3) Oral and intravenous glucose administration (n = 11), 4) Oral and intravenous Na-lactate administration (n = 10), and 5) Oral and intravenous Na-ß-hydroxybutyrate (BHB) administration (n = 8). All 5 trials included healthy males. RESULTS: Compared with a 10-h fasting period, the median LEAP2 concentration was 38% lower following 36 h of fasting (P < 0.001). Oral administration of glucose elevated, whereas intravenous glucose administration lowered LEAP2 concentration (intervention x time, P = 0.001), resulting in a mean difference of 9 ng/mL (95% confidence interval [CI]: 1, 17) after 120 min. Oral lactate increased, and intravenous lactate decreased LEAP2 (intervention x time, P = 0.007), with a mean difference between interventions of 10 ng/mL (95% CI: 6, 15) after 120 min. In contrast, oral and intravenous administration of BHB reduced the LEAP2 concentration (main effect of time, P < 0.001). CONCLUSIONS: Our investigations show that LEAP2 concentration was lower after a 36-h fast than an overnight fast and that oral delivery of glucose and lactate elevated LEAP2 concentration compared with intravenous administration, whereas LEAP2 concentrations decreased with both oral and intravenous BHB. This indicates that the LEAP2 concentration is sensitive to intestinal exposure to specific substrates, highlighting the need for future studies exploring the relationship between nutrients and LEAP2. This trial was registered at clinicaltrials.gov as NCT01840098, NCT03204877, NCT04299815, NCT03935841, and NCT01705782.

X chromosome dosage and the genetic impact across human tissues.

BACKGROUND: Sex chromosome aneuploidies (SCAs) give rise to a broad range of phenotypic traits and diseases. Previous studies based on peripheral blood samples have suggested the presence of ripple effects, caused by altered X chromosome number, affecting the methylome and transcriptome. Whether these alterations can be connected to disease-specific tissues, and thereby having clinical implication for the phenotype, remains to be elucidated. METHODS: We performed a comprehensive analysis of X chromosome number on the transcriptome and methylome in blood, fat, and muscle tissue from individuals with 45,X, 46,XX, 46,XY, and 47,XXY. RESULTS: X chromosome number affected the transcriptome and methylome globally across all chromosomes in a tissue-specific manner. Furthermore, 45,X and 47,XXY demonstrated a divergent pattern of gene expression and methylation, with overall gene downregulation and hypomethylation in 45,X and gene upregulation and hypermethylation in 47,XXY. In fat and muscle, a pronounced effect of sex was observed. We identified X chromosomal genes with an expression pattern different from what would be expected based on the number of X and Y chromosomes. Our data also indicate a regulatory function of Y chromosomal genes on X chromosomal genes. Fourteen X chromosomal genes were downregulated in 45,X and upregulated in 47,XXY, respectively, in all three tissues (AKAP17A, CD99, DHRSX, EIF2S3, GTPBP6, JPX, KDM6A, PP2R3B, PUDP, SLC25A6, TSIX, XIST, ZBED1, ZFX). These genes may be central in the epigenetic and genomic regulation of sex chromosome aneuploidies. CONCLUSION: We highlight a tissue-specific and complex effect of X chromosome number on the transcriptome and methylome, elucidating both shared and non-shared gene-regulatory mechanism between SCAs.

Sex chromosome aneuploidies give rise to changes in the circular RNA profile: A circular transcriptome-wide study of Turner and Klinefelter syndrome across different tissues.

Purpose: The landscape of circular RNAs (circRNAs), an important class of non-coding RNAs that regulate gene expression, has never been described in human disorders of sex chromosome aneuploidies. We profiled circRNAs in Turner syndrome females (45,X; TS) and Klinefelter syndrome males (47,XXY; KS) to investigate how circRNAs respond to a missing or an extra X chromosome. Methods: Samples of blood, muscle and fat were collected from individuals with TS (n = 33) and KS (n = 22) and from male (n = 16) and female (n = 44) controls. CircRNAs were identified using a combination of circRNA identification pipelines (CIRI2, CIRCexplorer2 and circRNA_finder). Results: Differential expression of circRNAs was observed throughout the genome in TS and KS, in all tissues. The host-genes from which several of these circRNAs were derived, were associated with known phenotypic traits. Furthermore, several differentially expressed circRNAs had the potential to capture micro RNAs that targeted protein-coding genes with altered expression in TS and KS. Conclusion: Sex chromosome aneuploidies introduce changes in the circRNA transcriptome, demonstrating that the genomic changes in these syndromes are more complex than hitherto thought. CircRNAs may help explain some of the genomic and phenotypic traits observed in these syndromes.

Oral lactate slows gastric emptying and suppresses appetite in young males.

BACKGROUND: Lactate serves as an alternative energy fuel but is also an important signaling metabolite. We aimed to investigate whether oral lactate administration affects appetite-regulating hormones, slows gastric emptying rate, and dampens appetite. METHODS: Ten healthy male volunteers were investigated on two separate occasions: 1) following oral ingestion of D/L-Na-lactate and 2) following oral ingestion of isotonic iso-voluminous NaCl and intravenous iso-lactemic D/L-Na-lactate infusions. Appetite was evaluated by questionnaires and ad libitum meal tests were performed at the end of each study day. Gastric emptying rate was evaluated using the acetaminophen test. RESULTS: Plasma concentrations of growth differential factor 15 (GDF15, primary outcome) increased following oral and iv administration of lactate (p < 0.001) with no detectable difference between interventions (p = 0.15). Oral lactate administration lowered plasma concentrations of acylated ghrelin (p = 0.02) and elevated glucagon like peptide-1 (GLP-1, p = 0.045), insulin (p < 0.001), and glucagon (p < 0.001) compared with iv administration. Oral lactate administration slowed gastric emptying (p < 0.001), increased the feeling of being "full" (p = 0.008) and lowered the "anticipated future food intake" (p = 0.007) compared with iv administration. Food intake during the ad libitum meal test did not differ between the two study days. CONCLUSION: Oral lactate administration has a direct effect on the upper gastrointestinal tract, affecting gut hormone secretion, motility and appetite sensations which cannot be mediated through lactate in the systemic circulation alone. These data suggest that compounds rich in lactate may be useful in the treatment of metabolic disease. CLINICAL TRIAL REGISTRY NUMBER: NCT0429981, https://clinicaltrials.gov/ct2/show/NCT04299815.

Ischemic heart failure mortality is not predicted by cardiac insulin resistance but by diabetes per se and coronary flow reserve: A retrospective dynamic cardiac 18F-FDG PET study.

BACKGROUND & AIMS: The connection between peripheral insulin resistance (IR) and coronary artery disease is well-established. Both are major risk factors for the development of ischemic cardiomyopathy potentially leading to heart failure (HF). Whether cardiac IR also impacts overall survival and morbidity is still debated. We therefore aimed to test if cardiac IR predicts mortality and major cardiovascular events (MACE) in patients with HF scheduled for cardiac viability testing before revascularization. METHODS: This retrospective study included 131 patients with a clinical diagnosis of ischemic HF (114 (87%) male, 33 (25%) with diabetes) referred to a viability Rubidium-82 (perfusion) and dynamic 18F-Fluorodeoxyglucose (metabolism) positron emission tomography combined with computed tomography prior to a potential revascularization procedure. Cardiac IR was assessed by myocardial glucose uptake (MGU) in a remote (non-scarred) area of the left ventricle during a hyperinsulinemic-euglycemic clamp (1mIE/kg/min). RESULTS: MGU correlated with skeletal muscle glucose uptake (p < 0.001) and whole-body glucose uptake (M-value) (p < 0.001), whereas no association was observed for individuals with diabetes. MGU did not predict the risk of death or MACE. However, both overt diabetes and reduced coronary flow reserve predicted overall survival. CONCLUSION: Even though diabetes and related small-vessel disease is associated with increased mortality, cardiac IR per se does not predict cardiovascular morbidity and mortality.

[Euglycaemic ketoacidosis induced by ketogenic diet and intermittent fastingin a non-diabetic patient].

Elevated ketone bodies are usually present in patients, who have Type 1 diabetes with ketoacidosis but may also be seen in healthy persons during long-lasting exercise, fasting or on low-carb diets. Intermittent fasting and low-carb diets are popular with people wanting to lose weight. This is a case report of a healthy 51-year-old woman, who admitted with a five-day history of abdominal pain with sudden worsening. She had recently initiated an intermittent fasting regime and followed a low-carb diet. She was diagnosed with diet-induced euglycaemic ketoacidosis, normal level of glycated haemoglobin and normal kidney function. She required isotone glucose infusions for 48 hours.

Ischemic Stroke in Adults With Congenital Heart Disease: A Population-Based Cohort Study.

Background Congenital heart disease (CHD) is associated with risk factors for ischemic stroke including cardiac arrhythmias and heart failure. However, few long-term follow-up data exist on ischemic stroke risk and associated mortality in adults with CHD. Methods and Results Using Danish nationwide registries, we identified individuals aged ≥18 years diagnosed with CHD, at any age, from 1963 to 2017 and a sex and birth year-matched (1:10) general population comparison cohort. We computed risks, as well as sex and birth year-adjusted hazard ratios (aHRs) for ischemic stroke and 30-day post-stroke mortality in CHD adults compared with the general population. Analyses were stratified according to age <60 years (young) and ≥60 years (older). We identified 16 836 adults with CHD. The risk of ischemic stroke at age 60 years was 7.4% in the CHD cohort and 2.9% in the general population cohort. The adjusted hazard ratios for ischemic stroke compared with the general population was 3.8 (95% CI: 3.3-4.3) in young CHD adults and 1.6 (95% CI: 1.4-1.9) in older CHD adults. The adjusted hazard ratios for post-stroke mortality compared with the general population was 2.3 (95% CI: 1.2-4.4) in young CHD adults and 1.3 (95% CI: 0.9-1.9) in older CHD adults. Conclusions Both younger and older CHD adults have an increased risk of ischemic stroke and by 60 years of age 7.4% of CHD adults will have had an ischemic stroke. Post-stroke mortality was also increased in CHD adults compared with the general population.