BACKGROUND:Nephrolithiasis recurs after an initial episode within 5 years for 30-50% of stone formers without dietary and/or pharmacological therapy to prevent or reduce stone recurrence. Preventive interventions target increasing urine volume or altering urinary concentration of key risk factors: high calcium, oxalate or uric acid and low urinary citrate. Two strategies for achieving stone prevention involve an untailored generalized approach (empiric therapy) and an approach tailored to results from 24 h urine testing (selective therapy). METHODS:Adults with recurrent kidney stone disease were randomly assigned to empiric (Emp) or selective (Sel) therapy upon completing 24 h urine testing. Participants in the Emp group received standard guideline-based diet and medication therapy. Participants in the Sel group received therapy tailored to their 3 most severe urine abnormalities. Within-group differences in dietary and urinary variables were assessed via the Wilcoxon test and difference between groups in changes from baseline to 8 weeks via general linear modeling. RESULTS:The Emp group had a 33% reduction in dietary oxalic acid intake (p = 0.02), but no significant changes in intakes of water, sodium, animal-based protein, or servings of fruits and vegetables. There were also no significant changes in urine volume or urinary sodium excretion. Overall, Sel participants increased daily intake of water by 17% (p = 0.02), doubled their number of daily fruit/vegetable servings (p = 0.04), and reduced their oxalate (p = 0.04) and sodium (p = 0.05) intakes. Sel participants in the urinary citrate and calcium subgroups showed greater reductions in urinary calcium oxalate supersaturation (-38%) compared to the Emp group (-30%). CONCLUSIONS:The findings suggest that a more personalized approach with a limited number of dietary targets supports improvements that are less likely to occur with empiric therapy which reflects a "one size fits all" method. However, even with tailored therapy, the inter-individual variability in dietary intake and response to treatment must be considered as adherence to dietary recommendations is particularly challenging in a condition that is lifelong. This trial was registered at clinicaltrials. gov NCT05365477.

PURPOSE:To compare a strategy using testing to guide treatment, also known as selective therapy, with a strategy of initiating interventions without testing, termed empiric therapy, on urinary supersaturation of calcium oxalate and calcium phosphate. MATERIALS AND METHODS:In this single-center trial, adult individuals with recurrent idiopathic calcium stone disease were randomized to either an empiric or selective strategy. Participants received 24-hour urine testing at baseline, 4 weeks, and 8 weeks. Treatment in the empiric arm comprised dietary and fluid counseling and pharmacologic treatment with indapamide and potassium citrate irrespective of 24-hour urine results. For the selective arm, diet, and pharmacologic treatments, which included indapamide, potassium citrate, and/or allopurinol, were tailored based on urine testing at baseline and 4 weeks. The primary outcome was urinary supersaturation of calcium oxalate and calcium phosphate at 8 weeks. RESULTS:The analytic sample included 56 participants (mean [SD] age, 44.5 [13.2] years; 30 women [54%]), with 29 randomized to the empiric and 27 to the selective groups. At week 8, there were no significant differences comparing the empiric and selective arms with respect to mean [SD] urinary supersaturation of calcium oxalate (4.7 [2.9] vs 5.0 [2.9], respectively, P = .81) or calcium phosphate (1.3 [0.9] vs 1.4 [1.1], respectively, P = .58). Similarly, there were no significant differences at 8 weeks in urine volume and pH or in excretion of calcium, oxalate, citrate, uric acid, and sodium. CONCLUSIONS:In this short-term trial among individuals at high risk for stone recurrence, there was no statistically significant difference in the urinary stone risk comparing an empiric vs selective strategy for kidney stone prevention.

Abstract Background The electronic health record (EHR) provides an opportunity for extracting a wealth of up-to-date real-world longitudinal data. Although the main limitations of using EHR data have been well-recognized and well-described, under-recognized factors may threaten the reliability of inferences made regarding the impact of EHR variables on chronic disease outcomes. A problem not well-recognized is the impact of routinely acquired variables that are documented with every patient encounter regardless of the reason for the encounter such as vital signs, height, and body weight. Methods We utilized a landmark approach to identify occurrence of 10 cardiovascular-related disease outcomes after a 5-year observation period during which all body weights recorded in the EHR were used in multivariate cox regression modeling to identify the strongest of 9 weight-based predictor variables for each of the 10 disease outcomes. Results We found that the number of recorded weights, as an independent variable, was the strongest predictor for all 10 cardiovascular-related disease outcomes when compared to all other weight-based variables (lowest weight, highest weight, average weight, last weight, absolute weight change, maximum weight change, weight fluctuation, and weight cycling) as well as BMI. The findings demonstrate the importance of recognizing and accounting for the number of times a more frequently measured clinical variable, such as body weight, is recorded as it is critical to determine the true impact of other similar variables on disease outcomes when conducting longitudinal analysis of EHR data.

Abstract:The rs6923761 (Gly168Ser) missense variant in the glucagon-like peptide-1 receptor (GLP-1R) has been associated with favorable anthropometric and metabolic parameters in individuals with obesity but decreased responsiveness to incretin-based therapies. Here, we performed a pre-specified analysis of a randomized-controlled trial in individuals with obesity and pre-diabetes comparing treatment with the GLP-1R agonist liraglutide, the dipeptidyl peptidase 4 inhibitor sitagliptin or hypocaloric diet, and evaluated the effects of the rs6923761 variant on outcomes. We found significantly greater weight loss to liraglutide with each copy of the variant allele present, indicating a gene dose effect. In addition, individuals with the variant allele exhibited a significant reduction in the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 after liraglutide treatment. There was no effect of genotype on fasting glucose after liraglutide treatment, yet individuals with the variant allele exhibited decreased responsiveness to liraglutide and hypocaloric diet in measurements of fasting insulin, C-peptide, glucagon, and HOMA-IR. In conclusion, we found that the GLP-1R rs6923761 variant exerts a dual impact on liraglutide efficacy-enhancing weight loss while diminishing metabolic benefits. The observed associations could be consistent with the constitutive activation of the GLP-1R in the presence of this variant with reduced activation/signaling in response to pharmacologic agents, a pattern that has been observed with the rs10305492 variant in animal models. Future studies are needed to investigate the molecular mechanisms of associations with the rs6923761 variant.

AIMS:To evaluate changes in dietary intake following liraglutide treatment, compared to dietitian-supported caloric restriction and a weight-neutral control, and to assess dietary intake against nutrition recommendations. MATERIALS AND METHODS:Participants with obesity and prediabetes were randomly assigned 2:1:1 to liraglutide (1.8 mg/day), dietitian-supported caloric restriction (-390 kcals/day) or dipeptidyl peptidase-4 inhibitor (100 mg/day) for 14 weeks. Dietary intake was assessed via a single 24-h dietary recall pre- and postintervention. Within-group changes and between-group differences in macronutrient and micronutrient intake, diet quality and food sources were evaluated, and the proportion of participants meeting nutrition recommendations was calculated. RESULTS:Seventy participants (69% female, 83% white) were included. Average age was 49.4 ± 11.3 years, and mean BMI was 39.5 ± 6.1 kg/m2. Significant differences in change in percent calories from protein (p = 0.037), carbohydrates (p = 0.019) and added sugar (p = 0.002) were observed across groups, with those in the caloric restriction group having the greatest increase in protein and decreases in carbohydrates and added sugar. Micronutrient intake did not significantly differ between groups nor did Total Healthy Eating Index (HEI)-2020 scores. However, the caloric restriction group significantly improved their HEI component score for added sugar compared to the liraglutide group (p = 0.002) when adjusted for baseline intake. Despite the treatment group, participants failed to meet several of the same nutrition recommendations, including those for fruit, vegetable and dairy intake. CONCLUSIONS:Overall diet quality was poor across all groups. However, the caloric restriction group significantly reduced its added sugar intake, highlighting a potential benefit nutrition counselling may have for AOM users. Future research is needed to examine the long-term impact of AOM use on dietary intake, with and without nutrition guidance, to better inform clinical recommendations.

Context Repetitive bouts of weight loss and regain, termed weight cycling, may exaggerate the risk for cardiometabolic disease. We previously identified that weight cyclers were likely to have prescribed medications for hypertension, dyslipidemia, and diabetes-suggesting a high prevalence of cardiometabolic disease.Objective No prior study has compared relationships between longitudinal weight trajectory (weight stable, weight gainer, weight loser, or weight cycler) and commonly occurring specific cardiometabolic diseases among persons with similar high baseline body mass index (BMI).Methods Using de-identified electronic health record data from all adults treated at Vanderbilt University Medical Center between 1997 to 2020 and a landmark approach, we developed multivariate Cox proportional hazards regression models to determine relationships between weight trajectory and risk for 10 highly prevalent cardiometabolic diseases.Results Compared to weight stability, weight cycling associated with an almost 30% increased risk for obstructive sleep apnea [hazard ratio (HR) 1.28; 95% confidence interval (CI) 1.15-1.42], metabolic dysfunction-associated steatotic liver disease (HR 1.28; 95% CI 1.08-1.51), and type 2 diabetes (HR 1.23; 95% CI 1.10-1.38). Weight cycling also associated with a more than 50% increased risk for heart failure (HR 1.54; 95% CI 1.31-1.82), although both weight gain and weight loss also showed increased risk for heart failure (HR 1.29; 95% CI 1.08-1.55 and HR 1.32; 95% CI 1.10-1.58, respectively).Conclusion The relationship between weight cycling and cardiometabolic disease risk was independent of having high baseline BMI, which was similar among weight trajectory groups. The present findings support promoting either weight stability at high BMI or weight loss if able to be maintained to prevent the incidence of a variety of cardiometabolic diseases.

Background The effect of recent onset metabolic dysfunction on coronary artery disease (CAD) risk is poorly understood. We developed a large data set linking metabolic phenotypes and clinical outcomes to quantify CAD risks associated with adverse metabolic transition. Methods Clinical parameters, measures of metabolic dysfunction components (diabetes, hypertension, elevated triglycerides, and low high‐density lipoprotein) and incident CAD were curated in a clinical cohort from a single quaternary medical center. Associations between body weight, metabolic abnormalities, and changes in metabolic health status were assessed for prevalent and incident CAD. Results Increasing body mass index category, presence of metabolic dysfunction (>2 components), and number of metabolic abnormalities were associated with prevalent CAD among 844 841 individuals. In time‐to‐event analyses (N=69 272), ~38% of subjects initially free of any metabolic dysfunction abnormality developed ≥1 abnormality over a 3‐year run‐in period. All metabolic abnormalities, whether new‐onset or preexisting, significantly increased 10‐year CAD event probability, and there was a progressive increase in 10‐year CAD risk with increasing burden of metabolic abnormalities. In models adjusting for metabolic dysfunction, 10‐year CAD risk increased for individuals with body mass index >25 kg/m2 (hazard ratio, 3.8). Compared with individuals with a body mass index of 25 kg/m2, any short‐term weight gain or loss of >5% increased or decreased CAD risk, respectively, in individuals with a body mass index of 35 kg/m2. Conclusions In a large clinical cohort, the transition to metabolic dysfunction is common, occurs rapidly, and significantly increases incident CAD risk. The effect of body weight and weight loss on CAD risk is nonlinear. Interventions to prevent progression to metabolic dysfunction are needed.

BACKGROUND AND AIMS:The prevalence of metabolic syndrome has been increasing in young adults, concomitant with the occurrence of increased abdominal adiposity. We previously reported that consuming tree nuts, as replacement for typical high-carbohydrate snacks, reduces visceral fat and waist circumference in young adults who have one or more metabolic syndrome risk factors. We aimed to investigate the effects of tree nuts snack consumption on plasma and adipose tissue fatty acid profiles along with changes in the expression of adipose tissue genes involved in thermogenesis, glycemia, adipocyte signaling, lipolysis, and immunity. METHODS:A randomized parallel-arm 16-week intervention trial was conducted in 84 adults aged 22-36 years. Participants in both groups were provided with caloric goals for weight maintenance, daily menus, and pre-portioned snacks at every other week visits with study registered dietitians. Changes in dietary fatty acid intakes, plasma and abdominal subcutaneous adipose tissue (SAT) triglycerides fatty acid profiles using gas-liquid chromatography, and the expression of 241 genes in abdominal SAT were evaluated. RESULTS:Consuming tree nuts snacks increased mono- and polyunsaturated fatty acid intakes yielding a 9-fold greater dietary unsaturated to saturated fat ratio. The tree nuts snack group also had significantly greater improvements in plasma 16:1/16:0 ratio; plasma phospholipids oleic and gamma linolenic acid content; plasma diglycerides, triglycerides, and cholesterol esters oleic acid content; and total plasma monounsaturated fatty acids. While abdominal SAT only showed trends for increased oleic acid content and unsaturated to saturated fat ratio, the tree nuts snacks participants had altered expression of 13 genes in abdominal SAT that have roles in nutrient sensing, energy homeostasis, and vulnerability to obesity. CONCLUSIONS:Replacing typical high-carbohydrate snacks with tree nuts results in more favorable dietary, plasma, and adipose tissue fatty acid profiles that could aid in preventing the development of excess adiposity and cardiometabolic disease states including metabolic syndrome. CLINICAL TRIAL REGISTRY:This trial was registered at clinicaltrials.gov NCT03969264.

HIV and obesity are conditions of impaired lipid storage where ectopic lipid accumulates in organs and tissues, promoting glucose intolerance and insulin resistance. Persons with HIV (PWH) are at high risk for diabetes, and one indicator of risk is the density of organs and tissues involved in glucose metabolism, which reflects ectopic lipid content and can be quantified using CT-tissue attenuation. We investigated relationships between subcutaneous adipose (SAT), visceral adipose (VAT), liver, pancreas, and skeletal muscle densities with biomarkers of glycemic/insulinemic status. Demographic, anthropometric, and clinical data were utilized with automated segmentation of CT morphometric data from images acquired at the 3rd lumbar vertebra level in PWH who had normoglycemia, prediabetes, and T2DM. Of 217 PWH, 29.0% had prediabetes and 30.4% had T2DM. Liver, pancreas, and skeletal muscle densities were lower, and SAT density was higher, in PWH with T2DM. No differences were observed for VAT density. Receiver operating curves adjusted for age, sex and BMI showed tissue densities had similar ability to discriminate glycemic/insulinemic status. Adjusted multivariable logistic regression showed higher SAT density associated with higher glucose (p = 0.002), HbA1c (p < 0.001), and diabetes status (p < 0.001). Lower liver density is associated with diabetes status (p = 0.007) and higher HbA1c (p = 0.03), whereas lower skeletal muscle density is associated with higher glucose (p = 0.03) and insulin (p = 0.04). Tissue densities, which differed significantly among the three groups, were robustly associated with various biomarkers of glycemic/insulinemic status. CT-morphometrics may enhance the detection of metabolic perturbations and diabetes risk, possibly earlier than some clinical biomarkers.

Background: Daily energy intake from snacking behaviors has increased over the past few decades, during which the prevalence of obesity and metabolic syndrome has risen to epidemic proportions. There remains considerable room for improvement in the overall quality of dietary intakes of the U.S. population when compared to national recommendations. Food cravings may contribute to the types of snacks chosen for consumption, and thus, the frequency of foods and food groups consumed, and the overall nutritional quality of the diet. Methods: Eighty-four young (28.5 ± 4.3 years) adults with at least one metabolic syndrome risk factor participated in a parallel-arm single-blind randomized trial designed to compare effects of consuming a mix of tree nuts versus typical high-carbohydrate food items as between-meal snacks for 16 weeks. Cravings for 28 common foods via the Food Craving Inventory, short-term dietary intakes via 24 h multi-pass methodology, food group frequency via the Rapid Eating Assessment for Participants, usual hunger and fullness via visual analog scales, appetite-regulating hormones, and diet quality via the Healthy Eating Index—2015 were measured at baseline and end of study. Results: Participants in the TNsnack group had significant decreases in cravings for high sweet items and fast-food items, which were associated with decreased frequency of desserts and salty foods along with increased intake of higher protein items. In contrast, no significant reductions in food cravings or preference for sweets were observed in the CHOsnack group. Decreased cravings for sweets by TNsnack participants were associated with increased total GLP-1 levels: cake (r = −0.35, p = 0.03), brownies (r = −0.44, p = 0.02), candy (r = −0.36, p = 0.03) and ice cream (r = −0.33, p = 0.04). Overall, the total diet quality score improved by 19% among TNsnack participants. Conclusions: Replacing more typical between-meal snacks with tree nuts may reduce food cravings, particularly for sweeter food items that are likely to be nutrient poor and energy dense. By reducing cravings and frequency of intake, consuming tree nuts as snacks could facilitate having a higher quality, more nutrient-dense diet and mitigate potential negative effects of snacking on metabolic health in young adults.

A comprehensive analytical strategy for multiomics analysis of dried blood spots (DBS) has been developed, featuring prespotted stable isotope internal standards (SIIS) for enhanced quantitation. The method combines an optimized Folch extraction protocol for dried plasma spots with high-resolution mass spectrometry analysis using a Thermo Q Exactive Orbitrap mass spectrometer coupled to a Dionex Ultimate 3000 ultrahigh performance liquid chromatography system. This internal quantitative DBS approach addresses key analytical challenges in microsampling applications through strategic incorporation of SIIS directly into the sampling matrix, enabling reliable normalization with improved extraction efficiency. The analytical workflow successfully integrates the simultaneous analysis of metabolites and lipids, demonstrating broad molecular coverage from minimal sample volumes in the microliter range. Method applicability was demonstrated using fasting plasma samples from a cohort of persons with HIV, revealing distinct molecular profiles between diabetic and nondiabetic participants, with hundreds of metabolites and thousands of lipids identified. The analytical platform leverages the inherent advantages of DBS, including simplified sample collection, enhanced stability during storage, and reduced biohazard risk during transportation. This methodology represents a significant advancement in quantitative DBS analysis, particularly valuable for large-scale clinical studies where conventional biobanking presents logistical challenges. The integration of SIIS into the microsampling device establishes a robust foundation for reliable multiomics analysis in resource-limited settings where whole blood or plasma storage is infeasible.

Our recent study showed weight cycled mice have increased adipose mast cells compared to obese mice by single cell RNA-sequencing. Here, we aimed to confirm and elucidate these changes. Further analysis of our dataset showed that our initial mast cell cluster could subcluster into two unique populations: one with very high expression of classical mast cell markers and another with elevated lipid handling and antigen presentation genes. This new mast cell cluster accounted for most of the mast cells in the weight cycled group although it was not possible to detect the different populations by new studies with flow cytometry or Toluidine blue staining in mice, possibly due to a downregulation in classical mast cell genes. Interestingly, a pilot study in humans did suggest the existence of two mast cell populations in subcutaneous adipose tissue from obese women that appear similar to the murine populations detected by sequencing; one of which was significantly correlated with weight variance. Together, these data suggest that weight cycling may induce a unique population of mast cells similar to lipid associated macrophages. Future studies will focus on isolation of these cells to better determine their lineage, differentiation, and functional roles.

OBJECTIVES:Skeletal muscle fat infiltration (myosteatosis) is a clinical condition distinct from visceral and hepatic lipid accumulation and contributes to metabolic dysregulation, sarcopenia, and frailty in people with HIV (PWH). Altered subcutaneous adipose tissue (SAT) function contributes to visceral fat deposition and hepatic steatosis, but there are few data on SAT gene expression and myosteatosis in PWH on long-term antiretroviral therapy (ART). DESIGN:A longitudinal analysis of 40 PWH on contemporary ART with sustained viral suppression to assess relationships between SAT gene transcripts and computed tomography (CT) imaging of skeletal muscle density, where lower density indicates higher lipid content, and area. CT imaging also measured other fat depots, including visceral adipose tissue (VAT) volume and liver density. METHODS:SAT gene transcripts were quantified using a NanoString panel of 255 immune and 77 adipocyte-related genes. Linear mixed-effects models assessed baseline SAT gene expression and changes in skeletal muscle over a median of 3.3 years. RESULTS:Decreasing skeletal muscle density over time correlated with increasing VAT volume and declining liver density. Gene-by-visit interaction revealed 34 SAT genes associated with muscle density change and 15 genes associated with muscle area change. Two key CCR4-binding chemokines, CCL17 and CCL22, were linked to reductions in both muscle density and area. CONCLUSION:A subset of SAT gene transcripts is associated with changes in skeletal muscle density and area over time, suggesting interventions to modulate SAT immune activity or improve lipid handling may hold therapeutic potential to slow the progression of myosteatosis and sarcopenia in PWH.

BACKGROUND:Persons with human immunodeficiency virus (HIV) on long-term antiretroviral therapy (ART) have exaggerated accumulation of ectopic fat and cardiometabolic disease risk. OBJECTIVES:The objective of this study was to characterize longitudinal changes in habitual diet and macronutrient oxidation in relation to changes in abdominal adipose tissue and ectopic fat sites using magnetic resonance and computed tomography imaging. METHODS:A prospective cohort of 49 males with HIV had comprehensive assessments at baseline, 52 wk (year 1), and 104 wk (year 2). Linear mixed effects models accounted for the correlation structure in the data and estimated effects over time. Fixed effects included baseline value of the outcome, age, body mass index [BMI (in kg/m2)], time since HIV diagnosis, and duration of ART. RESULTS:The consumption of simple carbohydrates decreased over time (total and added sugars, P = 0.03) concomitant with increased ratio of fatty acid to carbohydrate oxidation (P = 0.01). The amount of abdominal subcutaneous adipose tissue decreased 15% (P < 0.0001), and the amount of visceral adipose tissue (VAT) decreased 7% (P = 0.009) simultaneously with improved subcutaneous adipose tissue and VAT densities. Improvement in VAT density is associated with reduced fat fraction of the liver (r = -0.28, P = 0.04) and thighs (r = -0.41, P = 0.03), indicating overall reduced ectopic fat accumulation. However, pancreas density decreased (P = 0.03), and no statistically significant change was observed in skeletal muscle density (P = 0.16), suggesting tissue-specific impacts. CONCLUSIONS:These findings support the relationship between dietary carbohydrate intake, fat oxidation rate, and fat mobilization to reduce ectopic lipid deposition in persons with HIV. Although modest changes in dietary intakes show potential for improving metabolic flexibility and body composition among individuals on long-term ART, some organs and tissues may not respond in tandem with other depots of ectopic fat.

OBJECTIVE:The accumulation of excess lipids within skeletal muscle, which can progress to overt myosteatosis, is more common among persons with HIV (PWH) and contributes to the development of frailty, impaired mobility, and metabolic dysregulation. Excess free fatty acids (FFA) can impair muscle mitochondrial function, which is reflected in higher plasma levels of several acylcarnitines. We assessed the relationship between CT-determined skeletal muscle density and plasma acylcarnitines among male PWH on long-term antiretroviral therapy. DESIGN:Cross-sectional analysis of two prospectively recruited clinical cohorts with harmonized study procedures and imaging. METHODS:Linear regression models assessed the relationship of fasting plasma acylcarnitines measured by liquid chromatography/mass spectrometry and skeletal muscle density measured by CT, adjusted for study cohort, age, body mass index (BMI), CD4 + cell count, visceral adipose tissue area, total plasma triglycerides, and insulin resistance. RESULTS:Among 160 male PWH (median age 54 years, median BMI 30.5 kg/m 2 , and 41% Black), higher plasma levels of short-chain acetylcarnitine (C2 : 0) and isobutyrylcarnitine (C4 : 0), the medium chain hexanoylcarnitine (C6 : 1), and the long chain myristoylcarnitine (C14 : 0) and palmitoylcarnitine (C16 : 0) were associated with skeletal muscle density, while others approached significance. None of the C3 and C5 acylcarnitines, largely the products of branched-chain amino acid metabolism, were associated with skeletal muscle density. CONCLUSIONS:CT measurements of skeletal muscle density in male PWH appear to identify impaired mitochondrial FFA oxidation as measured by plasma FFA metabolites, which could serve as a biomarker for future intervention studies to mitigate skeletal muscle deterioration and metabolic dysregulation.

Heart failure is a prevalent disease worldwide. While it is well accepted that heart failure involves changes in myocardial energetics, what alterations that occur in fatty acid oxidation and glucose oxidation in the failing heart remains controversial. The goal of the study are to define the energy metabolic profile in heart failure induced by obesity and hypertension in aged female mice, and to attempt to lessen the severity of heart failure by stimulating myocardial glucose oxidation. 13-Month-old C57BL/6 female mice were subjected to 10 weeks of a 60

Metabolic effects of glucagon-like peptide-1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We tested the hypothesis that GLP-1 receptor (GLP-1R) agonists exert weight loss-independent, GLP-1R-dependent effects that differ from effects of increasing endogenous GLP-1. Individuals with obesity and pre-diabetes were randomized to 14 weeks of the GLP-1R agonist liraglutide, hypocaloric diet, or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin. The GLP-1R antagonist exendin (9-39) and placebo were administered in a two-by-two crossover study during mixed meal tests. Liraglutide and diet, but not sitagliptin, caused weight loss. Liraglutide improved insulin sensitivity measured by HOMA-IR, HOMA2 and the Matsuda index after two weeks, prior to weight loss. Liraglutide decreased fasting and post-prandial glucose, decreased insulin and C-peptide, and decreased fasting glucagon. In contrast, diet-induced weight loss improved insulin sensitivity by HOMA-IR and HOMA2, but not Matsuda index, and did not decrease glucose. Sitagliptin increased endogenous GLP-1 and GIP without altering insulin sensitivity or fasting glucose, but decreased post-prandial glucose and glucagon. Notably, sitagliptin increased GIP without altering weight. Acute GLP-1R antagonism increased glucose in all groups, increased Matsuda index and fasting glucagon during liraglutide, and increased endogenous GLP-1 during liraglutide and sitagliptin. Thus, liraglutide exerts rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity that are not achieved by increasing endogenous GLP-1.

Heart failure with preserved ejection fraction (HFpEF) is a major health problem with limited treatment options. Although optimizing cardiac energy metabolism is a potential approach to treating heart failure, it is poorly understood what alterations in cardiac energy metabolism actually occur in HFpEF. To determine this, we used mice in which HFpEF was induced using an obesity and hypertension HFpEF protocol for 10 weeks. Next, carvedilol, a third-generation β-blocker and a biased agonist that exhibits agonist-like effects through β arrestins by activating extracellular signal-regulated kinase, was used to decrease one of these parameters, namely hypertension. Heart function was evaluated by invasive pressure-volume loops and echocardiography as well as by ex vivo working heart perfusions. Glycolysis and oxidation rates of glucose, fatty acids, and ketones were measured in the isolated working hearts. The development of HFpEF was associated with a dramatic decrease in cardiac glucose oxidation rates, with a parallel increase in palmitate oxidation rates. Carvedilol treatment decreased the development of HFpEF but had no major effect on cardiac energy substrate metabolism. Carvedilol treatment did increase the expression of cardiac β arrestin 2 and proteins involved in mitochondrial biogenesis. Decreasing bodyweight in obese HFpEF mice increased glucose oxidation and improved heart function. This suggests that the dramatic energy metabolic changes in HFpEF mice hearts are primarily due to the obesity component of the HFpEF model. SIGNIFICANCE STATEMENT: Metabolic inflexibility occurs in heart failure with preserved ejection fraction (HFpEF) mice hearts. Lowering blood pressure improves heart function in HFpEF mice with no major effect on energy metabolism. Between hypertension and obesity, the latter appears to have the major role in HFpEF cardiac energetic changes. Carvedilol increases mitochondrial biogenesis and overall energy expenditure in HFpEF hearts.

AIMS:Heart failure with preserved ejection fraction (HFpEF) is a prevalent disease worldwide. While it is well established that alterations of cardiac energy metabolism contribute to cardiovascular pathology, the precise source of fuel used by the heart in HFpEF remains unclear. The objective of this study was to define the energy metabolic profile of the heart in HFpEF. METHODS AND RESULTS:Eight-week-old C57BL/6 male mice were subjected to a '2-Hit' HFpEF protocol [60% high-fat diet (HFD) + 0.5 g/L of Nω-nitro-L-arginine methyl ester]. Echocardiography and pressure-volume loop analysis were used for assessing cardiac function and cardiac haemodynamics, respectively. Isolated working hearts were perfused with radiolabelled energy substrates to directly measure rates of fatty acid oxidation, glucose oxidation, ketone oxidation, and glycolysis. HFpEF mice exhibited increased body weight, glucose intolerance, elevated blood pressure, diastolic dysfunction, and cardiac hypertrophy. In HFpEF hearts, insulin stimulation of glucose oxidation was significantly suppressed. This was paralleled by an increase in fatty acid oxidation rates, while cardiac ketone oxidation and glycolysis rates were comparable with healthy control hearts. The balance between glucose and fatty acid oxidation contributing to overall adenosine triphosphate (ATP) production was disrupted, where HFpEF hearts were more reliant on fatty acid as the major source of fuel for ATP production, compensating for the decrease of ATP originating from glucose oxidation. Additionally, phosphorylated pyruvate dehydrogenase levels decreased in both HFpEF mice and human patient's heart samples. CONCLUSION:In HFpEF, fatty acid oxidation dominates as the major source of cardiac ATP production at the expense of insulin-stimulated glucose oxidation.

BACKGROUND AND AIMS:The cardiometabolic disease-associated metabolite, alpha-aminoadipic acid (2-AAA) is formed from the breakdown of the essential dietary amino acid lysine. However, it was not known whether elevated plasma levels of 2-AAA are related to dietary nutrient intake. We aimed to determine whether diet is a determinant of circulating 2-AAA in healthy individuals, and whether 2-AAA is altered in response to dietary modification. METHODS AND RESULTS:We investigated the association between 2-AAA and dietary nutrient intake in a cross-sectional study of healthy individuals (N = 254). We then performed a randomized cross-over dietary intervention trial to investigate the effect of lysine supplementation (1 week) on 2-AAA in healthy individuals (N = 40). We further assessed the effect of a vegetarian diet on 2-AAA in a short-term (4-day) dietary intervention trial in healthy omnivorous women (N = 35). We found that self-reported dietary intake of animal products, including meat, poultry, and seafood, was associated with higher plasma 2-AAA cross-sectionally (P < 0.0001). Supplementary dietary lysine (5g/day) caused no significant increase in plasma 2-AAA; however, plasma 2-AAA was altered by general dietary modification. Further, plasma 2-AAA was significantly reduced by a short-term vegetarian diet (P = 0.003). CONCLUSION:We identified associations between plasma 2-AAA and consumption of animal products, which were validated in a vegetarian dietary intervention trial, but not in a trial designed to specifically increase the 2-AAA amino acid precursor lysine. Further studies are warranted to investigate whether implementation of a vegetarian diet improves cardiometabolic risk in individuals with elevated 2-AAA.