Nutritional and metabolic regulation of the metabolite dimethylguanidino valeric acid: an early marker of cardiometabolic disease.

Dimethylguanidino valeric acid (DMGV) is a marker of fatty liver disease, incident coronary artery disease, cardiovascular mortality, and incident diabetes. Recently, it was reported that circulating DMGV levels correlated positively with consumption of sugary beverages and negatively with intake of fruits and vegetables in three Swedish community-based cohorts. Here, we validate these results in the Framingham Heart Study Third Generation Cohort. Furthermore, in mice, diets rich in sucrose or fat significantly increased plasma DMGV concentrations. DMGV is the product of metabolism of asymmetric dimethylarginine (ADMA) by the hepatic enzyme AGXT2. ADMA can also be metabolized to citrulline by the cytoplasmic enzyme DDAH1. We report that a high-sucrose diet induced conversion of ADMA exclusively into DMGV (supporting the relationship with sugary beverage intake in humans), while a high-fat diet promoted conversion of ADMA to both DMGV and citrulline. On the contrary, replacing dietary native starch with high-fiber-resistant starch increased ADMA concentrations and induced its conversion to citrulline, without altering DMGV concentrations. In a cohort of obese nondiabetic adults, circulating DMGV concentrations increased and ADMA levels decreased in those with either liver or muscle insulin resistance. This was similar to changes in DMGV and ADMA concentrations found in mice fed a high-sucrose diet. Sucrose is a disaccharide of glucose and fructose. Compared with glucose, incubation of hepatocytes with fructose significantly increased DMGV production. Overall, we provide a comprehensive picture of the dietary determinants of DMGV levels and association with insulin resistance.

Point-of-care NT-proBNP monitoring for heart failure: observational feasibility study in primary care.

BACKGROUND: Around one million individuals in the UK have heart failure (HF), a chronic disease that causes significant morbidity and mortality. N-terminal pro-B-type natriuretic peptide (NT-proBNP) monitoring could help improve the care of patients with HF in the community. AIM: The aim of this study is to provide evidence to support the routine use of point-of-care (POC) NT-proBNP monitoring in primary care. DESIGN & SETTING: In this observational cohort study, the Roche Cobas h 232 POC device was used to measure NT-proBNP in 27 patients with HF at 0, 6, and 12 months, with a subset reanalysed in the laboratory for comparison. METHOD: Data were analysed for within-person and between-person variability and concordance with laboratory readings using Passing-Bablok regression. GPs reported whether POC results impacted clinical decisionmaking, and patients indicated their willingness to participate in long-term cohort studies using the Likert acceptability scale. RESULTS: Within-person variability in POC NT-proBNP over 12 months was 881 pg/mL (95% confidence interval [CI] = 380 to 1382 pg/mL). Between-person variability was 1972 pg/mL (95% CI = 1,525 to 2791 pg/mL). Passing-Bablok regression showed no significant systematic difference between POC and laboratory measurements. Patients indicated a high level of acceptability, and GP decisionmaking was affected for at least one visit in a third of patients. CONCLUSION: Within-person variability in POC NT-proBNP is around half of between-person variability, so detecting changes could be of use in HF management. High patient acceptability and impact on clinical decisionmaking warrant further investigation in a larger long-term cohort study.

National and regional registries for congenital heart diseases: Strengths, weaknesses and opportunities.

BACKGROUND: We aim to establish a new and informative bi-national Registry for Congenital Heart Disease (CHD) patients in Australia and New Zealand, to document the burden of disease and clinical outcomes for patients with CHDs across the lifespan. When planning for the implementation of this Registry, we sought to evaluate the strengths and weaknesses of existing national and large regional CHD databases. METHODS: We characterised 15 large multi-institutional databases of pediatric and/or adult patients with CHD, documenting the richness of their datasets, the ease of linkage to other databases, the coverage of the target cohort and the strategies utilised for quality control. RESULTS: The best databases contained demographic, clinical, physical, laboratory and patient-reported data, and were linked at least to the national/regional death registry. They also employed automatic data verification and regular manual audits. Coverage ranged from around 25% of all eligible CHD cases for larger databases to near 100% for some smaller registries of patients with specific CHD lesions, such as the Australia and New Zealand Fontan Registry. CONCLUSIONS: Existing national and regional CHD databases have strengths and weaknesses; few combine complete coverage with high quality and regularly audited data, across the broad range of CHDs.

Deletion of the diabetes candidate gene Slc16a13 in mice attenuates diet-induced ectopic lipid accumulation and insulin resistance.

Genome-wide association studies have identified SLC16A13 as a novel susceptibility gene for type 2 diabetes. The SLC16A13 gene encodes SLC16A13/MCT13, a member of the solute carrier 16 family of monocarboxylate transporters. Despite its potential importance to diabetes development, the physiological function of SLC16A13 is unknown. Here, we validate Slc16a13 as a lactate transporter expressed at the plasma membrane and report on the effect of Slc16a13 deletion in a mouse model. We show that Slc16a13 increases mitochondrial respiration in the liver, leading to reduced hepatic lipid accumulation and increased hepatic insulin sensitivity in high-fat diet fed Slc16a13 knockout mice. We propose a mechanism for improved hepatic insulin sensitivity in the context of Slc16a13 deficiency in which reduced intrahepatocellular lactate availability drives increased AMPK activation and increased mitochondrial respiration, while reducing hepatic lipid content. Slc16a13 deficiency thereby attenuates hepatic diacylglycerol-PKCε mediated insulin resistance in obese mice. Together, these data suggest that SLC16A13 is a potential target for the treatment of type 2 diabetes and non-alcoholic fatty liver disease.

µ-Opioid and dopamine-D2 receptor expression in the nucleus accumbens of male Sprague-Dawley rats whose sucrose consumption, but not preference, decreases after nerve injury.

Functional-anatomical changes in reward related brain circuits are described in chronic pain patients who report anhedonia or depressed mood. In pre-clinical rodent models of neuropathic pain there are varying reports of the effects of nerve injury on the motivation to consume sucrose, although hedonic responses to sucrose appear unchanged. These observations are derived from brief periods of exposure to sucrose. When sucrose is available ad libitum over a period of 21 days, there are marked individual differences in consumption. The motivation for, and hedonic experience of, drinking sucrose is mediated in part by dopamine-D2 and µ-opioid receptors in the nucleus accumbens (NAc). This study investigated the effects of chronic constriction injury (CCI) on ad libitum sucrose consumption in male Sprague Dawley rats and the expression of accumbal dopamine D2 and µ-opioid receptors. Nerve injury reduced sucrose drinking predominantly in rats with the highest pre-injury consumption levels. Despite these reductions in consumption, sucrose preferences were stable. In the NAc of rats whose sucrose consumption was affected by CCI, immunohistochemical analyses revealed bilateral reductions of dopamine D2-receptor expression in the core and shell; and a lateralised reduction of µ-opioid receptor expression in the core and dorsomedial shell of the right NAc. These alterations in receptor expression are located in regions which have been identified as hedonic hot and coldspots along an affective-motivational keyboard which directs behaviours either towards, or away from salient stimuli. These changes likely underlie the reduction in sucrose consumption observed in a subgroup of rats following nerve injury.