Accumulating data from several large, placebo-controlled studies suggests that sodium-glucose transporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 receptor (GLP-1) receptor agonists offer therapeutic benefits in the management of cardiovascular diseases, regardless of the patient’s diabetic status. In addition to their effects on glucose excretion, SGLT2 inhibitors have a positive impact on systemic metabolism. The aim of this study was to establish a non-invasive preclinical model of metabolic syndrome (MetS) to investigate the effects of novel antidiabetic therapies beyond glucose reduction, independent of obesity. Eighteen healthy adult Beagle dogs were fed an isocaloric Western diet (WD) for ten weeks. Biospecimens were collected at baseline (BAS1) and after ten weeks of WD feeding (BAS2) for measurement of blood pressure (BP), serum chemistry, lipoprotein profiling, fasting blood glucose, glucagon, insulin, NT-proBNP, BUN, creatinine, angiotensins, oxidative stress biomarkers, serum, urine and fecal metabolomics. Differences between BAS1 and BAS2 were analyzed using non-parametric Wilcoxon signed-rank testing with continuity correction. The isocaloric WD model induced significant variations in several markers of MetS, including elevated BP, increased glucose levels, and reduced HDL-cholesterol. It also caused an increase in circulating NT-proBNP levels, a decrease in serum bicarbonate levels, and significant changes in general metabolism, lipids, and biogenic amines. Short-term, isocaloric feeding with a WD in dogs replicates key biological features of MetS while also causing low-grade metabolic acidosis and elevating natriuretic peptides. These findings support the use of the WD canine model for studying the metabolic effects of new antidiabetic therapies independent of obesity.

Objective To quantify the inter-dependency between maternal metabolic risk factors and their association with birthweight and cord blood insulin (CBI) level. Design Prospective cohort study. Setting Guangzhou Women and Children’s Medical Centre (GWCMC). Population Pregnant women with a singleton pregnancy who delivered at GWCMC between Jan 2015 and Jun 2016 and had umbilical cord blood retained (total 1522). Methods Multivariable linear regression and Additive Bayesian Network analysis were used to investigate the association between maternal metabolic risk factors (pre-pregnancy body mass index [BMI], fasting glucose, lipid profiles, and early gestational weight gain [GWG]) and their interdependency in predicting birthweight and CBI concentrations. Main outcome measures Birthweight and cord blood insulin. Results High maternal pre-pregnancy BMI was strongly associated with neonatal birthweight (standardized adjusted regression coefficient [βstd] = 0.27, 95%CI 0.22-0.32) directly; and with CBI indirectly. Maternal fasting glucose was positively associated with increased CBI (βstd=0.12, 95%CI 0.07-0.17). Maternal GWG was positively associated with increased birthweight, but not with CBI. None of the maternal lipids profile was independently associated with birthweight or CBI. Conclusions Maternal pre-pregnancy overweight/obesity is the most influential upstream metabolic risk factor for both maternal and neonatal metabolic health, therefore weight management should be addressed from the preconception period. Maternal dyslipidaemia appears to be secondary to maternal metabolic dysfunction with no clear causality relationship with metabolic adverse outcomes in neonates.