A Preclinical Model of Obesity-Independent Metabolic Syndrome for Studying the Effects of Novel Antidiabetic Therapy Beyond Glycemic Control

Abstract

Abstract 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 by reducing inflammation and oxidative stress, shifting metabolism towards ketone body production, and suppressing glycation end-product signaling. 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 isocalorically a Western diet (WD) adjusted from parameters of the National Health and Nutrition Examination Survey for ten weeks. Blood samples were collected at baseline (BAS1) when dogs were fed their regular diet, and then again after ten weeks of WD feeding (BAS2) for measurement of blood count and serum chemistry, lipoprotein profiling, fasting blood glucose, glucagon, insulin, NT-proBNP, BUN, creatinine, angiotensins and oxidative stress biomarkers. Blood pressure (BP) was measured at BAS1 and BAS2 using Doppler. Serum, urine and fecal metabolomics were derived by mass spectrometry to assess general metabolism, complex lipids and biogenic amines. Differences between BAS1 and BAS2 were analyzed using non-parametric Wilcoxon signed rank testing with continuity correction, as appropriate. Body weight changes did not exceed 13% after ten weeks of feeding with the WD. The isocaloric WD model induced significant variations in several markers of MetS, including (1) elevated BP, (2) increased fasting glucose levels, and (3) reduced HDL-cholesterol. It also triggered a significant decrease in circulating insulin, as well as an increase in circulating NT-proBNP levels and a decrease in serum bicarbonate levels. Marked and significant changes in overall metabolism, lipids, and biogenic amines were finally reported at BAS2. 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.