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\begin{document}

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



\author[1]{Jonathan Mochel}%
\author[2]{Jessica Ward}%
\author[3]{Thomas Blondel}%
\author[2]{Debosmita Kundu}%
\author[2]{Maria Merodio}%
\author[3]{Claudine Zemirline}%
\author[3]{Emilie Guillot}%
\author[4]{Ryland  Giebelhaus}%
\author[4]{Paulina de la Mata}%
\author[2]{Chelsea Iennarella-Servantez}%
\author[2]{April Blong}%
\author[4]{Seo Lin Nam}%
\author[4]{James  Harynuk}%
\author[5]{Jan Suchodolski}%
\author[6]{Asta Tvarijonaviciute}%
\author[6]{José Joaquín  Cerón}%
\author[1]{Agnes Bourgois-Mochel}%
\author[7]{Faiez Zannad}%
\author[8]{Naveed Sattar}%
\author[1]{Karin Allenspach}%
\affil[1]{University of Georgia}%
\affil[2]{Iowa State University}%
\affil[3]{Ceva Santé Animale}%
\affil[4]{University of Alberta}%
\affil[5]{Texas A\&M University}%
\affil[6]{University of Murcia}%
\affil[7]{Universite de Lorraine}%
\affil[8]{University of Glasgow}%


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  \date{May 17, 2024}


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\begin{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. 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.%
\end{abstract}%



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