Abstract 3921: KD3010, a PPARβ/δ Selective Small Molecule Agonist, Improves Hyperglycemia And Insulin Resistance while alleviating Rosiglitazone-Induced Side Effects in Murine Models
KD3010 is a highly selective and potent PPARδ agonist, affecting multiple facets of diabesity and metabolic syndrome but lacking activity against the G- protein coupled receptor (GPCR) GPR40. We demonstrate that KD3010 exhibits anti-hyperglycemic, insulin-sensitizing and lipid lowering effects in the leptin resistant db/db mice. In 12 week old db/db mice, oral administration of KD3010 (10 mg/kg/day) for 7 days reduced fasting hyperglycemia (37 ± 9.5%; p< 0.05), hemoglobinA1C (HbA1C, 14.5 ± 2.6 %) and triglyceride (42 ± 12.1%; p< 0.05) levels. Elevated serum transaminases (AST and ALT) observed in these mice was also reduced by KD3010 (40 ± 11.3%; p< 0.05) demonstrating the potential in improving steatotic liver function. Marked improvement in peripheral insulin sensitivity was also observed following short term treatment with KD3010 (10 mg/kg/day; 2 weeks) as demonstrated by reduced glucose excursion (AUC-glucose reduced by 36 ± 10.3%; p< 0.05) during glucose tolerance test (GTT). These metabolic effects of KD3010 were accompanied by changes in expression of genes in relevant tissues and metabolic pathways. KD3010 treatment downregulated expression of gluconeogenic genes, Glucose-6-Phosphatase and Fructose-Bis-Phosphatase in the liver, upregulated ABCA1 in the monocytes, and downregulated NPC1L1 in the small intestine. Additionally, genes for lipolysis and mitochondrial β-oxidation were upregulated in the muscle both in vivo and in myotubes, in vitro. The metabolic effects of KD3010 in the db/db mice were independent of any weight loss. KD3010 had similar spectrum of metabolic effects in leptin deficient ob/ob mice. In this mouse model, KD3010 also attenuated key side effects of rosiglitazone, such as weight gain and impaired liver function. Finally, activation of PPARδ by KD3010 significantly improved insulin sensitizating effects of sub-optimal doses of rosiglitazone, thus demonstrating a rosiglitazone-sparing effect. In conclusion, the preclinical profile of KD3010 addresses underlying causes of diabesity and metabolic syndrome either as a monotherapy or in combination with other standards of clinical care.