MSDC-0602K, A Novel Insulin-Sensitizer Improves Insulinemia and Fatty Liver Disease Alone and in Addition to Liraglutide in Mice

Aims/hypothesis Insulin sensitizers and incretin mimetics are antidiabetic agents with vastly different mechanisms of action. Additionally, while thiazolidinedione (TZD) insulin sensitizers are associated with the side-effect of weight gain, glucagon-like peptide-1 receptor agonists (GLP-1RAs) can induce weight loss. We hypothesized that combination therapy with a novel TZD insulin sensitizer and the GLP-1RA Liraglutide would more significantly improve mouse models of diabetes and nonalcoholic steatohepatitis (NASH) compared to individual therapy. Methods db/db mice were treated with the novel TZD MSDC-0602K by oral gavage, Liraglutide (Lira) by s.c. injection, combination 0602K+Lira, or both vehicle solutions. Vehicle-treated db/ + mice were included as non-obese controls. To assess treatment effects on nonalcoholic fatty liver disease, MS-NASH mice were similarly treated with vehicle, either drug individually, or in combination. Lastly, islets were isolated from C57BL/6J mice to assess glucose-stimulated insulin secretion (GSIS). Results 0602K-treated db/db mice displayed slight weight gain but completely corrected glycemia and markedly improved glucose tolerance. Lira slightly reduced body weights and modestly improved glycemia. 0602K+Lira combination still induced slight weight gain but completely corrected glycemia and improved glucose tolerance beyond lean db/ + levels. As expected, 0602K resulted in reduced plasma insulin, whereas Lira further increased the hyperinsulinemia of db/db mice. Surprisingly, 0602K+Lira treatment reduced plasma insulin and C-peptide to the same extent as mice treated with 0602K alone. 0602K did not directly reduce GSIS in isolated islets, thus the reduced insulinemia with 0602K is likely compensatory due to improved insulin action. In the MS-NASH mouse model, both 0602K or Lira alone improved plasma ALT and AST, and liver histology, but more significant improvements were observed with 0602K+Lira combination therapy. 0602K or 0602K+Lira also increased pancreatic insulin content in both db/db and MS-NASH mice. Conclusions MSDC-0602K corrected glycemia and reduced insulinemia when given alone, or in combination with Lira. However, 0602K+Lira combination more significantly improved glucose tolerance in db/db mice, and more significantly improved liver histology in MS-NASH mice. ### Competing Interest Statement J.R.C. is an employee, chief scientific officer, and stockholder of Cirius Therapeutics which is developing MSDC-0602K for NASH. All other authors declare no relationships or conflicts of interest.