1. Academic Validation
  2. Novel insulin sensitizer MSDC-0602K improves insulinemia and fatty liver disease in mice, alone and in combination with liraglutide

Novel insulin sensitizer MSDC-0602K improves insulinemia and fatty liver disease in mice, alone and in combination with liraglutide

  • J Biol Chem. 2021 Jan-Jun;296:100807. doi: 10.1016/j.jbc.2021.100807.
Dakota R Kamm 1 Kelly D Pyles 1 Martin C Sharpe 1 Laura N Healy 2 Jerry R Colca 3 Kyle S McCommis 4
Affiliations

Affiliations

  • 1 Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St Louis, Missouri, USA.
  • 2 LNH Tox Path Consulting LLC, Newbury Park, California, USA.
  • 3 Cirius Therapeutics, Kalamazoo, Michigan, USA; Cirius Therapeutics, San Diego, California, USA.
  • 4 Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St Louis, Missouri, USA. Electronic address: kyle.mccommis@health.slu.edu.
Abstract

Insulin sensitizers and incretin mimetics are antidiabetic agents with vastly different mechanisms of action. Thiazolidinedione (TZD) Insulin sensitizers are associated with weight gain, whereas glucagon-like peptide-1 receptor agonists can induce weight loss. We hypothesized that combination of a TZD Insulin sensitizer and the glucagon-like peptide-1 receptor agonist liraglutide would more significantly improve mouse models of diabetes and nonalcoholic steatohepatitis (NASH). Diabetic db/db and MS-NASH mice were treated with the TZD MSDC-0602K by oral gavage, liraglutide (Lira) by s.c. injection, or combination 0602K+Lira. Lira slightly reduced body weight and modestly improved glycemia in db/db mice. Comparatively, 0602K-treated and 0602K+Lira-treated mice exhibited slight weight gain but completely corrected glycemia and improved glucose tolerance. 0602K 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 reduce glucose-stimulated Insulin secretion in vivo, or in isolated islets, indicating the reduced insulinemia was likely compensatory to improved Insulin sensitivity. In MS-NASH mice, both 0602K or Lira alone improved plasma alanine aminotransferase and aspartate aminotransferase, as well as liver histology, but more significant improvements were observed with 0602K+Lira treatment. 0602K or 0602K+Lira also increased pancreatic Insulin content in both db/db and MS-NASH mice. In conclusion, MSDC-0602K corrected glycemia and reduced insulinemia when given alone, or in combination with Lira. However, 0602K+Lira combination more significantly improved glucose tolerance and liver histology, suggesting that this combination treatment may be an effective therapeutic strategy for diabetes and NASH.

Keywords

NAFLD; NASH; beta cell; diabetes; hyperinsulinemia; insulin resistance; insulin secretion; metabolism.

Figures
Products