Back to Search
Start Over
Novel insulin sensitizer MSDC-0602K improves insulinemia and fatty liver disease in mice, alone and in combination with liraglutide
- Source :
- The Journal of Biological Chemistry
- Publication Year :
- 2021
-
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.
- Subjects :
- 0301 basic medicine
Male
insulin secretion
medicine.medical_treatment
GLP-1RA, glucagon-like peptide-1 receptor agonist
DMSO, dimethyl sulfoxide
Biochemistry
Mice
Non-alcoholic Fatty Liver Disease
AST, aspartate transaminase
insulin resistance
Nonalcoholic fatty liver disease
Hyperinsulinemia
Insulin
DMEM, Dulbecco's modified Eagle's medium
diabetes
Fatty liver
NASH
RIP, rat insulin promoter
NEFA, nonesterified fatty acid
hyperinsulinemia
Drug Therapy, Combination
Female
TZD, thiazolidinedione
NASH, nonalcoholic steatohepatitis
MPC, mitochondrial pyruvate carrier
medicine.drug
Research Article
medicine.medical_specialty
Veh, vehicle solution
ALT, alanine transaminase
TAG, triacylglyceride
GSIS, glucose-stimulated insulin secretion
03 medical and health sciences
Insulin resistance
Diabetes mellitus
Internal medicine
NAFLD
medicine
Animals
Hypoglycemic Agents
TBST, Tris-buffered saline with Tween-20
Molecular Biology
Glucagon-like peptide 1 receptor
030102 biochemistry & molecular biology
Liraglutide
business.industry
nutritional and metabolic diseases
Acetophenones
Cell Biology
medicine.disease
beta cell
Mice, Inbred C57BL
PPARγ, peroxisome proliferator-activated receptor γ
030104 developmental biology
Endocrinology
Lira, liraglutide
Thiazolidinediones
NAFLD, nonalcoholic fatty liver disease
business
metabolism
Subjects
Details
- ISSN :
- 1083351X
- Volume :
- 296
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....be842022a0f9bc0e85ea8d47048c5426