In Lab, SLU Researchers Find Benefits for Diabetes, Fatty Liver Disease When Combining Two Anti-Diabetes Drugs

05/24/2021

ST. LOUIS - A Saint Louis University research team, led by Kyle S. McCommis, Ph.D., assistant professor in Biochemistry and Molecular Biology, found that combining two classes of anti-diabetes drugs provides superior benefits in mouse models of diabetes and fatty liver disease.

“These two classes of diabetes drugs have vastly different mechanisms of action, so we hypothesized they could enhance each other’s activities to result in better therapeutic efficacy against these metabolic diseases,” said McCommis. “We thought both increasing insulin production and reversing insulin resistance would greatly improve metabolic function in these mice.”

One class, insulin sensitizers, counteract the insulin resistance that commonly occurs in obesity and allows insulin to once again be effective in its target tissues. The other class, GLP-1 receptor agonists, improves blood sugar levels by slowing stomach emptying and increasing insulin production by the pancreas.

The findings, “Novel insulin sensitizer MSDC-0602K improves insulinemia and fatty liver disease in mice, alone and with liraglutide” were published online May 19 in the Journal of Biological Chemistry.

In these studies, obese and diabetic db/db mice were treated either with the insulin sensitizer MSDC-0602K, which is currently in clinical development for the treatment of nonalcoholic steatohepatitis, the GLP-1RA liraglutide, or both.

MSDC-0602K alone corrected the blood glucose levels of db/db mice back to lean control mouse levels. However, additive effects of both therapies came to light when mice were directly tested for their ability to handle glucose during a glucose tolerance test.

“During this test, both MSDC-0602K and liraglutide improved blood glucose levels, but the combination of MSDC-0602K and liraglutide reduced blood glucose levels even beyond lean control mice,” McCommis said.

The combination therapy also provided insight into the control of insulin secretion by the pancreas. One of the mechanisms of liraglutide is to increase insulin secretion, and blood insulin concentrations were increased by liraglutide in this study. On the other hand, insulin sensitizers such as MSDC-0602K decrease insulin concentrations since insulin is working better and therefore less of it is needed. When MSDC-0602K and liraglutide were combined, mice still displayed lower insulin concentrations, similar to when they were treated with MSDC-0602K alone. Moreover, there was increased insulin inside the pancreatic islets.

“This suggests that MSDC-0602K, alone or in combination with liraglutide, can preserve pancreatic beta cell function by reducing excessive insulin secretion in diabetes” McCommis said.

Another reason to test combination therapy is that the addition of GLP1-RA may be able to prevent a common side effect of insulin sensitizers, which is moderate weight gain.

“Liraglutide tends to reduce body weight in both humans and animal models, so we hoped that it would counteract the slight weight gain we observe with MSDC-0602K treatment,” McCommis said. “However, mice treated with MSDC-0602K+liraglutide continued to display slight weight gain, albeit with greatly improved metabolic profiles.

Nonalcoholic steatohepatitis is a common comorbidity of diabetic patients in which the liver becomes injured from excessive fat accumulation and inflammation. No approved therapies currently exist for nonalcoholic steatohepatitis, so this drug combination was also tested in a mouse model of the disease. While both therapies on their own resulted in moderate improvements in liver pathology, the most significant improvements occurred with combination of MSDC-0602K and liraglutide.

Overall, this study suggests that combining these two classes of diabetes therapies results in superior treatment of both diabetes and fatty liver disease, and supports testing similar interventions in humans.

Coauthors include research assistants Dakota Kamm and Kelly Pyles; Martin Sharpe, a SLU undergraduate student in McCommis’ lab; Laura Healy, LNH Tox Path Consulting LLC; and Jerry Colca, Cirius Therapeutics. Colca is an employee, chief scientific officer and stockholder of Cirius Therapeutics, which is developing MSDC-0602K for NASH. 

Saint Louis University School of Medicine

Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious diseases.