Study: Type 2 Diabetes Treatments May Be More Effective When Combined


A new study published in the August 26 edition of Science Advances shows that the effectiveness of a two-pronged Type 2 diabetes treatment improves when drugs are linked by a heat-sensitive tether. This is compared to when treatments are concurrently administered, according to biomedical engineers at Duke University.

This new approach is centered around Type 2 diabetes drug, glucagon-like peptide-1 (GLP-1), and the drug candidate, fibroblast growth factor 21 (FGF21). In experimentation with diabetic mice, these two drugs appeared to create tight glycemic control and weight reduction. When they were coupled with the slow-release function of an elastin-like polypeptide, the effects also lasted longer than one week with a single injection.

"In the burgeoning field of multi-functioning single-molecule diabetes drug design, researchers primarily unite drugs that are similar in size, structure and function," said Caslin Gilroy, a postdoctoral scholar at the University of California, Berkeley, who led the research. "Being able to combine such structurally distinct drugs into a single molecule while maintaining the bioactivity and stability of each is a big technological achievement."

Most drug combinations use small peptides from the same family as GLP-1. However, Gilroy and Ashutosh Chilkoti, the Alan L. Kaganov Distinguished Professor of Biomedical Engineering at Duke, chose to work with FGF21 for their research. FGF21 regulates insulin sensitivity, energy expenditure and fat metabolism.

"FGF21 functions through a different mechanism than GLP-1, and we hypothesized that the two drugs would complement each other nicely," said Gilroy. "GLP-1 increases insulin secretion by the pancreas, while FGF21 enhances the body's response to the insulin. GLP-1 reduces food intake, while FGF21 helps burn more calories."

The researchers’ study verified that GLP-1 and FGF21 retain their respective functions and potencies when they are linked together. Mice treated with the GLP-1/FGF21 combination drug were also better able to recover from a glucose challenge, compared to either drug alone.

This is not the first batch of research to show that combination therapies may be more effective for Type 2 diabetes A study published in Cell Metabolism in May by researchers from the UT Southwestern Medical Center showed that a lower dose of the drug, rosiglitazone, may be beneficial when paired with an experimental drug called Compound A.

In mice experimentation, the combination of Compound A with a minimal dose of rosiglitazone resulted in a similar degree of insulin sensitization as the maximum dose of rosiglitazone. This is critical, as some experts have deemed high doses of rosiglitazone to be risky.

"The very low dose we used in this study showed no side effects -- no weight gain, no fluid retention -- in mouse models," said Dayoung Oh, Ph.D., senior author of the study, assistant professor of internal medicine, and a researcher in UT Southwestern's Touchstone Center for Diabetes Research.

Additional research will be needed to check for bone loss and heart problems at a lower dose. However, those effects may be eliminated or lessened by reducing the dose of rosiglitazone.

Rosiglitazone acts on the anti-diabetic target, PPARy, in fat cells. It can be leveraged by combining it with an agonist or an activator as well. In experimentation, mice that received rosiglitazone alone did not show improved insulin sensitivity.

Approximately 34 million Americans live with diabetes, and 90 to 95% of those cases are Type 2 diabetes, according to the Centers for Disease Control and Prevention.

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