Researchers at the Salk Institute have identified a key protein, Med14, that plays a central role in how GLP-1 drugs benefit pancreatic beta cells. These drugs, known as glucagon-like peptide-1 receptor agonists, are widely used to treat diabetes and have also been found to promote weight loss and improve cardiovascular health.
GLP-1 drugs work by mimicking a natural hormone in the body that helps regulate blood sugar by promoting insulin secretion. Unlike the naturally occurring hormone, which is quickly broken down after meals, synthetic GLP-1 drugs remain active for longer periods. This prolonged activity may explain some of their additional benefits.
"The fact that these drugs based off our hormones are stable seems to be important to the longer-term effects we're witnessing in pancreatic beta cells and other tissues," said Sam Van de Velde, PhD, first author of the study and staff scientist at Salk. "To understand how we are getting these longer-term effects, we need to study these drugs on a longer time scale—and that's exactly what we did."
The research team focused on understanding what happens inside pancreatic beta cells during extended exposure to GLP-1 drugs. They discovered that Med14—a component of the Mediator complex involved in gene regulation—undergoes phosphorylation after GLP-1 activation. When they mutated Med14 so it could not be phosphorylated, the beneficial gene expression changes normally seen with long-term GLP-1 drug use were lost in both cell lines and mouse models.
With functional Med14 present, gene programs supporting beta cell growth and improved response to high-sugar environments were activated. The researchers noted that while their experiments were not conducted in humans, some genes regulated by Med14 phosphorylation are linked to type 2 diabetes risk in people.
"Our findings unexpectedly reveal that phosphorylation of just a small part of the Med14 protein plays a significant role in the response to GLP-1 drugs—and in the metabolic response to hormones more broadly," said Reuben Shaw, PhD, professor at Salk and director of the National Cancer Institute-Designated Salk Cancer Center. "Now there are many new questions to answer, from validating our findings in human tissues to seeing whether Med14 has a similar role in other cells and organs."
The researchers plan further studies on whether similar mechanisms occur outside pancreatic beta cells since cAMP—the messenger molecule between GLP-1 and Med14—is used throughout various tissues.
Other contributors to this study include Jungting Yu, K. Garrett Evensen, Edmund Pakhlevanyan, and April Williams from Salk. The research was funded by grants from organizations such as the National Institutes of Health (5R01 DK083834, R35 CA220538), Breakthrough T1D (INO-2022-1125-A-N), Paul F. Glenn Foundation for Biology of Ageing Research, Clayton Foundation for Medical Research, and Leona M. and Harry B. Helmsley Charitable Trust.
