After developing blockbuster GLP-1 drugs like semaglutide, which have revolutionized the treatment of type II diabetes and obesity, scientists are now investigating potential applications of these medicines in the treatment of a wide range of health concerns, including neurodegenerative disorders, cardiovascular disease, and even cancer.
Previous research has shown that prolonged GLP-1 exposure has long-term effects on the pancreas, rewiring the metabolism and allowing pancreatic beta cells to resist stress, but how and why this occurs was unclear. “I set out to try and identify molecular mechanisms inside the cells that would make this long-term effect happen,” said molecular biologist and genomics researcher Sam Van de Velde, of the Salk Institute for Biological Studies.
Genomics researcher Sam Van de Velde, of the Salk Institute for Biological Studies, set out to identify the molecular mechanisms inside cells that modulate the long-term effects of GLP-1 exposure.
Salk Institute
Using a multiomics approach, Van de Velde and his colleagues found that GLP-1 exposure causes phosphorylation of a key protein, leading to large-scale, long-term remodeling of gene expression in pancreatic beta cells.1 “What [we] uncovered was basically a molecular switch in the cell, which, if it gets flipped, it turns on hundreds of genes simultaneously,” said Van de Velde, who coauthored the study. “Ultimately, the fact that these genes are not expressed in the same way anymore results in a partial reprogramming of these cells that allows them to thrive much better in [stressful] environments.”
GLP-1 Induces Widespread Gene Expression Changes and Cell Remodeling
GLP-1 drugs were first approved for the treatment of diabetes because of their ability to trigger the beta cells of the pancreas to secrete insulin. “Later, [researchers] also found out that GLP-1 has more prolonged effects on pancreatic beta cells that go beyond just a very acute induction of insulin secretion,” explained Van de Velde. “That prolonged effect has to do with an increase in stress resistance of these cells, and keeping them more viable in the face of, for example, diabetes.”
Van de Velde, who has worked extensively in gene transcription and cellular signaling, has always been interested in how hormones regulate gene expression. Hormone spikes cause strong, but transient, changes in gene expression. However, GLP-1 drugs are stable analogs of a hormone produced by the human body. Their stable formulation is designed to last for long periods, allowing them to have much more sustained effects than natural GLP-1, which has an extremely short half-life in the body. “That's where the real therapeutic effect of these drugs comes in, because they remain circulating in our body much longer,” said Van de Velde.
The team began by exposing INS-1 cells, a rat insulinoma cell line commonly used as a model of pancreatic beta cells, to a GLP-1 receptor agonist drug for either short (one hour) or long (16 hours) time periods and measuring the transcriptional responses. While short-term exposure caused changes in a limited set of genes, long-term exposure drove much more significant transcriptional changes. The treatment affected over 1,000 genes associated with a range of functions, protein secretion, protein processing in the endoplasmic reticulum, growth factor signaling, cell differentiation, cholesterol biosynthesis, and fatty acid oxidation were all significantly dialed up. “The other fascinating, more long-term [effect] is that it reprograms the metabolism of the beta cells as well, and shifts the fat metabolism of the cell,” said Van de Velde. “It also alters gene expression in pathways that are also [involved] in glucose processing or glucose metabolism.”
Fishing For Phosphorylated Proteins Reveals a GLP-1-Activated Switch
Van de Velde and his colleagues theorized that the long-term effects of GLP-1 drugs on gene expression in the pancreas might be due to some kind of regulatory protein undergoing phosphorylation, a key regulatory mechanism that controls a range of cellular processes, including the activation or inactivation of enzymes and receptors. To test their hypothesis, the team went on a ‘fishing expedition,' performing a proteomics screen in cells after long-term exposure to the drug. “We started out just trying to find a protein that gets [a phosphorylation modification] specifically after you add [the hormone],” he said.
Van de Velde didn’t have high hopes—most of the time, he said, these fishing expeditions return confusing results or just lead nowhere. However, the team quickly found what they were looking for: phosphorylation of a single serine residue in the mediator complex subunit 14 protein, or Med14. “Almost to my surprise, [we found] a transcriptional regulator that mediates this effect [on gene expression], on a genome-wide scale,” Van de Velde added.
The team confirmed that it was phosphorylation of Med14 driving the gene expression changes by creating a mutant cell line in which phosphorylation of Med14 was inhibited. Finally, they explored the phenomenon in a mouse model of type 2 diabetes, confirming a broad transcriptional response in mouse islet cells after long-term exposure to the drug.
While Van de Velde has since left the Salk Institute for an industry position, he hopes that further research will confirm these effects in humans and explore how GLP-1s change gene expression and remodel cells in other organs. “[This study was] just one cell type,” said Van de Velde. “You can look at the brain, the heart, the vasculature, the liver…the consequences could be profound.”
- Van de Velde S, et al. Med14 phosphorylation shapes genomic response to GLP-1 agonists. Proc Natl Acad Sci. 2026;123(10):e2536772123.
