The isolation of insulin 100 years ago opened the door to hope for millions of people with diabetes. Since then, insulin produced by the pancreas has been considered the primary means of treating conditions characterized by high blood sugar levels, such as diabetes. The new finding could lead to the development of new therapies to treat diabetes and also lays the groundwork for promising new avenues in metabolism research.
The study, published in Cell Metabolism on January 4, 2022, shows that a hormone called FGF1 regulates blood glucose by inhibiting the breakdown of fats . This is a catabolic process that goes by the name of lipolysis . Like insulin, FGF1 controls blood glucose by inhibiting lipolysis, although these two hormones do so in different ways. It is precisely the difference that could allow FGF1 to be used to safely and successfully lower blood glucose for people with insulin resistance.
“Finding a second hormone that suppresses lipolysis and lowers glucose is a scientific breakthrough,” says Ronald Evans, the paper’s co-lead author and March Dimes Professor of Molecular and Developmental Biology. “We have identified a new player in the regulation of fat lipolysis that will help us understand how energy stores are managed in the body.”
When we eat, energy-rich fats and glucose enter the bloodstream. The role of insulin is to transport these nutrients to the cells of muscle and fat tissue, where they are used immediately or stored for later use. Those people who show insulin resistance do not efficiently remove glucose from the blood, so a more marked lipolysis increases the levels of fatty acids. These extra fatty acids speed up glucose production in the liver, exacerbating already high glucose levels. It should be added that fatty acids accumulate in the organs, increasing insulin resistance, which is a characteristic of diabetes and obesity.
The laboratory had already shown that injection of FGF1 drastically reduced blood glucose in mice and that sustained treatment with FGF1 decreased insulin resistance. But how he acted remained a mystery.
The article in question was published in Nature in 2014: Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer . “FGF1 offers a new method of controlling glucose in a powerful and unexpected way,” Ronadl Evans, director of Salk’s Gene Expression Laboratory, said at the time.
The study was conducted on mice with diet-induced diabetes, equivalent to type 2 diabetes in humans. “With FGF1, we haven’t seen hypoglycemia or other common side effects,” said Salk Jae Myoung Suh, a member of the Evans lab. “It may be that FGF1 leads to a more normal type of response compared to other drugs, as it is rapidly metabolized in the body and targets certain types of cells,” he added.
More than seven years have passed and the team knows much more about the role of FGF1 in glucose regulation and lipolysis inhibition.
In the current work, the team investigated the mechanisms behind these phenomena and how they were related. They first showed that FGF1 suppresses lipolysis, as does insulin. They then showed that FGF1 regulates glucose production in the liver, as does insulin. Both of these similarities led the group to question whether FGF1 and insulin carry the same signaling pathways to regulate blood glucose.
Insulin was known to suppress lipolysis through PDE3B, an enzyme that initiates a signaling pathway. For this reason the team tested a whole range of similar enzymes, the first being PDE3B. But they were surprised to find that FGF1 uses a different pathway: PDE4.
“This mechanism is basically a second cycle, with all the advantages of a parallel path. In insulin resistance, insulin signaling is affected. However, with a different signaling cascade, if one doesn’t work, the other can. This way, you still have control of lipolysis and blood glucose regulation,” says Gencer Sancar, first author of the study and a postdoctoral researcher in the Evans lab.
The discovery of the PDE4 pathway opens up great opportunities for new drug discovery and basic research focused on hyperglycemia and insulin resistance.
“The unique ability of FGF1 to induce sustained glucose lowering in insulin-resistant diabetic mice is a promising therapeutic route for diabetic patients. We hope that understanding this pathway will lead to better treatments for diabetic patients”, says Michael Downes, another of the co-authors of the article and a scientist in the Evans laboratory. “Now that we have a new pathway, we can figure out its role in energy homeostasis in the body and how to manipulate it.”
The research has been funded by the National Institutes of Health, the Nomis Foundation, the March of Dimes, the Deutsche Forschungsgemeinschaft (DFG), the Netherlands Organization for Scientific Research, the European Foundation for the Study of Diabetes, and the National Foundation for Diabetes. Swiss Science.
Original article: FGF1 and insulin control lipolysis by convergent pathways.
