Researchers Discover New Molecule for Blood Sugar Regulation Independent of Insulin

Investigators from Salk Institute have discovered a new molecule produced in fat tissue that could act similarly to insulin, rapidly regulating blood glucose levels.

According to the researchers, this finding could lead to new therapeutics for the treatment of diabetes and could also lay the foundation for promising new avenues in metabolism research. The study found that the FGF1 hormone regulates blood glucose by inhibiting fat breakdown, although it works differently than insulin. Importantly, this difference could allow FGF1 to be used to safely lower blood glucose in individuals who are resistant to insulin.

“Finding a second hormone that suppresses lipolysis and lowers glucose is a scientific breakthrough,” said co-senior author Ronald Evans, PhD, in a press release. “We have identified a new player in regulating fat lipolysis that will help us understand how energy stores are managed in the body.”

Energy-rich fats and glucose enter the bloodstream from the diet. Insulin usually transfers these nutrients to cells in the muscles and fat tissue, where they are either used immediately or stored for later use.

In individuals with insulin resistance, however, glucose is not efficiently removed from the blood and higher lipolysis increases the fatty acid levels. These extra fatty acids accelerate glucose production from the liver, which compounds the already elevated glucose levels. Furthermore, fatty acids accumulate in organs, exacerbating the insulin resistance.

Earlier research found that injecting FGF1 in mice dramatically lowered blood glucose levels, and chronic treatment with FGF1 helped relieve insulin resistance; however, the mechanism of action remained unknown, according to the study.

In their current work, the researchers investigated the mechanisms of action and how they were linked. First, according to the press release, they found that FGF1 suppresses lipolysis as insulin does. Then they found that FGF1 regulates the production of glucose in the liver, and these similarities led the team to wonder whether FGF1 and insulin use the same signaling pathways to regulate blood glucose.

The team already knew that insulin suppresses lipolysis through PDE3B, an enzyme that initiates a signaling pathway, so they tested a full array of similar enzymes starting with PDE3B. The investigators were surprised, however, to find that FGF1 used the PDE4 pathways.

“This mechanism is basically a second loop, with all the advantages of a parallel pathway,” said first author Gencer Sancar, PhD, in the press release. “In insulin resistance, insulin signaling is impaired. However, with a different signaling cascade, if one is not working, the other can. That way you still have the control of lipolysis and blood glucose regulation.”

Discovering this use of the PDE4 pathways presents new opportunities for drug discovery and research on hyperglycemia and insulin resistance, according to the study authors. The researchers hope to investigate the possibility of modifying FGF1 to improve PDE4 activity and added that another route could be targeting multiple points in the signaling pathway before PDE4 is activated.

“The unique ability of FGF1 to induce sustained glucose lowering in insulin-resistant diabetic mice is a promising therapeutic route for diabetic patients,” said co-senior author Michael Downes, MD, PhD, in the press release. “Now that we’ve got a new pathway, we can figure out its role in energy homeostasis in the body and how to manipulate it.”

REFERENCE

Salk Researchers Find a New Route for Regulating Blood Sugar Levels Independent of Insulin. News release. Salk Institute; January 4, 2022. Accessed January 6, 2022. https://www.salk.edu/news-release/salk-researchers-find-a-new-route-for-regulating-blood-sugar-levels-independent-of-insulin/