New molecular pathway controls blood glucose, circumventing insulin resistance

January 5, 2022

NOMIS Awardee Ronald M. Evans — who is leading the project The Science of Health: The Fundamental Mechanisms of Organ Communication — and colleagues have found a new route for regulating blood sugar levels independent of insulin.

The discovery of insulin 100 years ago opened a door that would lead to life and hope for millions of people with diabetes. Ever since then, insulin, produced in the pancreas, has been considered the primary means of treating conditions characterized by high blood sugar (glucose), such as diabetes. Now, Salk scientists have discovered a second molecule, produced in fat tissue, that, like insulin, also potently and rapidly regulates blood glucose. Their finding could lead to the development of new therapies for treating diabetes, and also lays the foundation for promising new avenues in metabolism research.

From left: Emma Tilley, Kyeongkyu Kim, Ruth Yu, Gencer Sancar, Ronald Evans, Annette Atkins and Michael Downes (Photo: Salk Institute)

The study, which was published in Cell Metabolism on January 4, 2022, shows that a hormone called FGF1 regulates blood glucose by inhibiting fat breakdown (lipolysis). Like insulin, FGF1 controls blood glucose by inhibiting lipolysis, but the two hormones do so in different ways. Importantly, this difference could enable FGF1 to be used to safely and successfully lower blood glucose in people who suffer from insulin resistance.

“Finding a second hormone that suppresses lipolysis and lowers glucose is a scientific breakthrough,” says co-senior author and Professor Ronald Evans, holder of the March of Dimes Chair in Molecular and Developmental Biology. “We have identified a new player in regulating 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. Insulin normally shuttles these nutrients to cells in muscles and fat tissue, where they are either used immediately or stored for later use. In people with insulin resistance, 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, compounding the already high glucose levels. Moreover, fatty acids accumulate in organs, exacerbating the insulin resistance—characteristics of diabetes and obesity.

Previously, the lab showed that injecting FGF1 dramatically lowered blood glucose in mice and that chronic FGF1 treatment relieved insulin resistance. But how it worked remained a mystery.

In the current work, the team investigated the mechanisms behind these phenomena and how they were linked. First, they showed that FGF1 suppresses lipolysis, as insulin does. Then they showed that FGF1 regulates the production of glucose in the liver, as insulin does. These similarities led the group to wonder if FGF1 and insulin use the same signaling (communication) pathways to regulate blood glucose.

It was already known that insulin suppresses lipolysis through PDE3B, an enzyme that initiates a signaling pathway, so the team tested a full array of similar enzymes, with PDE3B at the top of their list. They were surprised to find that FGF1 uses a different pathway—PDE4.

Continue reading this Salk Institute release

Read the Cell Metabolism publication: FGF1 and insulin control lipolysis by convergent pathways