New route for regulating blood sugar independent of insulin

Ever since its discovery 100 years ago, insulin has been considered the primary means of treating conditions characterised by high blood sugar (glucose), such as diabetes. Now, scientists at the Salk Institute for Biological Studies have discovered that a hormone known as FGF1, produced in fat tissue, also potently and rapidly regulates blood glucose — a breakthrough that could lead to the development of new treatments for people who suffer from insulin resistance.

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.

The Salk Institute had previously shown that injecting the hormone 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, published in the journal Cell Metabolism, the researchers investigated the mechanisms behind these phenomena and how they were linked.

First, they showed that FGF1 suppresses fat breakdown (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 signalling (communication) pathways to regulate blood glucose.

It was already known that insulin suppresses lipolysis through PDE3B, an enzyme that initiates a signalling 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.

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

Finding the PDE4 pathway opens new opportunities for drug discovery and basic research focused on high blood glucose (hyperglycaemia) and insulin resistance, with co-senior author Professor Ronald Evans saying of the breakthrough, “We have identified a new player in regulating fat lipolysis that will help us understand how energy stores are managed in the body.”

The scientists are now eager to investigate the possibility of modifying FGF1 to improve PDE4 activity. Another route is targeting multiple points in the signalling 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, a senior staff scientist at Salk.

“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.”

Image caption: Insulin and FGF1 both regulate blood sugar levels using independent pathways. Image credit: Salk Institute.

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