Scientists at the prestigious Salk Institute have discovered a second insulin-like molecule produced by fat tissue that, like insulin, quickly regulates blood glucose. In a new study, they found that although the hormone has almost identical effects on the human body as insulin, it uses a different molecular pathway, thereby potentially circumventing insulin resistance. The remarkable findings could lead to novel treatments for diabetes and may even open the doors to new areas of metabolic research.
Before insulin was discovered in the 1920s at the University of Toronto, patients with type 1 diabetes rarely lived for more than a year or two. But after the hormone was successfully isolated it quickly saved lives, going on to become one of the most important medical breakthroughs of the 20th century. Today, millions of people across the world are diagnosed with type 1 or type 2 diabetes and benefit from insulin treatments. However, these treatments aren't perfect due to problems arising from insulin resistance.
Insulin is released by your pancreas to lower blood sugar and keep it in the normal range. It achieves this goal by inhibiting the breakdown of fat cells into free fatty acids, a process known as lipolysis. In people with insulin resistance, glucose is not removed properly from the blood because the liver, fat, and muscles don't respond well to insulin signaling. Furthermore, lipolysis occurs in excess, leading to increases in fatty acid levels, which prompt the liver to produce more glucose, compounding the already high blood sugar levels. This positive feedback loop can exacerbate insulin resistance, which characterizes diabetes and obesity.
The pancreas compensates by producing more insulin to help glucose from the food enter your cells. But if excess glucose in the blood remains high, the patient is at risk of developing prediabetes and, eventually, type 2 diabetes.
But insulin isn't alone in regulating blood sugar in the body. In a new study published in the journal Cell Metabolism, Salk scientists showed that a hormone called FGF1 also regulates blood glucose through inhibiting lipolysis -- a behavior that remarkably mirrors that of insulin.
“Finding a second hormone that suppresses lipolysis and lowers glucose is a scientific breakthrough,” says Professor Ronald Evans, co-senior author of the new study and Director of the Gene Expression Laboratory at Salk. “We have identified a new player in regulating fat lipolysis that will help us understand how energy stores are managed in the body.”
Previously, researchers injected FGF1 into mice with insulin resistance, resulting in dramatically lower blood sugar levels. However, why exactly this happens remained a mystery until Evans and colleagues showed that FGF1 suppresses lipolysis and regulates the production of glucose in the liver. That's exactly what insulin does, which begs the question: do these molecules also share the same pathways to regulate blood sugar?
Turns out that they don't and that's actually fantastic news. Insulin suppresses lipolysis through PDE3B, an enzyme that initiates the signaling pathway, whereas the FGF1 hormone works through the PDE4 pathway.
“This mechanism is basically a second loop, with all the advantages of a parallel pathway. 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,” says first author Gencer Sancar, a postdoctoral researcher in the Evans lab.
Since FGF1 uses a different pathway, the authors hope that the hormone will prove to be a new promising therapeutic route for diabetic patients.