In mice with diet-induced diabetes — the equivalent of type 2 diabetes in humans — a single injection of the protein FGF1 is enough to restore blood sugar levels to a healthy range for more than two days. The discovery by Salk Institute for Biological Studies scientists, published in the journal Nature, could lead to a new generation of safer, more effective diabetes drugs.
The team found that sustained treatment with the protein doesn’t merely keep blood sugar under control, but also reverses insulin insensitivity. Equally exciting, the newly developed treatment doesn’t result in side effects common to most current diabetes treatments.
“Controlling glucose is a dominant problem in our society,” says Ronald M. Evans, director of Salk’s Gene Expression Laboratory and corresponding author of the paper. “And FGF1 offers a new method to control glucose in a powerful and unexpected way.”
In 2012, Evans and his colleagues discovered that a long-ignored growth factor had a hidden function: it helps the body respond to insulin. Unexpectedly, mice lacking the growth factor, called FGF1, quickly develop diabetes when placed on a high-fat diet, a finding suggesting that FGF1 played a key role in managing blood glucose levels. This led the researchers to wonder whether providing extra FGF1 to diabetic mice could affect symptoms of the disease.
Evans’ team injected doses of FGF1 into obese mice with diabetes to assess the protein’s potential impact on metabolism. Researchers were stunned by what happened: they found that with a single dose, blood sugar levels quickly dropped to normal levels in all the diabetic mice.
The researchers found that the FGF1 treatment had a number of advantages over the diabetes drug Actos, which is associated with side effects ranging from unwanted weight gain to dangerous heart and liver problems. Importantly, FGF1, even at high doses, did not trigger these side effects or cause glucose levels to drop to dangerously low levels. Instead, the injections restored the body’s own ability to naturally regulate insulin and blood sugar levels, keeping glucose amounts within a safe range and effectively reversing the core symptoms of diabetes.
Salk postdoctoral research fellow Jae Myoung Suh, a member of Evans’ lab and first author of the new paper, says, “It may be that FGF1 leads to a more ‘normal’ type of response compared to other drugs because it metabolizes quickly in the body and targets certain cell types.”
The mechanism of FGF1 still isn’t fully understood — nor is the mechanism of insulin resistance — but Evans’ group discovered that the protein’s ability to stimulate growth is independent of its effect on glucose, bringing the protein a step closer to therapeutic use.
Pinning down the signaling pathways and receptors that FGF1 interacts with is one of the first questions Evans says he’d like to address. He’s also planning human trials of FGF1 with collaborators, but it will take time to fine-tune the protein into a therapeutic drug.
“We want to move this to people by developing a new generation of FGF1 variants that solely affect glucose and not cell growth,” he says. “If we can find the perfect variation, I think we will have on our hands a very new, very effective tool for glucose control.”
- Suh JM, Jonker JW, Ahmadian M, Goetz R, Lackey D, et al. Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature. 2014; doi: 10.1038/nature13540