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One injection stops diabetes in its tracks

Jae Myoung Suh, Annette Atkins, Michael Downes, Maryam Ahmadian, Ronald Evans and Ruth Yu of the Gene Expression Laboratory

From left: Jae Myoung Suh, Annette Atkins, Michael Downes, Maryam Ahmadian, Ronald Evans and Ruth Yu of the Gene Expression Laboratory

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, published in the journal Nature, could lead to a new generation of safer, more effective diabetes drugs.

The team, led by Ronald Evans, found that sustained treatment with the protein doesn’t merely keep blood sugar under control, but also reverses insulin insensitivity, the underlying physiological cause of diabetes. 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 Evans, director of Salk’s Gene Expression Laboratory and holder of the March of Dimes Chair at Salk. “FGF1 offers a new method to control glucose in a powerful and unexpected way.”

Type 2 diabetes, which can be brought on by excess weight and inactivity, has skyrocketed over the past few decades around the world. Almost 30 million Americans are estimated to have the disease, where glucose builds up in the bloodstream because not enough sugar-carting insulin is produced or because cells have become insulin-resistant, ignoring signals to absorb sugar. As a chronic disease, diabetes can cause serious health problems and has no specific cure. Rather it is managed–with varying levels of success–through a combination of diet, exercise and pharmaceuticals.

Diabetes drugs currently on the market aim to boost insulin levels and reverse insulin resistance by changing expression levels of genes to lower glucose levels in the blood. But drugs, such as Byetta, which increase the body’s production of insulin, can cause glucose levels to dip too low and lead to life-threatening hypoglycemia, as well as other side effects.

In 2012, Evans and his colleagues discovered that a long-ignored growth factor, FGF1, had a hidden function: it helps the body respond to insulin. Unexpectedly, mice lacking 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.

In the new work, 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: with a single dose, blood sugar levels quickly dropped to normal levels in all the diabetic mice.

“Many previous studies that injected FGF1 showed no effect on healthy mice,” says Michael Downes, a senior staff scientist and co-corresponding author of the new work. “However, when we injected it into a diabetic mouse, we saw a dramatic improvement in glucose.”

FGF1–even at high doses–did not cause glucose levels to drop to dangerously low levels, a risk factor associated with many glucoselowering agents. Instead, the injections restored the body’s own ability to naturally regulate insulin and blood sugar levels, keeping glucose amounts within a safe range–effectively reversing the core symptoms of diabetes.

The mechanism of FGF1 still isn’t fully understood 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.