and Medicine for Seniors
One Injection Stops Diabetes in Its Tracks Report
FGF1 treatment reverses symptoms of type 2 diabetes
in mice without side effects
16, 2014 - 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 scientists, published today 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, the underlying physiological cause of diabetes.
Equally exciting, the newly developed treatment
doesn't result in side effects common to most current diabetes
"Controlling glucose is a dominant problem in our
Ronald M. Evans, director of Salk's
Gene Expression Laboratory, La
Jolla, California, and corresponding author of the paper. "And FGF1
offers a new method to control glucose in a powerful and unexpected
Type 2 diabetes, which can be brought on by excess
weight and inactivity, has skyrocketed over the past few decades in the
United States and 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
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
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 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
"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."
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, a risk factor associated with many
glucose-lowering 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.
"With FGF1, we really haven't seen hypoglycemia or
other common side effects," says Salk postdoctoral research fellow Jae
Myoung Suh, a member of Evans' lab and first author of the new paper.
"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
"There are many questions that emerge from this
work and the avenues for investigating FGF1 in diabetes and metabolism
are now wide open," Evans says.
Pinning down the signaling pathways and receptors
that FGF1 interacts with is one of the first questions 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."
Other researchers on the study were Maryam Ahmadian,
Eiji Yoshihara, Weiwei Fan, Yun-Qiang Yin, Ruth T. Yu, and Annette R.
Atkins of the Salk Institute for Biological Studies; Weilin Liu, Johan
W. Jonker, Theo van Dijk, and Rick Havinga of the University of
Groningen; Christopher Liddle of the University of Sydney; Denise
Lackey, Olivia Osborn, and Jerrold M. Olefsky of the University of
California at San Diego; and Regina Goetz, Zhifeng Huang, and Moosa
Mohammadi of the New York University School of Medicine.
Ronald Evans is a
Howard Hughes Medical Institute
investigator and is also supported by grants from the
National Institutes of Health, the
Leona M. and Harry B. Helmsley Charitable
Glenn Foundation for Medical Research,
CIRM, and the
Ellison Medical Foundation. Other
study authors received grants from the National Institutes of Health,
Australian National Health and Medical
Research Council, the
European Research Council, the
Human Frontier Science Program, the
Netherlands Organisation for Scientific
Research, and the
Dutch Digestive Foundation.
About the Salk Institute for Biological
The Salk Institute for Biological Studies reports to be one of the
world's preeminent basic research institutions, where internationally
renowned faculty probes fundamental life science questions in a unique,
collaborative and creative environment. Focused both on discovery and on
mentoring future generations of researchers, Salk scientists make
groundbreaking contributions to our understanding of cancer, aging,
Alzheimer's, diabetes and infectious diseases by studying neuroscience,
genetics, cell and plant biology, and related disciplines.
Faculty achievements have been recognized with
numerous honors, including Nobel Prizes and memberships in the National
Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas
Salk, MD, the Institute is an independent nonprofit organization and
diabetes at Salk