ONE INJECTION STOPS DIABETES IN ITS TRACKS
Treatment reverses symptoms of type 2 diabetes in mice without side effects
From the FMS Global News Desk of Jeanne Hambleton
Embargo expired: 16-Jul-2014 1:00 PM EDT
Source Newsroom: Salk Institute for Biological Studies
Newswise — LA JOLLA—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 does not merely keep blood sugar under control, but also reverses insulin insensitivity, the underlying physiological cause of diabetes. Equally exciting, the newly developed treatment does not 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.”
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 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 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.
“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 have not 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 is not 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.
“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 would like to address. He is 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 Trust, the Glenn Foundation for Medical Research, Ipsen/Biomeasure, CIRM, and the Ellison Medical Foundation. Other study authors received grants from the National Institutes of Health, the 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 Studies:
The Salk Institute for Biological Studies is 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 architectural landmark.
NEW GENE DISCOVERED STOPS SPREAD OF DEADLY CANCER
From The FMS Global News Desk of Jeanne Hambleton
Embargo expired: 17-Jul-2014 12:00 PM EDT
Source Newsroom: Salk Institute for Biological Studies
Citations Molecular Cell
Newswise — LA JOLLA—Scientists at the Salk Institute have identified a gene responsible for stopping the movement of cancer from the lungs to other parts of the body, indicating a new way to fight one of the world’s deadliest cancers.
By identifying the cause of this metastasis—which often happens quickly in lung cancer and results in a bleak survival rate—Salk scientists are able to explain why some tumors are more prone to spreading than others. The newly discovered pathway, detailed today in Molecular Cell, may also help researchers understand and treat the spread of melanoma and cervical cancers.
“Lung cancer, even when it is discovered early, is often able to metastasize almost immediately and take hold throughout the body,” says Reuben J. Shaw, Salk professor of molecular and cell biology and a Howard Hughes Medical Institute early career scientist.
“The reason behind why some tumors do that and others don not has not been very well understood. Now, through this work, we are beginning to understand why some subsets of lung cancer are so invasive.”
Lung cancer, which also affects nonsmokers, is the leading cause of cancer-related deaths in the country (estimated to be nearly 160,000 this year). The United States spends more than $12 billion on lung cancer treatments, according to the National Cancer Institute.
Nevertheless, the survival rate for lung cancer is dismal: 80 percent of patients die within five years of diagnosis largely due to the disease’s aggressive tendency to spread throughout the body.
To become mobile, cancer cells override cellular machinery that typically keeps cells rooted within their respective locations. Deviously, cancer can switch on and off molecular anchors protruding from the cell membrane (called focal adhesion complexes), preparing the cell for migration. This allows cancer cells to begin the processes to traverse the body through the bloodstream and take up residence in new organs.
In addition to different cancers being able to manipulate these anchors, it was also known that about a fifth of lung cancer cases are missing an anti-cancer gene called LKB1 (also known as STK11). Cancers missing LKB1 are often aggressive, rapidly spreading through the body. However, no one knew how LKB1 and focal adhesions were connected.
Now, the Salk team has found the connection and a new target for therapy: a little-known gene called DIXDC1. The researchers discovered that DIXDC1 receives instructions from LKB1 to go to focal adhesions and change their size and number.
When DIXDC1 is “turned on,” half a dozen or so focal adhesions grow large and sticky, anchoring cells to their spot. When DIXDC1 is blocked or inactivated, focal adhesions become small and numerous, resulting in hundreds of small “hands” that pull the cell forward in response to extracellular cues.
That increased tendency to be mobile aids in the escape from, for example, the lungs and allows tumor cells to survive travel through the bloodstream and dock at organs throughout the body.
“The communication between LKB1 and DIXDC1 is responsible for a ‘stay-put’ signal in cells,” says first author and Ph.D. graduate student .
“DIXDC1, which no one knew much about, turns out to be inhibited in cancer and metastasis.”
Tumors, Shaw and collaborators found in the new research, have two ways to turn off this “stay-put” signal. One is by inhibiting DIXDC1 directly. The other way is by deleting LKB1, which then never sends the signal to DIXDC1 to move to the focal adhesions to anchor the cell.
Given this, the scientists wondered if reactivating DIXDC1 could halt a cancer’s metastasis. The team took metastatic cells, which had low levels of DIXDC1, and overexpressed the gene. The addition of DIXDC1 did indeed blunt the ability of these cells to be metastatic in vitro and in vivo.
“It was very, very surprising that this gene would be so powerful,” says Goodwin.
“At the start of this study, we had no idea DIXDC1 would be involved in metastasis. There are dozens of proteins that LKB1 affects; for a single one to control so much of this phenotype was not expected.”
Right now, there is no specific treatment for cancers harboring LKB1 or DIXDC1 alterations, but those with a deletion of either gene would likely see results from cancer drugs that target the focal adhesions, says Shaw.
“The good news is that this finding predicts that patients missing either gene should be sensitive to new therapies targeting focal adhesion enzymes, which are currently being tested in early-stage clinical trials,” says Shaw, who is also a member of the Moores Cancer Center and an adjunct professor at the University of California, San Diego.
“By identifying this unexpected connection between DIXDC1 and LKB1 in certain tumors, we have expanded the potential patient population that may be good candidates for these therapies,” adds Goodwin.
Collaborators included Robert U. Svensson of the Salk Institute, Hua Jane Lou and Benjamin E. Turk of Yale University School of Medicine, and Monte M. Winslow of Stanford University.
The work was funded by: grants from the National Cancer Institute, the Howard Hughes Medical Institute, the Samuel Waxman Cancer Research Foundation, and the Leona M. and Harry B. Helmsley Charitable Trust.
Well done Salk – a double whammy in new research. We wish these young researchers and learned Professors good luck with their great discoveries.