TAG: "Diabetes"

Stem cell therapy coming of age


With first clinical trials, UC San Diego pushes stem cell therapies into new era.

Photos by Erik Jepsen, UC San Diego

In 2004, the therapeutic potential of stem cells persuaded more than 7 million Californians to approve Proposition 71, which allocated a whopping $3 billion for research and development of stem cell-based drugs and therapies that might someday address a medical dictionary’s worth of diseases and conditions.

Now, stem cell research is being put to the test in full force as years of cellular and animal studies make the leap to human clinical trials—a requisite step before any new drug or therapy is approved for market. Nowhere is this progress more visible than at UC San Diego, which in recent weeks has launched the three first stem-cell-based clinical trials in patients to pursue potential treatments for spinal cord injury, Type 1 diabetes and chronic lymphocytic leukemia.

And last week, the California Institute for Regenerative Medicine (CIRM), the state stem cell agency established by Prop.71, named the Sanford Stem Cell Clinical Center at UC San Diego Health System one of three “alpha clinics,” a highly sought-after designation that comes with an $8 million grant to further speed stem cell clinical development. The other two alpha clinic sites are City of Hope hospital near Los Angeles and UCLA, which is partnering with UC Irvine.

“A UC San Diego alpha clinic will provide a vital infrastructure for establishing a comprehensive regenerative medicine clinical hub that can support the unusual complexity of first-in-human stem cell-related clinical trials,” said Dr. Catriona Jamieson, deputy director of the Sanford Stem Cell Clinical Center, director of the UC San Diego Moores Cancer Center stem cell program and the alpha clinic grant’s principal investigator.

“The designation is essential in much the same manner that comprehensive cancer center status is an assurance of scientific rigor and clinical quality. It will attract patients, funding agencies and study sponsors to participate in, support and accelerate novel stem cell clinical trials and ancillary studies for a range of arduous diseases.”

Lawrence Goldstein, director of the UC San Diego Stem Cell Program and Sanford Center

Such work is well underway. Last week, doctors at UC San Diego and Veterans Affairs San Diego Healthcare System, in collaboration with the San Diego-based biotechnology firm ViaCyte, Inc., treated the first patient in an unprecedented phase one-two trial of a stem-cell-derived therapy for patients with Type 1 diabetes. The trial involves implanting specially encapsulated embryonic stem-cell-derived cells under the skin where it’s hoped they will mature into pancreatic beta and other cells able to produce a continuous supply of needed insulin and other substances.

Last month, a 26-year-old woman paralyzed in a car accident a year ago successfully underwent the first experimental procedure to test whether neural stem cells injected at the site of a spinal cord injury is safe and could be an effective treatment. It is hoped that the procedure – the first of four in the phase one trial sponsored by the Sanford Center and Maryland-based Neuralstem Inc. – will ultimately lead to a treatment in which transplanted neural stem cells will develop into new neurons that bridge the gap created by an injury, replace severed or lost nerve connections and restore at least some motor and sensory function.

Also last month, researchers at UC San Diego Moores Cancer Center and the Sanford Center treated the first participant in a novel phase one trial to assess the safety of a monoclonal antibody treatment that targets cancer stem cells in patients with chronic lymphocytic leukemia, the most common form of blood cancer.

“What we are seeing after years of work is the rubber hitting the road,” said Lawrence Goldstein, director of the UC San Diego Stem Cell Program and Sanford Center. “These are three very ambitious and innovative trials. Each followed a different development path; each addresses a very different disease or condition. It speaks to the maturation of stem cell science that we’ve gotten to the point of testing these very real medical applications in people.”

Goldstein noted that the number of patients involved in these first trials is small. Their focus is upon treatment with low doses to assess safety, but also with hope of patient benefit. As these trials progress – and additional trials are launched – Goldstein predicts greater numbers of patients will be enrolled at UC San Diego, the Sanford Center and elsewhere.

Achieving alpha clinic status should help, he said. One element of the new grant is expanded public outreach to raise awareness and understanding of stem cell science, in part to combat what Goldstein calls “stem cell tourism” and the marketing of unproven, unregulated and potentially dangerous therapies.

“Clinical trials are the fastest and safest way to develop therapies that are truly safe and that actually work. You want to prove that a new therapy will work for more than just a single, random patient. These alpha clinic awards not only provide valuable support that will help accelerate experimental stem cell therapies into clinical trials, they also bring with them a ‘stamp of approval’ that our center meets important standards set by peers for testing of stem cell therapy trials.”

The alpha grant reflects CIRM’s continued support for UC San Diego’s stem cell research and development efforts. Since 2004, CIRM has approved 74 awards totaling more than $147 million to UC San Diego stem cell scientists and programs. The three clinical trials launched are just the first of many to come, said alpha clinic principal investigator Jamieson. Other trials for heart failure, amyotrophic lateral sclerosis (Lou Gehrig’s disease) and blindness are in the planning stages.

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Two UC centers named stem cell ‘alpha clinics’

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‘Treasure in saliva’ may reveal deadly diseases early enough to treat them


UCLA research holds promise for diagnosing Type 2 diabetes, gastric cancer, other diseases.

Xinshu (Grace) Xiao and David Wong, UCLA (Photo by Reed Hutchinson, UCLA)

UCLA research could lead to a simple saliva test capable of diagnosing — at an early stage — diabetes and cancer, and perhaps neurological disorders and autoimmune diseases.

The study, the most comprehensive analysis ever conducted of RNA molecules in human saliva, reveals that saliva contains many of the same disease-revealing molecules that are contained in blood. It was published online today (Oct. 29) by the peer-reviewed journal Clinical Chemistry and will be published in the journal’s January 2015 special print issue, “Molecular Diagnostics: A Revolution in Progress.”

“If we can define the boundaries of molecular targets in saliva, then we can ask what the constituents in saliva are that can mark someone who has pre-diabetes or the early stages of oral cancer or pancreatic cancer — and we can utilize this knowledge for personalized medicine,” said Dr. David Wong, a senior author of the research and UCLA’s Felix and Mildred Yip Endowed Professor in Dentistry.

Wong said the test also holds promise for diagnosing Type 2 diabetes, gastric cancer and other diseases. “If you don’t look in saliva, you may miss important indicators of disease,” Wong said. “There seems to be treasure in saliva, which will surprise people.”

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Researchers pinpoint genetic risks, cellular culprits in autoimmune diseases


New software tool helps make sense of previous genetic data on MS, Type 1 diabetes.

Alex Marson, UC San Francisco

Scores of autoimmune diseases afflicting 1 in 12 Americans — ranging from Type 1 diabetes to multiple sclerosis (MS) to rheumatoid arthritis to asthma — mysteriously cause the immune system to harm tissues within our own bodies. Now, a new study pinpoints the complex genetic origins for many of these diseases, a discovery that may lead to better diagnosis and ultimately to improved treatments.

A team of scientists from UC San Francisco, the Broad Institute of MIT and Harvard, and Yale School of Medicine developed a new mathematical tool to more deeply probe existing DNA databases. In so doing they discovered how certain DNA variations, when inherited, are likely to contribute to disease.

By applying their method to analyzing data from previous studies of 21 different autoimmune diseases, the research team has deepened scientific understanding of the genetic underpinnings of a wide range of these disorders. They also found the specific immune cells most responsible for the diseases. Their study is published online today (Oct. 29) in Nature.

The researchers examined a wealth of data from 39 large-scale studies called genome-wide association studies (GWAS). Teams of scientists in recent years have conducted GWAS — typically enlisting thousands of study participants — to identify large blocks of DNA within the human genome within which genetic variants are implicated as risk factors for common diseases. But examination of GWAS data to date has seldom pointed to altered proteins, as surprisingly few protein-encoding gene variants within these broad swaths of DNA have been associated with the diseases under investigation.

Instead, the genetic risks identified through GWAS more often appear to be associated with DNA variations that do not reside within genes. The nature of this risk has defied understanding until now, fueling a perception that few medical benefits have thus far emerged from large-scale studies of human genetic variation being conducted in the wake of the initial Human Genome Project.

In the new study the researchers found that the presence of specific genetic variants in different autoimmune diseases can alter patterns of activity of genes in particular ways that affect functions of the immune system. This was true despite the fact that the genetic variants are not within genes.

To make their discoveries, the researchers developed software and used next-generation sequencing techniques to probe “epigenetic” characteristics of specialized immune cells, in which gene activity is affected without changes to the DNA sequence itself within the affected genes.

The team discovered that a majority of key DNA changes associated with autoimmune diseases occur in functional bits of DNA known as “enhancers.”

Although DNA exists within cells as long, stringy molecules, DNA can bend back upon itself with the support of the chromosome’s structural proteins, so that one piece of DNA may interact with another. Enhancers fold in this way to bind to DNA switches that turn genes on. In general the enhancers identified in the Nature study as playing a role in autoimmune disease were DNA sequences that did not match DNA-sequence motifs previously thought to be essential to enhancers, and had not previously been seen as having any functional role.

“Once again, research is revealing new meaning in the world of DNA once thought of as junk — short, seemingly random DNA sequences that in fact serve meaningful roles in human physiology,” said Alex Marson, M.D., Ph.D., UCSF Sandler Faculty Fellow and the corresponding author for the study.

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Stem cell science takes bold step at UC San Diego


Three first-in-human clinical trials are underway.

A 26-year-old woman paralyzed after a motor vehicle accident a year ago has successfully undergone a first-in-human experimental procedure to test whether neural stem cells injected at the site of a spinal cord injury is safe and could be an effective treatment.

The procedure, conducted on Sept. 30 under the auspices of the Sanford Stem Cell Clinical Center at UC San Diego Health System and in collaboration with Neuralstem Inc., a Maryland-based biotechnology firm, is the first of four in the phase one clinical trial. Post safety testing, it’s hoped that the transplanted neural stem cells will develop into new neurons that bridge the gap created by the injury, replace severed or lost nerve connections and restore at least some motor and sensory function.

The patient, whose identity remains confidential for privacy reasons, has been discharged and is recovering without complication or adverse effects at home, said Joseph Ciacci, M.D., principal investigator and neurosurgeon at UC San Diego Health System.

The spinal cord injury trial is one of three recent groundbreaking stem cell efforts at UC San Diego, supported by the Sanford Stem Cell Clinical Center, to make the significant leap from laboratory to first-in-human clinical trials.

Last month, researchers at UC San Diego Moores Cancer Center and the Sanford Stem Cell Clinical Center launched a novel phase one trial to assess the safety of a monoclonal antibody treatment that targets cancer stem cells in patients with chronic lymphocytic leukemia, the most common form of blood cancer.

And later this month, the first patient is scheduled to receive an unprecedented stem cell-based therapy designed to treat type 1diabetes in another phase one clinical trial at UC San Diego.

“What we are seeing after years of work is the rubber hitting the road,” said Lawrence Goldstein, Ph.D., director of the UC San Diego Stem Cell program and Sanford Stem Cell Clinical Center at UC San Diego Health System. “These are three very ambitious and innovative trials. Each followed a different development path; each addresses a very different disease or condition. It speaks to the maturation of stem cell science that we’ve gotten to the point of testing these very real medical applications in people.”

To be sure, Goldstein said, the number of patients involved in these first trials is small. The initial focus is upon treatment with low doses to assess safety, but also with hope of patient benefit. As these trials progress – and additional trials are launched – Goldstein predicts greater numbers of patients will be enrolled at UC San Diego and the Sanford Stem Cell Clinical Center and elsewhere.

“Clinical trials are the safest way to pursue potential therapies. You want to prove that a new therapy will work for more than just a single, random patient.”

While stem cell-based trials are beginning to emerge around the country, Goldstein noted that San Diego continues to assert itself as a stem cell research hub and a leading force for translating basic discoveries into medical applications, now and in the future.

“These innovative trials are the result of some truly rare features you find at UC San Diego and in the region,” he said. “There is a unique sense of collaboration and communication here among scientists in academia, clinical medicine and the biotechnology industry. An enterprise like the Sanford Center can promote and accelerate the very complex processes of research, development and testing so that the right people make the right connections and the right ideas and trials get fast-tracked, but in a way that ensures fundamentally the safety of patients while striving for benefit.”

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Neural stem cell transplants and spinal cord injuries
The Neuralstem phase one clinical trial, conducted over five years with four patients, is designed to assess the safety and efficacy of an approach that might, it is hoped, someday be a treatment for paralyzing spinal cord injuries.

In preclinical studies, Ciacci and Martin Marsala, M.D., a professor in the Department of Anesthesiology at UC San Diego School of Medicine and the Sanford Consortium for Regenerative Medicine, and colleagues grafted human neural stem cells into rats with spinal cord injuries. The introduced cells showed extensive growth and connected to remaining nerve cells near the injury site, resulting in significantly improved motor function with minimal side effects in animal models.

The goal now is to determine whether similar effects occur in human patients. The researchers will also test for possible therapeutic benefits, such as reduced paralysis and improvements in motor and sensory function, bowel and bladder function and pain levels.

VC-01 and Type 1 diabetes
In collaboration with ViaCyte Inc., a San Diego-based biotechnology firm specializing in regenerative medicine, UC San Diego researchers led by principal investigator Robert Henry, M.D., professor of medicine in the Division of Endocrinology and Metabolism at UC San Diego and chief of the Section of Endocrinology, Metabolism & Diabetes at the Veterans Affairs San Diego Healthcare System, have launched the first-ever phase one-two clinical trial of a stem cell-derived therapy for patients with Type 1 diabetes. The first procedure is planned for later this month, with a second tentatively scheduled in mid-November.

Type 1 diabetes mellitus is a life-threatening chronic condition in which the pancreas produces little or no insulin, a hormone needed to allow glucose to enter cells to produce energy. It is typically diagnosed during childhood or adolescence, but can also strike adults. Though far less common than Type 2 diabetes, which occurs when the body becomes resistant to insulin, Type 1 may affect up to 3 million Americans with emotionally and financially devastating consequences. Standard treatment involves daily injections of insulin and rigorous management of diet and lifestyle. Currently, there is no cure.

The two-year trial will involve approximately 40 study participants at four to six testing sites, with San Diego being first. The trial will assess the safety, tolerability and efficacy of varying doses of VC-01, which involves implanting specially encapsulated embryonic stem cell-derived cells under the skin of patients where it’s hoped they will safely mature into pancreatic beta and other cells able to produce a continuous supply of needed insulin and other substances.

Development and testing of VC-01 is funded, in part, by the California Institute for Regenerative Medicine (CIRM), Sanford Stem Cell Clinical Center and JDRF, formerly known as the Juvenile Diabetes Research Foundation. Clinical testing and coordination is provided by UC San Diego Clinical and Translational Research Institute.

Cirmtuzumab and leukemia
Researchers at UC San Diego Moores Cancer Center and the Sanford Stem Cell Clinical Center have launched a phase one human clinical trial to assess the safety and efficacy of a new monoclonal antibody for patients with chronic lymphocytic leukemia (CLL), the most common form of blood cancer in adults.

The drug, called cirmtuzumab, targets a molecule called ROR1 that normally is used only by embryonic cells during early development, but which is abnormally exploited by cancer cells to promote tumor growth and spread, otherwise known as metastasis. Metastasis is responsible for 90 percent of all cancer-related deaths.

Because ROR1 is not used by normal adult cells, scientists believe it is a unique marker of cancer cells in general and cancer stem cells in particular. ROR1 appears to drive tumor growth and disease spread and scientists think that presents an excellent novel target for anti-cancer therapy.

Cirmtuzumab was developed at Moores Cancer Center in the laboratory of Thomas Kipps, M.D., Ph.D., who led this effort as one of six projects initially funded through CIRM’s HALT leukemia grant to co-principal investigators Dennis Carson, M.D., and Catriona Jamieson, M.D., Ph.D.  The drug’s name acknowledges CIRM’s continued support in a “Disease Team III” award, which provides some of the resources needed for a clinical trial. The Leukemia and Lymphoma Society has also provided additional support.

The trial will involve patients with relapsed or refractory CLL receiving an intravenous infusion every 14 days at Moores Cancer Center, followed by regular monitoring and clinic visits to assess efficacy and identify and manage any adverse effects. Initial treatment is planned for two months.

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Diabetes in a dish


With NIH grant, researchers hope to build bits of miniature pancreas.

Stem cells differentiating into pancreatic cells. Cells are made visible by blue dye. Transcription factors show in green and red.

Although type 1 diabetes can be controlled with insulin injections and lifestyle modifications, major advances in treating the disease have not been made in more than two decades and there remain fundamental gaps in what is understood about its causes and how to halt its progression.

With a 5-year, $4-million grant from the National Institutes of Health, researchers at the UC San Diego School of Medicine and bioengineers at UC San Diego Jacobs School of Engineering, with colleagues at UC Irvine and Washington University in St. Louis hope to change this.

The team’s goal is to bioengineer a miniature pancreas in a dish, not the whole pancreas but the organ’s irregularly shaped patches – called Islets of Langerhans – that regulate the body’s blood sugar levels.

“The bottleneck to new cures for type 1 diabetes is that we don’t have a way to study human beta cells outside of the human body,” said Maike Sander, M.D., professor in  the departments of pediatrics and cellular and molecular medicine and director of the Pediatric Diabetes Research Center at UC San Diego and Rady Children’s Hospital-San Diego. “If we are successful, we will for the first time be able to study the events that trigger beta cell destruction.”

Beta cells in islets secrete the hormone insulin. In patients with type 1 diabetes, the beta cells are destroyed and the body loses its ability to regulate blood sugar levels. Researchers, however, are unsure of the mechanism by which beta cells are lost. Some researchers believe that the disease may be triggered by beta cell apoptosis (self-destruction); others believe that the body’s immune system initiates attacks on these cells.

To actually bioengineer the pancreas’ endocrine system, researchers plan to induce human stem cells to develop into beta cells and alpha cells, as well as other cells in the islet that produce hormones important for controlling blood sugar levels. These cells will then be co-mingled with cells that make blood vessels and the cellular mass will be placed within a collagen matrix mimicking the pancreas. The matrix was developed by Karen Christman, Ph.D., associate professor of bioengineering at the Jacobs School of Engineering.

“Our previous work with heart disease has shown that organ-specific matrices help to create more mature heart cells in a dish,” Christman said. “I am really excited to apply the technology to diabetes research.”

If the pancreatic islets can be successfully bioengineered, researchers could conduct mechanistic studies of beta cell maturation, replication, reprogramming, failure and survival. They say new drug therapies could be tested in the 3-D culture. It also would be possible to compare beta cells from people with and without the disease to better understand the disease’s genetic component. Such work might eventually lead to treatments for protecting or replacing beta cells in patients.

The project is being funded through the National Institutes of Health Consortium on Human Islet Biomimetics.

Other grant co-recipients include Christopher Hughes, Ph.D., chair, Molecular Biology and Biochemistry School of Biological Sciences, UC Irvine; and Steven George, M.D., Ph.D., chair of the Department of Biomedical Engineering at Washington University in St. Louis.

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Diabetes doesn’t slow down UCLA student


She forms campus group to educate public on ways to prevent diabetes.

UCLA student Megan Cory, who is doing research on diabetes, was diagnosed with the disease when she was 14. She is not only working to educate people about diabetes prevention, but helped raise funds for the Larry L. Hillblom Islet Research Center at UCLA, headed by Dr. Peter Butler (right).

It seems that everything in Megan Cory’s life has pointed her toward a career in medicine. It’s what she has wanted to do all her life — even after she got some bad news about her own health that would have frightened and discouraged most people.

Instead of lamenting her diagnosis of type 1 diabetes, she has used that health condition to benefit UCLA and the community in several ways.

Ever since childhood, Cory has been fascinated by what doctors do. From her interactions with a neighbor and a family friend who were both doctors, she knew early on she wanted to be just like them.

“Ever since then, I knew that doctors make people feel better,” said Cory, now 20 years old and a UCLA biochemistry major with a minor in theater.  “The cool thing is that … everything that’s happened to me since then has strengthened my wanting to be a doctor. It’s my calling. I didn’t have an epiphany. I felt like this my whole life, and I know I’m headed in the right direction.”

Her decision to pursue medicine was also affirmed when she was diagnosed with type 1 diabetes.

Cory had always been active — almost tirelessly so — in theater, science fairs and athletics. “Everything you can think of, I was involved in,” she said. But at age 13, she was also constantly thirsty, and even though she was eating more, she was losing weight. So her parents took her to see a doctor who, at first, thought she was simply too busy.  A visit to a cardiologist whose sister was an endocrinologist brought a diagnosis. “He smelled my breath, and he knew something was wrong,” Cory said.

She learned she had type 1diabetes two days after her 14th birthday. It’s a day she will never forget. “I can play it like a movie in my head,” she said.

Her mother and father were sitting in the exam room while Cory was lying on the bed when the doctor gave them the news. Her mother passed out, and her father was devastated. Cory cried — but only because she didn’t understand what it all meant.

“After a few minutes, I stopped crying, and I asked myself, ‘Why are you crying? You don’t even know what it is,’” she recalled. “I stood up and asked the doctor, ‘What’s next? What do I need to do? This diabetes thing is not going to stop me from doing the things that I love.’”

Impressed with her positive attitude, her doctors later asked her to talk to other teens with diabetes. So many of them think of diabetes as a form of punishment, making it difficult for them to deal with it, she said.

“I think of it another way: Diabetes is manageable; it’s just a little inconvenience, a little extra something you have to do,” she said.

That isn’t to say it’s not serious, she points out to teens with diabetes. But at least people with diabetes have the means to control their disease, which is something that people with other diseases can’t do. “Be thankful that we have something we can control,” she tells them.

Cory has also led by example. In high school, she became a Texas state tennis champion three times in a row from 2009 through 2011. She participated in various diabetes-related programs for young people, was a finalist in the 2010 International Science Fair and performed in plays, mostly in musicals.

Now a student at UCLA, her focus is on preparing for medical school and helping her peers with diabetes and others who are dedicated to educating people about both types of diabetes. She started DiaBeaters, a campus group that promotes a healthy lifestyle to help prevent the disease.

This summer, students in DiaBeaters talked about prevention to students and parents attending the UCLA Medicine Pediatrics Comprehensive Care Center Sports Fair in Santa Monica. Cory is hoping to reach out to more high school students as well as local and other businesses throughout Los Angeles.

Through DiaBeaters, she also helped raise $1,000 for the Larry L. Hillblom Islet Research Center at UCLA for diabetes research.

Cory, who’s now interested in becoming an endocrinologist, has been conducting research at the Hillblom center on alpha mass in non-diabetic people over their adult lifespans. Alpha cells produce glucagon, which helps maintain blood sugar levels between meals. She’s found that this mass remains constant with age even as the tissue around it withers away.

Dr. Peter Butler, director of the Hillblom center, said he’s been particularly impressed with Cory’s enthusiasm and diligence in her research, as well as her commitment of time and support to the cause.

“She has been a most welcome student volunteer in the UCLA islet research center,” Butler said. “She is passionate about the need to bring greater awareness to the student community about diabetes. We are fortunate to have her here at UCLA.”

This summer Cory applied to the David Geffen School of Medicine at UCLA and other medical schools. She said she hopes she can stay on this campus to continue growing DiaBeaters, working on her research and staying involved with the biochemistry society BiochemASE, which she co-founded.

“I want to show people that when something bad comes into your life, there’s a different way to approach it,” Cory said.

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Prions can trigger ‘stuck’ wine fermentations


Findings may have implications for better understanding diabetes.

A chronic problem in winemaking is “stuck fermentation,” when yeast that should be busily converting grape sugar into alcohol and carbon dioxide prematurely shuts down, leaving the remaining sugar to instead be consumed by bacteria that can spoil the wine.

A team of researchers including UC Davis yeast geneticist Linda Bisson has discovered a biochemical communication system behind this problem.  Working through a prion — an abnormally shaped protein that can reproduce itself — the system enables bacteria in fermenting wine to switch yeast from sugar to other food sources without altering the yeast’s DNA.

“The discovery of this process really gives us a clue to how stuck fermentations can be avoided,” said Bisson, a professor in the Department of Viticulture and Enology. “Our goal now is to find yeast strains that essentially ignore the signal initiated by the bacteria and do not form the prion, but instead power on through the fermentation.”

She suggests that the discovery of this biochemical mechanism, reported today (Aug. 28) in the journal Cell, may also have implications for better understanding metabolic diseases, such as Type 2 diabetes, in humans.

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Low-income diabetics up to 10 times likelier to lose a limb than wealthier patients


Most amputations preventable with earlier medical care, UCLA researchers say.

Carl Stevens, UCLA

It’s no secret that poverty is bad for your health. Now a new UCLA study demonstrates that California diabetics who live in low-income neighborhoods are up to 10 times more likely to lose a toe, foot or leg than patients residing in more affluent areas of the state. Earlier diagnosis and proper treatment could prevent many of these amputations, the researchers say.

The study authors hope their findings, published in the August issue of Health Affairs, will motivate public agencies and medical providers to reach out to patients at risk of late intervention and inspire policymakers to adopt legislation to reduce barriers to care.

“I’ve stood at the bedsides of diabetic patients and listened to the surgical residents say, ‘We have to cut your foot off to save your life,’” said lead author Dr. Carl Stevens, a clinical professor of medicine at the David Geffen School of Medicine at UCLA. “These patients are often the family breadwinners and parents of young children — people with many productive years ahead of them.

“When you have diabetes, where you live directly relates to whether you’ll lose a limb to the disease,” added Stevens, an emergency physician for 30 years at Harbor–UCLA Medical Center. ”Millions of Californians have undergone preventable amputations due to poorly managed diabetes. We hope our findings spur policymakers nationwide to improve access to treatment by expanding Medicaid and other programs targeting low-income residents, as we did in California in 2014.”

Dylan Roby, UCLA

The authors used data from the UCLA Center for Health Policy Research’s California Health Interview Survey, which estimated the prevalence of diabetes among low-income populations by ZIP code. They blended these statistics with household-income figures from the U.S. Census Bureau and hospital discharge data from the Office of Statewide Health Planning and Development that tracked diabetes-related amputations by ZIP code.

The result was a detailed set of maps showing diabetic amputation rates by neighborhood for patients 45 and older — the age range at greatest risk for amputation from disease complications.

“Neighborhoods with high amputation rates clustered geographically into hot spots with a greater concentration of households falling below the federal poverty level,” said co-author Dylan Roby, director of health economics at the UCLA Center for Health Policy Research and an assistant professor at the UCLA Fielding School of Public Health. “Amputation rates in California were 10 times higher in the poorest neighborhoods, like Compton and East Los Angeles, than in the richest neighborhoods, such as Malibu and Beverly Hills.”

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Patient-centered research projects receive funding


UC Berkeley, UC Davis among recipients.

Heather Young, UC Davis

Two University of California research projects have been approved for funding in the latest round of awards by the Patient-Centered Outcomes Research Institute (PCORI).

A research project led by the Betty Irene Moore School of Nursing at UC Davis was approved for a $2.1 million award to study improving health for individuals with diabetes. Associate Vice Chancellor for Nursing and Dean Heather M. Young will lead the research project at UC Davis. The study will focus on individuals with diabetes and determine if innovative approaches, including mobile technology and nurse coaching, help those people better manage the chronic disease.

Young noted that researchers from other centers and organizations — including the UC Center for Information Technology Research for the Improvement of Society (CITRIS), the UC Davis Clinical Translational Science Center and the Initiative for Wireless Health and Wellness at UC Davis — contributed to foundational research for this study and will play important roles in completing this three-year project.

Stephen Shortell, UC Berkeley

Also, a research project led by the Center for Healthcare Organizational and Innovation Research (CHOIR) at the UC Berkeley School of Public Health was approved for a $2.1 million award to study the delivery of care to patients with diabetes and cardiovascular diseases. Under the leadership of professors Stephen Shortell and Hector Rodriguez, center researchers will study the impact of patient activation and engagement in two large accountable care organizations — Advocate Health Care in Chicago and HealthCare Partners in Los Angeles. The study will see whether patients with diabetes or cardiovascular diseases who receive care from practices that more fully involve their patients have better clinical outcomes and satisfaction with their care than those that do not.

The studies are two of 33 proposals PCORI approved for $54.8 million in funding this week to advance the field of patient-centered comparative effectiveness research and provide patients, health care providers, and other clinical decision makers with information that will help them make better-informed choices.

Earlier this year, the National Institutes of Health and PCORI joined together to support a clinical trial to test individually tailored interventions to prevent fall-related injuries. That award, made by the NIH’s National Institute on Aging and funded by PCORI as part of the two organizations’ Falls Injuries Prevention Partnership, is expected to total $30 million over the five-year project.

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DDT linked to slow metabolism, obesity and diabetes


Study shows developmental exposure to DDT can affect female offspring.

Exposure of pregnant mice to the pesticide DDT is linked to an increased risk of obesity, diabetes, high cholesterol and related conditions in female offspring later in life, according to a study led by the University of California, Davis.

The study, published online today (July 30) in the journal PLOS ONE, is the first to show that developmental exposure to DDT increases the risk of females later developing metabolic syndrome — a cluster of conditions that include increased body fat, blood glucose and cholesterol.

DDT was banned in the United States in the 1970s but continues to be used for malaria control in countries including India and South Africa.

Scientists gave mice doses of DDT comparable to exposures of people living in malaria-infested regions where it is regularly sprayed, as well as of pregnant mothers of U.S. adults who are now in their 50s.

“The women and men this study is most applicable to in the United States are currently at the age when they’re more likely to develop metabolic syndrome, because these are diseases of middle- to late adulthood,” said lead author Michele La Merrill, assistant professor of environmental toxicology at UC Davis.

The scientists found that exposure to DDT before birth slowed the metabolism of female mice and lowered their tolerance of cold temperature. This increased their likelihood of developing metabolic syndrome and its host of related conditions.

“As mammals, we have to regulate our body temperature in order to live,” La Merrill said. “We found that DDT reduced female mice’s ability to generate heat. If you’re not generating as much heat as the next guy, instead of burning calories, you’re storing them.”

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Mechanism that clears excess of pancreatic protein linked with Type 2 diabetes


Autophagy appears to not work properly, contributing to destruction of insulin-producing beta cells.

People with Type 2 diabetes have an excess of a protein called islet amyloid polypeptide, or IAPP, and the accumulation of this protein is linked to the loss of insulin-producing pancreatic beta cells.

What causes this accumulation of IAPP in pancreatic beta cells of people with diabetes has remained a mystery. But a team of researchers from the Larry L. Hillblom Islet Research Center led by Dr. Peter Butler, professor of medicine at UCLA, may have found an answer in autophagy, a process that clears damaged and toxic proteins from cell.

In a study published online July 18 in the peer-reviewed Journal of Clinical Investigation, the UCLA researchers suggest that, in people who do not have Type 2 diabetes, autophagy prevents the accumulation of toxic forms of IAPP. In people with Type 2 diabetes, the process appears to not work properly, contributing to the destruction of beta cells. As the body’s insulin producers, beta cells play a key role in maintaining healthy blood sugar levels.

“Only a few previous studies have reported that autophagy is important for beta cell function and survival,” said Safia Costes, a research scientist at the Hillblom Center and the study’s co-first author. “Those studies, however, were not conducted to address the role of this process in the regulation of the amyloidogenic protein, which is an important contributor to Type 2 diabetes.”

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New compound treats both blindness and diabetes in animal studies


UCSF-led study offers fresh insights into role of cellular stress in degenerative illnesses.

In a new study led by UC San Francisco scientists, a chemical compound designed to precisely target part of a crucial cellular quality-control network provided significant protection, in rats and mice, against degenerative forms of blindness and diabetes.

In addition to opening a promising drug-development path for the wide range of diseases caused by cell loss, the new research offers a new view of the workings of the unfolded protein response (UPR), a cellular “life-or-death” signaling network: When cells are under stress, the UPR works to ensure that they produce properly configured proteins, but those cells not up to this task are quickly prompted by the UPR to self-destruct.

A component of the UPR known as the IRE1 pathway has generally been thought to handle the protective aspects of this response, promoting cell survival by providing cells with the biological resources they need to cope with stress, while a complementary pathway, called PERK, has been associated with cell death.

But in the new research, published in today’s (July 10) edition of Cell, when researchers used KIRA6, a small-molecule kinase inhibitor they designed to inhibit the actions of IRE1α — the molecular sensor that triggers the IRE1 pathway — they blocked cell death and preserved function in experimental models of two human diseases.

In two rat models of retinitis pigmentosa, a disease in which light-sensing cells in the eye progressively die off, causing blindness, KIRA6 preserved both the number of these cells and visual function. And in mice from a strain known as Akita, which carry a genetic mutation that causes diabetes in early life as stressed insulin-producing beta cells of the pancreas degenerate, KIRA6 protected beta cells from cell death, leading to a twofold increase in insulin production and improving blood glucose control.

“This is a huge advance in our field,” said co-senior author Scott A. Oakes, M.D., associate professor of pathology at UCSF. “On the surface these would seem to be two very different diseases, but IRE1-induced cell death is at the root of both of them.”

The results are the culmination of “a gigantic project,” first to establish that the IRE1 pathway could drive degenerative disease, and then to design and test compounds to head off the damage, said UCSF’s Feroz Papa, M.D., Ph.D., associate professor of medicine and co-senior author, and a member of the California Institute for Quantitative Biosciences. “It took four years, over a hundred separate experiments in various contexts — not counting replications — and involved 24 researchers working in seven labs across four cities.”

KIRA6 is the latest in a series of compounds (the acronym stands for “Kinase-Inhibiting RNase Attenuators”) that were originally designed and synthesized in the labs of study co-authors Dustin J. Maly, Ph.D., associate professor of chemistry at The University of Washington, Seattle, and Bradley J. Backes, Ph.D., associate professor of medicine at UCSF.

“While KIRA6 showed efficacy in animals,” said Papa, “it is important to stress that more optimization through medicinal chemistry efforts is needed to develop this class of compounds to the stage where they could be tested for efficacy in humans through clinical trials.”

Oakes and Papa said that support from the Cleveland, Ohio-based Harrington Discovery Institute was crucial to sustaining this complex collaboration. Both scientists were 2013 winners of Scholar-Innovator Awards from the institute, which is part of The Harrington Project for Development and Discovery a $250 million national model to accelerate the development of medical breakthroughs by physician-scientists into medicines that benefit patients. Other critical support for the work came from the National Institutes of Health, the Juvenile Diabetes Research Foundation, the Burroughs Wellcome Fund, the American Cancer Society and the Howard Hughes Medical Institute.

Other UCSF researchers on the project included Douglas B. Gould, Ph.D., associate professor of ophthalmology; Michael German, M.D., professor of medicine; postdoctoral fellows Rajarshi Ghosh, Ph.D., and Likun Wang, Ph.D., and graduate student Eric S. Wang, all co-first authors; postdoctoral fellows Aeid Igbaria, Ph.D., Shuhei Morita, M.D., Ph.D., Kris Prado, M.D., Maike Thamsen, Ph.D., Hector Macias, Ph.D., and Marcel V. Alavi, Ph.D.; former research associate Deborah Caswell; graduate student Kurt F. Weiberth; and research associate Micah J. Gliedt. The team was also joined by other colleagues from The University of Washington, Seattle; The Miller School of Medicine at The University of Miami, Florida; and the Albert Einstein College of Medicine, in Bronx, New York.

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