TAG: "Diabetes"

Forging ahead in fight against hemochromatosis


Research advances are improving prognosis for hereditary blood-iron overload disorder.

By Tom Vasich, UC Irvine

Since coming to the UC Irvine School of Medicine in 1998, Christine and Gordon McLaren have been leading the way in the research and treatment of hemochromatosis, a hereditary disease that causes the body to absorb too much iron from ingested food.

The excess iron is stored in various organs – especially the liver, heart and pancreas – and can poison them, precipitating such life-threatening conditions as cirrhosis and liver cancer, heart arrhythmias and diabetes. Once considered a rare disease, hemochromatosis is now recognized as one of the most common inherited disorders, affecting as many as 1 million people in the U.S.

Christine McLaren is a professor of epidemiology, and Dr. Gordon McLaren is a professor of medicine specializing in hematology and oncology who practices in the Veterans Affairs Long Beach Healthcare System.

Over the past few months, the wife and husband have made noteworthy strides: Last September, they received a $2 million grant from the National Institute of Diabetes & Digestive & Kidney Diseases to investigate the genetic modifiers of iron status in hemochromatosis. And a study the McLarens presented in December at the annual meeting of the American Society of Hematology was a “Best of ASH” honoree.

Here, they discuss their work:

How did you both acquire an interest in this field?

Christine: We developed a focus on the disorder independently. Early in my career, I provided statistical consulting for hematologists who had research projects involving iron overload and iron deficiency. Meanwhile, Gordon has had a long-standing interest for over 30 years in the area of iron metabolism, with an emphasis on hemochromatosis.

In 2000, after Gordon and I had joined the faculty at UCI, we were fortunate to receive National Institutes of Health funding to work together and to screen more than 20,000 primary care patients for iron overload and hereditary hemochromatosis at UCI ambulatory care clinics.

The primary goal of that research was to contribute to a national epidemiologic study of iron overload and hereditary hemochromatosis in a multicenter, multiethnic, primary care-based sample of over 100,000 people.

How are people susceptible to hemochromatosis?

Gordon: Generally, iron overload occurs only in people with two copies of the hemochromatosis gene (one copy inherited from each parent). The frequency of having two copies in the European-American population is about 5 per 1,000 persons.

However, not all people with two copies of the gene will develop iron overload. Thus, we think there must be other factors – such as mutations in other genes affecting dietary iron absorption – that are required for the disease to become fully manifest, and this is what we’re studying.

If we can identify what causes the difference, we may be able to use this information to predict which patients are at greater risk of developing iron overload and when to begin therapy to remove excess iron before it accumulates to toxic levels.

Interestingly, the frequency of the genetic predisposition to hemochromatosis among European-Americans is the same in men and women, but for reasons that are not completely understood, men are more likely to develop the full-blown syndrome.

What do you plan to accomplish with the $2 million in support from the National Institute of Diabetes & Digestive & Kidney Diseases?

Gordon: We’re leading a multidisciplinary team of investigators at eight research institutions in the U.S., Canada and Australia. To better understand the reasons for this variability in disease expression, our group will examine genetic factors in the susceptibility or resistance to iron overload in patients with a genetic predisposition for hemochromatosis across a wide range of geographic areas.

The purpose of this research is to identify other inherited traits that may interact to cause more severe disease in certain patients. It’s important to identify persons at risk because effective iron removal treatment is available, and beginning such therapy before iron overload becomes advanced can prevent disease complications.

Christine: This work can have important clinical applications, including the ability to identify young hemochromatosis patients at risk for potentially severe iron overload later in life, thereby influencing physicians’ recommendations for iron removal therapy and long-term follow-up. We’re hopeful that our findings will lead to new approaches that will inform the development of innovative prevention and treatment strategies tailored to the individual.

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Pens filled with high-tech inks for do-it-yourself sensors


New simple tool is opening door to where anyone will be able to build sensors, anywhere.

By Ioana Patringenaru, UC San Diego

A new simple tool developed by nanoengineers at the University of California, San Diego, is opening the door to an era when anyone will be able to build sensors, anywhere, including physicians in the clinic, patients in their home and soldiers in the field.

The team from the University of California, San Diego, developed high-tech bio-inks that react with several chemicals, including glucose. They filled off-the-shelf ballpoint pens with the inks and were able to draw sensors to measure glucose directly on the skin and sensors to measure pollution on leaves.

Skin and leaves aren’t the only media on which the pens could be used. Researchers envision sensors drawn directly on smart phones for personalized and inexpensive health monitoring or on external building walls for monitoring of toxic gas pollutants. The sensors also could be used on the battlefield to detect explosives and nerve agents.

The team, led by Joseph Wang, the chairman of the Department of NanoEngineering at the University of California, San Diego, published their findings in the Feb. 26 issue of Advanced Healthcare Materials. Wang also directs the Center for Wearable Sensors at UC San Diego.

“Our new biocatalytic pen technology, based on novel enzymatic inks, holds considerable promise for a broad range of applications on site and in the field,” Wang said.

The biggest challenge the researchers faced was making inks from chemicals and biochemicals that aren’t harmful to humans or plants; could function as the sensors’ electrodes; and retain their properties over long periods in storage and in various conditions. Researchers turned to biocompatible polyethylene glycol, which is used in several drug delivery applications, as a binder. To make the inks conductive to electric current they used graphite powder. They also added chitosan, an antibacterial agent which is used in bandages to reduce bleeding, to make sure the ink adhered to any surfaces it was used on. The inks’ recipe also includes xylitol, a sugar substitute, which helps stabilize enzymes that react with several chemicals the do-it-yourself sensors are designed to monitor.

Reusable glucose sensors

Wang’s team has been investigating how to make glucose testing for diabetics easier for several years. The same team of engineers recently developed non-invasive glucose sensors in the form of temporary tattoos. In this study, they used pens, loaded with an ink that reacts to glucose, to draw reusable glucose-measuring sensors on a pattern printed on a transparent, flexible material which includes an electrode. Researchers then pricked a subject’s finger and put the blood sample on the sensor. The enzymatic ink reacted with glucose and the electrode recorded the measurement, which was transmitted to a glucose-measuring device. Researchers then wiped the pattern clean and drew on it again to take another measurement after the subject had eaten.

Researchers estimate that one pen contains enough ink to draw the equivalent of 500 high-fidelity glucose sensor strips. Nanoengineers also demonstrated that the sensors could be drawn directly on the skin and that they could communicate with a Bluetooth-enabled electronic device that controls electrodes called a potentiostat, to gather data.

Sensors for pollution and security

The pens would also allow users to draw sensors that detect pollutants and potentially harmful chemicals sensors on the spot. Researchers demonstrated that this was possible by drawing a sensor on a leaf with an ink loaded with enzymes that react with phenol, an industrial chemical, which can also be found in cosmetics, including sunscreen. The leaf was then dipped in a solution of water and phenol and the sensor was connected to a pollution detector. The sensors could be modified to react with many pollutants, including heavy metals or pesticides.

Next steps include connecting the sensors wirelessly to monitoring devices and investigating how the sensors perform in difficult conditions, including extreme temperatures, varying humidity and extended exposure to sunlight.

“Biocompatible Enzymatic Roller Pens for Direct Writing of Biocatalytic Materials: ‘Do-it-yourself’ Electrochemical Biosensors” is authored by Amay J. Bandodkar, Wenzhao Jia, Julian Ramirez and Wang.

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Molecular link between obesity, type 2 diabetes reveals potential therapy


UC San Diego researchers find that inflammatory molecule LTB4 promotes insulin resistance.

By Heather Buschman, UC San Diego

Obesity causes inflammation, which can in turn lead to type 2 diabetes. What isn’t well established is how inflammation causes diabetes — or what we can do to stop it. Researchers at the UC San Diego School of Medicine have discovered that the inflammatory molecule LTB4 promotes insulin resistance, a first step in developing type 2 diabetes. What’s more, the team found that genetically removing the cell receptor that responds to LTB4, or blocking it with a drug, improves insulin sensitivity in obese mice. The study is published today (Feb. 23) by Nature Medicine.

“This study is important because it reveals a root cause of type 2 diabetes,” said Jerrold M. Olefsky, M.D., professor of medicine, associate dean for scientific affairs and senior author of the study. “And now that we understand that LTB4 is the inflammatory factor causing insulin resistance, we can inhibit it to break the link between obesity and diabetes.”

Here’s what’s happening in obesity, according to Olefsky’s study. Extra fat, particularly in the liver, activates resident macrophages, the immune cells living there. These macrophages then do what they’re supposed to do when activated — release LTB4 and other immune signaling molecules to call up an influx of new macrophages. Then, in a positive feedback loop, the newly arriving macrophages also get activated and release even more LTB4 in the liver.

This inflammatory response would be a good thing if the body was fighting off an infection. But when inflammation is chronic, as is the case in obesity, all of this extra LTB4 starts activating other cells, too. Like macrophages, nearby liver, fat and muscle cells also have LTB4 receptors on their cell surfaces and are activated when LTB4 binds them. Now, in obesity, those cells become inflamed as well, rendering them resistant to insulin.

Once Olefsky and his team had established this mechanism in their obese mouse models, they looked for ways to inhibit it. First, they genetically engineered mice that lack the LBT4 receptor. When that approach dramatically improved the metabolic health of obese mice, they also tried blocking the receptor with a small molecule inhibitor. This particular compound was at one time being tested in clinical trials, but was dropped when it didn’t prove all that effective in treating its intended ailment. Olefsky’s team fed the prototype drug to their mice and found that it worked just as well as genetic deletion at preventing — and reversing — insulin resistance.

“When we disrupted the LTB4-induced inflammation cycle either through genetics or a drug, it had a beautiful effect — we saw improved metabolism and insulin sensitivity in our mice,” Olefsky said. “Even though they were still obese, they were in much better shape.”

Co-authors of this study include Pingping Li, Da Young Oh, Gautam Bandyopadhyay, William S. Lagakos, Saswata Talukdar, Olivia Osborn, Andrew Johnson, Heekyung Chung, Rafael Mayoral, Michael Maris, Jachelle M Ofrecio, Sayaka Taguchi, Min Lu, all at UC San Diego.

This research was funded, in part, by the National Institute of Diabetes and Digestive and Kidney Diseases (DK033651, DK074868, DK063491, DK09062), the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Merck Inc.

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Tobacco-smoking parents increase diabetes risk for children exposed in utero


“Smoking of parents is by itself a risk factor for diabetes, independent of obesity or birth weight.”

Credit: iStock

By Michele La Merrill and Kat Kerlin, UC Davis

Children exposed to tobacco smoke from their parents while in the womb are predisposed to developing diabetes as adults, according to a study from the University of California, Davis, and the Berkeley nonprofit Public Health Institute.

In the study, published today (Feb. 9) in the Journal of Developmental Origins of Health and Disease, women whose mothers smoked while pregnant were two to three times as likely to be diabetic as adults. Dads who smoked while their daughter was in utero also contributed to an increased diabetes risk for their child, but more research is needed to establish the extent of that risk.

“Our findings are consistent with the idea that gestational environmental chemical exposures can contribute to the development of health and disease,” said lead author Michele La Merrill, an assistant professor of environmental toxicology at UC Davis.

The study analyzed data from 1,800 daughters of women who had participated in the Child Health and Development Studies, an ongoing project of the Public Health Institute. The CHDS recruited women who sought obstetric care through Kaiser Permanente Foundation Health Plan in the San Francisco Bay Area between 1959 and 1967. The data was originally collected by PHI to study early risk of breast cancer, which is why sons were not considered in this current study.

In previous studies, fetal exposure to cigarette smoke has also been linked to higher rates of obesity and low birth weight. This study found that birth weight did not affect whether the daughters of smoking parents developed diabetes.

“We found that smoking of parents is by itself a risk factor for diabetes, independent of obesity or birth weight,” said La Merrill. “If a parent smokes, you’re not protected from diabetes just because you’re lean.”

The study was supported through funding from the National Institute of Environmental Health Sciences, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the California Breast Cancer Research Program Special Research Initiative.

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A gamechanger for pediatric diabetes


UC Santa Barbara scientists are developing a pediatric artificial pancreas.

UC Santa Barbara chemical engineers Frank Doyle (left) and Eyal Dassau with a model of their artificial pancreas for adults.

By Sonia Fernandez, UC Santa Barbara

Anyone who lives with Type 1 diabetes is all too familiar with the sheer amount of effort — and often round-the-clock attention — required to manage the disease. Food intake is closely monitored, as is physical activity, and the period between meals is carefully tracked in order to calculate appropriate insulin dosages, which have to be delivered at the right time.

All this to keep blood glucose levels within a healthy range.

For parents of children with Type 1 diabetes, the stress is amplified. Children’s unpredictable eating habits and food preferences, spontaneous physical activity and sensitivity to insulin require parents to be extra vigilant. The dreaded overnight hypoglycemia — a condition in which glucose levels drop to dangerously low levels between dinner and breakfast — requires parents to interrupt their own sleep habits so they can check their children’s blood sugar and give the child a snack if needed. Conversely, if the glucose reading is too high, they would need to administer insulin. And those eagerly anticipated birthday parties (complete with cake and ice cream), sleepovers and playdates? Only if the other parents involved can be trusted to monitor the child closely and respond to emergencies.

But with a $1.8-million, three-year grant from the National Institutes of Health, UC Santa Barbara chemical engineers Frank Doyle and Eyal Dassau and Yale University’s Dr. Stuart Weinzimer could make such hands-on care a thing of the past. And it could happen within a decade. The researchers and their teams are embarking on the development of artificial pancreas (AP) for children. The grant is the UC Santa Barbara researchers’ first award for a pediatric closed-loop study.

“I think one of the most important things we can do is alleviate parents’ fears of overnight hypoglycemia,” said Dassau, a research engineer in UC Santa Barbara’s Department of Chemical Engineering and the principal investigator on this study. “As a result, parents can get a full night’s sleep without having to worry what might happen at 4 a.m., or who’s awake to check their child’s glucose. That would be a big success.”

Over the past 12 years, Doyle, director of the Institute for Collaborative Biotechnologies at UC Santa Barbara, and his research group have developed the artificial pancreas, a combination of sensor technology and insulin pump, which, thanks to a control algorithm, reads levels of glucose and injects the appropriate amount of insulin based on the data, and the patient’s individual characteristics.

Thus far, the researchers have made great strides in developing UCSB’s AP for use in adults. In a collaboration with the William Sansum Diabetes Research Center in Santa Barbara, and in local and international clinical trials, the AP’s multinational team of researchers has been refining the device based on input from engineering, clinical and behavioral aspects of diabetes management.

Tailoring the device to manage pediatric diabetes, however, requires the researchers to consider an additional set of factors.

“Children have unpredictable eating habits,” said Dassau. “You can put a certain amount of food in front of them, but you don’t know whether they’re going to eat it all.” Additionally, they may graze throughout the day, and tend to be more spontaneous than adults with their physical activity. Also coming into play are the children’s general lack of awareness about their condition and their limited ability to inform parents and caregivers of any immediate health situations.

The protocols for diabetes management vary by age as well. With adults and teenagers who can predict their meals and mealtimes, insulin can be delivered subcutaneously about 15 minutes before eating to ensure an adequate amount of the hormone has reached the bloodstream by the time they eat. This “pre-meal bolus” is an ideal way to manage meal glucose control, as it allows insulin to be absorbed when the glucose surge arrives with the meal, and mimics as closely as possible the way a healthy individual’s body regulates blood sugar.

However, in younger children with Type 1 diabetes, because of unpredictable eating habits and higher sensitivity to insulin, the hormone must be delivered after the meal, which creates both a delay and the chance of a swing to the hypoglycemic extreme of the blood sugar range, due to the tendency to overcompensate.

According to the researchers, the first phase of research for the pediatric AP involves data collection. With clinical expertise from Weinzimer, a pediatric endocrinologist, professor at Yale School of Medicine and a leading expert on Type 1 diabetes in children, the researchers will tune the AP’s Zone MPC (model predictive control) algorithm to meet the specific challenges of managing pediatric diabetes.

“I would look for the following things in a pediatric version of an AP: safety above all; efficacy; reliability; and ease of use,” said Weinzimer. In addition to protecting against constant wild swings in blood sugar, which would in turn alleviate the high rates of anxiety, depression and burnout in parents, and prevent the additional problem of disrupted psychosocial development in children with Type 1 diabetes, he said. The device itself must perform in a predictable manner and not be overly complicated or burdensome to use.

“One of the things I appreciate most about Drs. Doyle and Dassau is that they are, above all, scientists. They are extremely knowledgeable about control systems for the artificial pancreas, world experts in fact, and they approach this field with scientific rigor and balance,” Weinzimer continued. “We have to be very careful as investigators not to minimize the potential risks and shortcomings in our systems as we test them. We have a moral duty to protect our patients. I firmly believe that these systems will be transformative in diabetes care, but we should not lose our scientific objectivity and skepticism. Frank and Eyal have always struck me as very balanced and circumspect in how they approach this field, and I am looking forward to working with them.”

“We’ve already proved in previous clinical trials that our medically inspired artificial pancreas design can handle unannounced meals and physical activity,” said Dassau, adding that bringing this design to the younger population of Type I diabetes patients would ease the burden on parents who worry about the extra cookie or surprise sugary treat. “We’ve already developed safety algorithms for hypo- and hyperglycemia that can be adjusted for young children.”

Because insulin requirements change as the child gets older, the algorithm will be adjusted and refined according to different age groups, the researchers noted.

The second phase of the project involves developing and in-clinic testing of an advisory system and an alert system for parents that both provides insight on strategies for the management of their children’s conditions in general, and informs them of impending hypo- or hyperglycemia.

At every phase, the researchers will conduct repeated evaluations and refinements to the algorithm as well as to the alert and advisory systems. The goal is to give parents and children the ability to be involved in the management of diabetes to the extent that they can be, while safeguarding against extremes when unexpected circumstances arise. Snacking, unscheduled naps, spur-of-the-moment activities or missed meals will no longer result in increased stress levels for both parents and children.

According to Doyle, who holds the Mellichamp Chair in Process Control at UC Santa Barbara, when his group started work on the artificial pancreas over a decade ago, the researchers found that subjects using the conventional multiple daily injection method of controlling blood sugar were able to keep their glucose level in a safe range for only slightly over 50 percent of the time.

“In our most recent trials, we have demonstrated that our algorithms can keep subjects in a safe range for 80 percent or more of the time,” he said. The UC Santa Barbara AP’s Health Monitoring System sends user alerts in the form of messages and audible signals when problems arise, such as blood sugars that are trending low. Additionally, Doyle’s AP researchers have two other active grants funding research to examine how the device can monitor its own operations and alert users to potential malfunctions.

In future studies, pediatric AP testing will move to an outpatient component, in which subjects are given free rein over what they eat and do, but at locations near the clinic, with supervision from technical staff.

“But the home is where we want to get,” said Doyle, “with the normal routine, with no interference or intrusion. The true end-game is at home.”

Research for the development of this artificial pancreas is supported by the National Institutes of Health, award number DP3DK104057.

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Temporary tattoo offers needle-free way to monitor glucose


‘Proof-of-concept’ tattoo could pave way for UC San Diego to explore others uses of device.

Nanoengineers at UC San Diego have tested a temporary tattoo that both extracts and measures the level of glucose in the fluid in between skin cells.

By Ioana Patringenaru

Nanoengineers at UC San Diego have tested a temporary tattoo that both extracts and measures the level of glucose in the fluid in between skin cells. This first-ever example of the flexible, easy-to-wear device could be a promising step forward in noninvasive glucose testing for patients with diabetes.

The sensor was developed and tested by graduate student Amay Bandodkar and colleagues in professor Joseph Wang’s laboratory at the NanoEngineering Department and the Center for Wearable Sensors at the Jacobs School of Engineering at UC San Diego. Bandodkar said this “proof-of-concept” tattoo could pave the way for the center to explore other uses of the device, such as detecting other important metabolites in the body or delivering medicines through the skin.

At the moment, the tattoo doesn’t provide the kind of numerical readout that a patient would need to monitor his or her own glucose. But this type of readout is being developed by electrical and computer engineering researchers in the Center for Wearable Sensors. “The readout instrument will also eventually have Bluetooth capabilities to send this information directly to the patient’s doctor in real-time or store data in the cloud,” said Bandodkar.

The research team is also working on ways to make the tattoo last longer while keeping its overall cost down, he noted. “Presently the tattoo sensor can easily survive for a day. These are extremely inexpensive — a few cents — and hence can be replaced without much financial burden on the patient.”

The center “envisions using these glucose tattoo sensors to continuously monitor glucose levels of large populations as a function of their dietary habits,” Bandodkar said. Data from this wider population could help researchers learn more about the causes and potential prevention of diabetes, which affects hundreds of millions of people and is one of the leading causes of death and disability worldwide.

People with diabetes often must test their glucose levels multiple times per day, using devices that use a tiny needle to extract a small blood sample from a fingertip. Patients who avoid this testing because they find it unpleasant or difficult to perform are at a higher risk for poor health, so researchers have been searching for less invasive ways to monitor glucose.

In their report in the journal Analytical Chemistry, Wang and his co-workers describe their flexible device, which consists of carefully patterned electrodes printed on temporary tattoo paper. A very mild electrical current applied to the skin for 10 minutes forces sodium ions in the fluid between skin cells to migrate toward the tattoo’s electrodes. These ions carry glucose molecules that are also found in the fluid. A sensor built into the tattoo then measures the strength of the electrical charge produced by the glucose to determine a person’s overall glucose levels.

“The concentration of glucose extracted by the non-invasive tattoo device is almost hundred times lower than the corresponding level in the human blood,” Bandodkar explained. “Thus we had to develop a highly sensitive glucose sensor that could detect such low levels of glucose with high selectivity.”

A similar device called GlucoWatch from Cygnus Inc. was marketed in 2002, but the device was discontinued because it caused skin irritation, the UC San Diego researchers note. Their proof-of-concept tattoo sensor avoids this irritation by using a lower electrical current to extract the glucose.

Wang and colleagues applied the tattoo to seven men and women between the ages of 20 and 40 with no history of diabetes. None of the volunteers reported feeling discomfort during the tattoo test, and only a few people reported feeling a mild tingling in the first 10 seconds of the test.

To test how well the tattoo picked up the spike in glucose levels after a meal, the volunteers ate a carb-rich meal of a sandwich and soda in the lab. The device performed just as well at detecting this glucose spike as a traditional finger-stick monitor.

The researchers say the device could be used to measure other important chemicals such as lactate, a metabolite analyzed in athletes to monitor their fitness. The tattoo might also someday be used to test how well a medication is working by monitoring certain protein products in the intercellular fluid, or to detect alcohol or illegal drug consumption.

Bandodkar was joined on the study by UC San Diego nanoengineers Wenzhao Jia, Ceren Yardımcı, Xuan Wang, Julian Ramirez and Wang, director of the Center for Wearable Sensors and SAIC Endowed Chair and distinguished professor in the NanoEngineering Department.

The publication is “Tattoo-Based Noninvasive Glucose Monitoring: A Proof-of-Concept Study,” published Dec. 12 in the journal Analytical Chemistry.

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Drug reduces diabetes symptoms in mice


Research involves a potent enzyme inhibitor discovered at UC Davis.

Bruce Hammock, UC Davis

Can diabetes be prevented and even reversed?

Yes, it can — at least in genetically obese mice, according to a newly published study by led by researchers Bruce Hammock at the University of California, Davis, and Joan Clària at the University of Barcelona. The research involves a potent enzyme inhibitor discovered by Hammock’s laboratory that dramatically reduces inflammation, inflammatory pain and neuropathic pain.

In the study, published in the Proceedings of the National Academy of Sciences, an enzyme called soluble epoxide hydrolase, or sEH, inhibitor both prevented the onset of diabetes and reversed the effects of diabetes in obese mice.

“Our previous studies show the drug we are working on will reduce the symptoms of diabetes in mice by itself,” Hammock said, “but the excitement about Joan Clària’s work is that if the mice have a genetically increased level of omega-3 fatty acids — the drug offers prevention or cure in mice.”

The Centers for Disease Control and Prevention estimates that 29.1 million Americans, or 9.3 percent of the population, have diabetes, which is characterized by abnormal blood glucose levels. This includes 8.1 million undiagnosed cases.

The new drug apparently works by stabilizing metabolites of an omega-3 fatty acid called DHA. These metabolites are thought to contribute to the beneficial effects of a diet high in omega-3 fatty acids, Hammock said. Previous UC Davis research in the laboratories of Hammock, Nipavan Chiamvimonvat, Robert Weiss, Anne Knowlton and Fawaz Haj showed that the enzyme reduces or reverses such diabetes-linked medical issues as renal failure, hypertension, diabetic pain, hardening of the arteries and heart failure.

“This exciting research brings mechanistic detail to understanding how omega-3 fatty acids in the diet exert important health effects,” said J. Bruce German, director of the UC Davis Foods for Health Institute, Department of Food Science and Technology, who was not involved in the diabetes-based research.

Clària is an associate professor at the Barcelona University School of Medicine and a senior consultant at the Biochemistry and Molecular Genetics Service of the Hospital Clínic of Barcelona.

In the paper, titled “Inhibition of Soluble Epoxide Hydrolase Modulates Inflammation and Autophagy in Obese Adipose Tissue and Liver: Role for Omega-3 Epoxides,” Clària described the administration of the sEH inhibitor as “a promising strategy to prevent obesity-related co-morbidities.”

Clària said the study also sheds more light on the role of sEH and omega-3 epoxides in insulin-sensitive tissues, especially the liver.

In addition to Clària and Hammock, the publication was first-authored by Cristina López-Vicario and co-authored by José Alcaraz-Quiles, Verónica García-Alonso, Bibiana Rius, Aritz Lopategi, Ester Titos  and Vicente Arroyo,  all of the Clària lab or associates; and Sung Hee Hwang of the Hammock Lab, UC Davis Department of Entomology and Nematology, and the UC Davis  Comprehensive Cancer Center.

Hammock is the founder and CEO of a start-up company, EicOsis, which is putting the new compounds into clinical trials for companion animals and the Pre-Investigational New Drug Application, or Pre-IND, Consultation Program for neuropathic pain in human diabetics.

The study was funded by Clària’s Spanish-initiated grants and by Hammock’s Research Project Grant (R01) and Superfund grants from the National Institutes of Health.

More information about the Hammock lab and about the Clària lab.

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Immune cells in brain respond to fat in diet, causing mice to eat


UCSF study indicates that microglia may play key role in shaping the brain’s response to diet.

By Jeffrey Norris, UC San Francisco

Immune cells perform a previously unsuspected role in the brain that may contribute to obesity, according to a new study by UC San Francisco researchers.

When the researchers fed mice a diet high in saturated milk fats, microglia, a type of immune cell, underwent a population explosion in the brain region called the hypothalamus, which is responsible for feeding behavior.

The researchers used an experimental drug and, alternatively, a genetic approach to knock out these microglia, and both strategies resulted in a complete loss of microglia-driven inflammation in the hypothalamus. Remarkably, doing so also resulted in the mice eating less food each day than did their untreated counterparts, without any apparent ill effects.

Furthermore, removing microglia from mice only reduced food intake when the content of saturated fat from milk in their diets was high. It had no effect on mice fed a low-fat diet or a diet high in other types of fat, including olive oil or coconut oil.

UCSF postdoctoral fellow Martin Valdearcos Contreras, Ph.D., first author on the paper, published in the Dec. 11 issue of Cell Reports, discovered that when mice consumed large amounts of saturated fats, the fat entered their brains and accumulated in the hypothalamus.

According to the senior scientist for the study, Suneil Koliwad, M.D., Ph.D., an assistant professor of medicine at the UCSF Diabetes Center, the microglia sense the saturated fat and send instructions to brain circuits in the hypothalamus. These instructions are important drivers of food intake, he said.

Microglia are primarily known for causing inflammation in the brain in response to infection or injury, but the new study indicates that they also play a key role in shaping the brain’s response to diet, according to Koliwad.

Outside the brain — in fat tissue, the liver, and muscles — other immune cells, called macrophages, trigger inflammation in response to “diet-induced obesity,” Koliwad said. This inflammation is implicated in triggering insulin resistance, a late stage event on the road to type 2 diabetes.

However, overeating causes microglia to accumulate much more quickly in the hypothalamus than macrophages accumulate in peripheral tissues, Koliwad said. But until now, the effects of this microglial build-up were unknown.

“As opposed to classically defined inflammation, in which immune cells build up in tissues where environmental insults have created disarray, microglial activation in the brain may be a part of a normal physiological process to remodel brain function in response to changes in the composition of food intake,” Koliwad said.

“When the intake of saturated fats is chronically high, this microglial sensory network may be hijacked, and this has the potential to mediate increased food consumption and promote more rapid weight gain.

“Targeting microglia may therefore be a novel way to control food intake in the face of consumption of a fat-rich diet, something that is quite common in today’s world,” he said.

The research was funded by the National Institutes of Health and by the UCSF Diabetes Family Fund.

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Bitter food but good medicine from cucumbers


UC Davis research could have applications in treating cancer, developing other food crops.

High-tech genomics and traditional Chinese medicine come together as researchers identify the genes responsible for the intense bitter taste of wild cucumbers. Taming this bitterness made cucumber, pumpkin and their relatives into popular foods, but the same compounds also have potential to treat cancer and diabetes.

“You don’t eat wild cucumber, unless you want to use it as a purgative,” said William Lucas, professor of plant biology at the University of California, Davis, and co-author on the paper published Nov. 28 in the journal Science.

That bitter flavor in wild cucurbits — the family that includes cucumber, pumpkin, melon, watermelon and squash — is due to compounds called cucurbitacins. The bitter taste protects wild plants against predators.

The fruit and leaves of wild cucurbits have been used in Indian and Chinese medicine for thousands of years, as emetics and purgatives and to treat liver disease. More recently, researchers have shown that cucurbitacins can kill or suppress growth of cancer cells.

Bitterness is known to be controlled by two genetic traits, “Bi” which confers bitterness on the whole plant, and “Bt,” which leads to bitter fruit. In the new work, Lucas, Sanwen Huang at the Chinese Academy of Agricultural Sciences and colleagues employed the latest in DNA sequencing technology to identify the exact changes in DNA associated with bitterness.

They also tasted a great many cucumbers. “Luckily this is an easy trait to test for,” Lucas said. “You just chomp on a cucumber leaf of fruit and your tongue gives you the readout!”

They were able to identify nine genes involved in making cucurbitacin and show that the trait can be traced to two transcription factors that switch on these nine genes, in either leaves or the fruit, to produce cucurbitacin.

The new research shows how domestication tweaked cucumber genetics to make the fruit more edible. Understanding that process might open up approaches to developing other food crops based on plants that are naturally either inedible or poor in nutrition, Lucas said.

It could also make it much easier to produce cucurbitacins in large enough quantities to use in clinical trials and potentially in medicine, Lucas said. For example the anti-malarial drug artemisinin, originally derived from traditional Chinese medicine, is now being produced either as a precursor molecule in yeast or through synthetic biology systems.

Other collaborators on the study included researchers at the Institute of Vegetables and Flowers, Beijing; Agricultural Genomics Institute, Shenzhen, China; Nanjing Agricultural University, Nanjing; Hunan Agricultural University, Changsha; Institute of Botany, Chinese Academy of Sciences, Beijing; Hunan Academy of Agricultural Sciences, Changsha; Wuhan University, Wuhan; Institute of Microbiology, Chinese Academy of Sciences, Beijing; Nihon University, Tokyo, Japan; and Wageningen University, Wageningen, The Netherlands.

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Global dietary choices show disturbing trends


UC Santa Barbara professor co-authors paper that examines global impact of what we eat.

David Tilman

The world is gaining weight and becoming less healthy, and global dietary choices are harming the environment.

Those are among the findings of a paper co-authored by David Tilman, a professor in the UC Santa Barbara Bren School of Environmental Science & Management, and Michael Clark, a graduate student at the University of Minnesota, where Tilman also is a professor. In “Global Diets Link Environmental Sustainability and Human Health,” published today (Nov. 12) in the journal Nature, the researchers find that rising incomes and urbanization around the world are driving a global dietary transition that is, in turn, diminishing the health of both people and the planet.

“These dietary shifts,” they write, “are greatly increasing the incidence of Type 2 diabetes, coronary heart disease and other chronic non-communicable diseases that lower global life expectancies.”

The paper is the first to show the global links among the elements of what Tilman refers to as the “tightly linked diet–environment–health trilemma.”

“Previous analyses have looked at the effects of diet in individual countries, but we are the first to examine the global impacts on both human health and the environment of diet as it is now and as it is becoming,” he says. “We gathered information on dietary trends and environmental impacts for 90 percent of the global population. Our data let us see how diets, health and the environment have been changing and where they are going.”

“Some of what we found is not surprising, but the global implications are frightening,” Tilman adds. “Most of us have heard that some diets are healthier, that eating too many calories is bad for you and that red meat harms the environment. We were surprised at how rapidly and consistently diets were changing around the world, how massively this would impact global health and how much it would increase global greenhouse gas emissions and the destruction of tropical forests and other ecosystems.”

Unhealthful diets linked to urbanization

The links between urbanization, increased wealth and unhealthful diets are clear, Tilman explains. When a country industrializes, the transition from a traditional rural diet to one that includes more processed meats and more empty calories can occur quickly. “People move to cities, leaving behind their own gardens where they grew fruits and vegetables,” Tilman said. “They’re working in a factory 12 hours a day, six or seven days a week, so they need food that’s cheap and fast. The cheapest, fastest food you can get is filled with starch, sugar, fat and salt. Almost overnight, they go from a healthy diet to one that has way too many calories and leads to diabetes and heart disease.”

Also, because people tend to eat more meat as they become wealthier, much of the expected 100-percent increase in crop production that will be required by 2050 would be used to feed not humans but livestock. To do that, much more land will need to be cleared, with the result that more habitat will be lost, more species will likely become extinct and increased runoff of agricultural fertilizers and pesticides will degrade streams, rivers, lakes, groundwater and oceans.

Alternative diets offer health benefits

Tilman suggests that hope — and help — lie in the widespread adoption of alternative diets that offer substantial health benefits and could reduce global agricultural greenhouse gas emissions, reduce land clearing and resultant species extinctions and help prevent a variety of diet-related chronic noncommunicable diseases.

Comparing conventional American omnivorous diets to the Mediterranean diet, a pescetarian diet (in which fish is the only animal protein) and a vegetarian diet, the compiled research showed that the three alternatives to the omnivorous diet decreased Type 2 diabetes by 16 to 41 percent, cancer by 7 to 13 percent and morality rates from coronary heart disease by 20 to 26 percent. Moreover, the authors show that these alternative diets could reduce global greenhouse gas emissions from food production by about 40 percent below what they would be if dietary trends continued.

To reach their conclusions, the researchers gathered all published life-cycle assessments covering “cradle to farm gate” greenhouse gas emissions for production systems of food crops, livestock, fisheries and aquaculture — some 500 studies, of which about 220 were useful. They also gathered 50 years of data for 100 of the world’s more populous nations to analyze global dietary trends and their drivers, using that information to forecast future diets should past trends continue.

To quantify the effects of alternative diets on mortality and on Type 2 diabetes, cancer and chronic coronary heart disease, they summarized results of eight major long-term studies on diet and health. Finally, they combined those relationships with projected increases in global population to forecast global environmental implications of current dietary trajectories and calculate the environmental benefits of diets associated with reduced rates of chronic noncommunicable diseases.

“Better diets are the solution to these big problems,” Tilman says. “Only better diets can prevent a massive global epidemic of chronic noncontagious disease. These same diets would also protect the environment. Since big food companies produce so much of what is eaten, we need them to be part of this solution. By developing, producing and advertising foods that are healthy and tasty, these companies can help their customers, the earth and their bottom line. It is a niche waiting to be filled.”

Tilman wonders if unhealthy foods laden with fats or sugars might grow into a health issue somewhat like smoking. “Throughout history, foods that tasted good were almost always healthy but scarce. Now we have thousands of inexpensive manufactured foods that taste good because of an overabundance of sugar, fat or salt but are bad for us. What is the ethics of selling such foods now that we know how bad they are for heath and the environment?”

The research generated a number of nuanced findings about the environmental impacts of various dietary choices. The following are among them:

  • While the difference in greenhouse gas emissions for animal-based versus plant-based foods is well known, emissions per gram of protein for beef and lamb are about 250 times those of legumes; pork, chicken, dairy, and fish have much lower emissions;
  • Twenty servings of vegetables have fewer greenhouse gas emissions than one serving of beef.
  • Fish caught by trawling, which involves dragging fishnets along the ocean floor, can have three times the emissions of fish caught by traditional methods.
  • And among cereal grains, rice has five times the emissions per gram of protein as wheat.

These and other facts demonstrate that there are many diets that are both good for the environment and healthy.

While Tilman does not expect to see quick societal changes in diet, he hopes that the paper will be seen by the right people who can influence the food supply and that it “can encourage people to think about this challenge and have a dialogue it.”

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UCSF sugar science initiative launched


Researchers highlight strong links between sugar and chronic disease.

By Kristen Bole, UC San Francisco

Researchers at UC San Francisco have launched SugarScience, a groundbreaking research and education initiative designed to highlight the most authoritative scientific findings on added sugar and its impact on health.

The national initiative is launching in partnership with outreach programs in health departments across the country, including the National Association of City and County Health Organizations and cities nationwide.

Developed by a team of UCSF health scientists in collaboration with scientists at UC Davis and Emory University School of Medicine, the initiative reflects an exhaustive review of more than 8,000 scientific papers that have been published to date on the health effects of added sugar.

The research shows strong evidence of links between the overconsumption of added sugar and chronic diseases, including Type 2 diabetes, heart disease and liver disease. It also reveals evidence linking sugar to Alzheimer’s disease and cancer, although the team assessed that more research is needed before those links can be considered conclusive.

Laura Schmidt, UC San Francisco

“The average American consumes nearly three times the recommended amount of added sugar every day, which is taking a tremendous toll on our nation’s health,” said Laura Schmidt, Ph.D., a UCSF professor in the Philip R. Lee Institute for Health Policy Studies and the lead investigator on the project. “This is the definitive science that establishes the causative link between sugar and chronic disease across the population.”

The initiative aims to bring scientific research out of medical journals and into the public domain by showcasing key findings that can help individuals and communities make informed decisions about their health. For example, SugarScience.org cites research showing that drinking just one can of soda per day can increase a person’s risk of dying from heart disease by nearly one-third, and can raise the risk of getting Type 2 diabetes by one-quarter.

More than 27 million Americans have been diagnosed with heart disease, which is the nation’s leading cause of death. Another 25.8 million Americans have Type 2 diabetes, caused by the body’s resistance to the hormone insulin coupled with the inability to produce enough insulin to regulate blood sugar levels. Of greatest concern is the rising number of children suffering from these chronic diseases.

Kristen Bibbins-Domingo, UC San Francisco

“Twenty years ago, Type 2 diabetes was unheard of among children, but now, more than 13,000 children are diagnosed with it each year,” said Kirsten Bibbins-Domingo, M.D., Ph.D., a UCSF professor of medicine, epidemiology and biostatistics, and director of the UCSF Center for Vulnerable Populations at San Francisco General Hospital and Trauma Center. “Diabetes is a devastating disease and we know that it is directly related to the added sugar we consume in food and beverages.”

Another rising concern is the impact of added sugar on Non-Alcoholic Fatty Liver Disease (NAFLD), which affects 31 percent of adults and 13 percent of children, and can lead to cirrhosis and liver failure.

“As pediatricians, we had evidence of the connection between sugar and diabetes, heart disease, and liver disease for years, but we haven’t had this level of definitive scientific evidence to back up our concerns,” said Robert Lustig, M.D., M.S.L., a pediatric endocrinologist at UCSF Benioff Children’s Hospital San Francisco and a member of the SugarScience team. “Our goal is to make that science digestible to the American public, and take the first step toward a national conversation based on the real scientific evidence.”

Robert Lustig, UC San Francisco

While there are no federal recommended daily values for added sugar, the American Heart Association recommends consuming less than 6 tsp. (25 g) for women and 9 tsp. (38 g) for men. Guidelines for children depend on caloric intake, but range between 3-6 tsp (12-25 g) per day. Americans currently consume 19.5 tsp. of added sugar, on average, every day.

Added sugar is defined as any caloric sweetener that is added in food preparation, at the table, in the kitchen or in a processing plant. It can be difficult for people to know how much sugar they are consuming, since roughly 74 percent of processed foods contain added sugar, which is listed under at least 60 different names on food labels.

The 12-member SugarScience team will continue to monitor scientific research about added sugar and will track findings at SugarScience.org. The initiative harnesses the power of UCSF’s extensive health sciences enterprise, which ranges from basic laboratory research to clinical, population and policy sciences, with an emphasis on translating science into public benefit. All four of UCSF’s graduate schools – dentistry, medicine, nursing and pharmacy – lead their fields in research funding from the National Institutes of Health, reflecting the caliber of their research. It also is aligned with the UC Global Food Initiative, which seeks to harness UC resources to address global food needs.

SugarScience is made possible by an independent grant from the Laura and John Arnold Foundation. It is supported by the Clinical and Translational Science Institute and the Philip R. Lee Institute for Health Policy Studies at UCSF.

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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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