From the DirectorWelcome to the winter edition of News from the Diabetes Center at UCSF. In this issue, we highlight a sampling of the exciting projects our team is leading. From basic science studies about the risk factors for diabetes to clinical trials that aim to prevent the disease from progressing, our talented investigators are spearheading the field’s most novel efforts to create new strategies for combatting all forms of diabetes.

You will also read about how we have further strengthened our formidable team through the recruitment of two new faculty members. Please join us in welcoming Anil Bhushan, PhD, and Julie Sneddon, PhD, to the Diabetes Center.

As always, none of our successes would be possible without the generosity of our friends in the community – including Mike and Loren Gordon, who recently established the UCSF Diabetes Innovation Fund to support our mission of finding a cure for diabetes.

We are grateful for your confidence in our work, and thank you once again for your philanthropic investment in the Diabetes Center at UCSF.

On behalf of our entire team, I wish you and your loved ones a wonderful holiday season.

Sincerely,

Matthias Hebrok, PhDDirector, Diabetes Center at UCSF Hurlbut-Johnson Distinguished Professor in Diabetes Research

Diabetes Center Receives $1.5 Million Gift to Advance Research for a Cure

News from the Diabetes Center at UCSF

For Mike Gordon, having the energy to participate in normal family life with his wife, Loren, and their two kids is a true gift – one that, just four years ago, seemed impossible to imagine.

After suffering severe complications from type 1 diabetes that rendered him constantly fatigued, Mike received a whole pancreas transplant at UCSF in 2010. The procedure “has been a life changer,” he says. He now has enough energy for backpacking trips, walks in nature, and most importantly, the simple joys in life, like reading to his daughter each night.

Longtime friends of the Diabetes Center, Mike and Loren are determined to help bring an end to the disease and its debilitating effects. To support the Diabetes Center’s mission of finding a cure, they have generously donated $1.5 million to establish the UCSF Diabetes Innovation Fund.

“The investigators at the Diabetes Center are the best in the world at what they do. We truly believe they are going to make an impact,” says Mike.

Inside: New Diabetes Center Faculty | Comparative Genomic Research in Obesity | Getting to the Roots of Autoimmune Disease Revamped Website | Understanding the Development of Type 1 Diabetes and How YOU Can Contribute to Research

Continued on page 4

The Gordon Family

W I N T E R 2 0 14

New FacultyCreates Strongest Beta Cell Team in the NationThis fall, the Diabetes Center further strengthened our preeminent research program by recruiting two exceptional new faculty members: Anil Bhushan, PhD, and Julie Sneddon, PhD. Bhushan studies how beta cells become fully functional after birth and how their numbers might be increased in adulthood. Sneddon’s work focuses on the supporting tissue that guides the development of beta cells and sustains their functionality. Bhushan’s and Sneddon’s expertise will help us to efficiently differentiate stem cells into fully functioning, insulin-producing beta cells. Their research holds great promise for the development of cell-based therapies for both type 1 and type 2 diabetes.

“With the arrival of Anil and Julie, we have elevated beta cell work at UCSF to new and unprecedented heights. We are delighted they have joined our team and look forward to collaborating with them to address outstanding questions in diabetes.” –Matthias Hebrok, PhD, Director, Diabetes Center at UCSF

Anil Bhushan, PhD, joins us from UCLA’s Department of Molecular, Cell and Developmental Biology

Julie Sneddon, PhD, joins us from Harvard University

Cohort Study Will Facilitate Unprecedented Comparative Genomic Research in ObesityA new cohort study led by Suneil Koliwad, MD, PhD, the Gerold Grodsky, PhD/JAB Chair in Diabetes Research, will provide UCSF’s diabetes investigators a rich source of data with which to better define obesity – and consequent risk for type 2 diabetes – across ethnicities.

Obesity is a leading risk factor for type 2 diabetes. However, it has become increasingly clear among diabetes clinicians that the nature of obesity in some ethnicities is much more aggressive with respect to its resulting diabetes risk than in others.

“The weight threshold at which people develop diabetes in the face of obesity is very different from one ethnic group to the next,” according to Koliwad. “What this means is that the severity of diabetes for an overweight African-American man, for example, and a South Asian man who, at a glance, appears to be far less overweight may in fact be the same.”

In an effort to explain why this is the case, Koliwad and his team are creating a diverse cohort of 180 patients who suffer from obesity and diabetes. Recruitment for the study is underway and currently concentrates on enrolling patients of Hispanic, ethnic Chinese, and Caucasian origins. The Koliwad lab will collect visceral and subcutaneous fat samples from the cohort enrollees, as well as develop bio-behavioral profiles for each patient.

Ultimately, the team proposes to use genomic analysis approaches – most of which were pioneered at UCSF – to study the cohort participants’ fat tissue and the cells within that tissue.

“By establishing which genes may differ in the context of obesity across ethnically distinct populations of people, and linking these variations with the severity of diabetes in these groups, we believe that we can understand in a way no one has yet appreciated what the most risk-inducing genes might be in the context of obesity,” said Koliwad.

The information Koliwad gathers will be vital not only to his own team’s research endeavors but also those of other diabetes investigators at UCSF. Tissue samples and data from the cohort study will be available for use by scientists across the campus for projects ranging from basic science experiments to detect whether ethnically specific genes impact the differentiation of stem cells into beta cells, to behavioral studies exploring potential links between ethnicity, diabetes, and depression.

Suneil Koliwad and team members Megan Robblee and Jess Porter Abate

2 News from the Diabetes Center at UCSF

UCSF researcher Alex Marson, MD, PhD, and his team have published findings that may speed up treatment for autoimmune diseases, including diabetes. Published late last month in the journal Nature, Marson’s paper titled “Genetic and epigenetic fine-mapping of causal autoimmune disease variants” – identifies a new method for determining the genetic changes that may contribute to autoimmune diseases.

“Our approach identifies likely causal risk genetic variants for 21 autoimmune diseases, such as diabetes, multiple sclerosis, and Crohn’s disease,” Marson, a physician who also runs a research lab at the Diabetes Center, said. “The same technique could be used to help unravel the causes of other complex diseases.”

Large-scale population genetic studies have previously highlighted hundreds of areas in the genetic code that are linked to autoimmune disease; however, these regions are peppered with multiple base-pair changes, making it hard to work out which are the crucial, disease-causing mutations.

Marson, his research team, and colleagues at the Broad Institute at the Massachusetts Institute of Technology and Harvard, have developed a new algorithm that enables these candidate causal variants to be teased out.

Getting to the Roots of Autoimmune DiseaseThe researchers also used next-generation sequencing techniques to probe “epigenetic” characteristics of specialized immune cells, in which gene activity is affected without actual changes to the DNA sequence itself.

The team discovered that a majority of key DNA changes associated with autoimmune diseases occur in functional bits of DNA known as “enhancers,” which act as molecular switches to control gene activity.

“Autoimmune disease risk tends to be linked to variations in cell-type-specific enhancers that are activated during the stimulation of immune cells,” Marson said. “The integrated genetic approach to studying diabetes and other diseases is teaching us fundamental lessons about the underlying pathology, and I hope, moving us closer to new drugs to reverse this pathology.”

“Alex Marson and his team represent the innovative thinking of the Diabetes Center at UCSF,” Matthias Hebrok, PhD, and director of the Center, said. “His groundbreaking research will provide new clues regarding the defects underlying autoimmune diseases. His work provides novel information for other Diabetes Center investigators and moves us closer toward finding a cure for diabetes.”

Alex Marson, MD, PhD

News from the Diabetes Center at UCSF 3

The Road to Transplant

Diagnosed with type 1 diabetes when he was just 22 months old, Mike, now 50, lived a generally healthy life well into early adulthood. By eating well, exercising, and closely matching his food intake and insulin dosage, he was able to keep his disease in check. He kept abreast of the latest diabetes research and was an early adopter of improved treatments and technologies, including human insulin, blood sugar meters, and the insulin pump.

“I used to describe my diabetes as a ‘nuisance disease’,” he explains. “I knew that I needed to take my insulin every day, just like I needed to brush my teeth. It was a normal part of my daily routine, and I kept my blood sugar levels decently controlled for nearly 26 years.”

That started to change as Mike neared his 30th birthday and began to experience intermittent bouts of diabetic neuropathy – nerve damage that initially manifested as sharp pains in his feet and quickly spread to his hands and forearms. Well aware that neuropathy increases risk for amputation in diabetes patients, Mike consulted with leading experts and tried every drug and alternative therapy available, but to no avail.

Mike’s neuropathy became more frequent by the time he had reached his early 40s. He also started to suffer from erratic swings in his blood sugar levels, despite his best efforts to control them. Often referred to as “brittle diabetes,” these hard-to-manage swings can cause episodes of extreme hypoglycemia or hyperglycemia.

Deteriorating Quality of Life

According to Loren, “Mike’s quality of life was very poor by this time. He wanted to continue working, so he would drag himself to work, then come home and immediately go to sleep. He had zero energy.”

“From that period we have so many family photos of just the kids and me, and not Mike. He was so often not feeling well that he missed out on a lot of events, and that really upset him,” she recalls.

“I felt guilty as a husband and as a father that I could not fully participate in our family life, but

I was also concerned for financial reasons. If there was nothing else I could do, I at least wanted to make sure that my family was well taken care of financially,” Mike says of his decision to continue working as a partner in a venture capital firm during this difficult time.

The End of the Rope

In Mike’s words, he had reached “the end of the rope” on Mother’s Day 2010, when an extreme episode of brittle diabetes nearly claimed his life. Loren found him unconscious on the patio, where he had fainted hours earlier. He was hypothermic, had blood streaming down his face from the forehead gash he had suffered from the fall, and had broken his spine in two places. When the paramedics arrived, they could not even detect a blood sugar level.

The terrifying events of the evening served as a wake-up call. Although Mike and Loren had tried all they could to improve Mike’s health – from modifying his diet and exercise regime to trying experimental therapies and alternative medicines – they realized the time had come to consider a pancreas transplant. A pancreas transplant involves implanting a healthy insulin-producing pancreas into a person whose pancreas can no longer supply sufficient insulin to the body. The healthy pancreas comes from either a deceased donor or in the form of a partial pancreas from a living donor.

Having already researched the top medical centers for pancreas transplants and spoken to other patients who had undergone the same surgery, the Gordons made the decision to come to UCSF. “This is a hard surgery to do and there are really only a few centers in the whole world that perform a lot of pancreas transplants each year. We felt

In giving to the Diabetes Center,

the Gordons recognize that

they are helping to fill a gap caused by

reduced funding from traditional

sources. One of the most

glaring gaps, they believe,

is the need to fund innovative

research that is deemed too risky to qualify

for grants.

Diabetes Center Receives $1.5 Million Gift to Advance Research for a CureContinued from front page

4 News from the Diabetes Center at UCSF

so fortunate that the one we knew the best – UCSF – was right in our backyard,” says Mike.

Mike underwent various qualification exams and, given the severity of his complications, became eligible for a transplant on September 15, 2010.

A New Life

The Gordons received the call at 10:30 p.m. on Sunday, October 3, 2010: a donor pancreas had become available and Mike was to report to UCSF immediately.

The surgery went well and Mike recalls waking up post-surgery. “My whole body was warm and I felt like I was alive for the first time in a long time. I felt life coursing through my veins. It was a very emotional moment because I knew that my donor had given his life so that I could live. I will be forever grateful,” he says.

Loren adds, “To me and to our family, it was a miracle. Every day I am filled with gratitude for the people at UCSF – the skilled surgeons, the compassionate nurses – who were so attentive to Mike and me and provided such fantastic care.”

Today, Mike’s routine includes taking immuno-suppression drugs twice a day. Gone are the sensors, insulin pumps, and constant worry about food and blood sugar levels. “Diabetes never gives you time off, there’s no break from wondering ‘What’s going on with my sugars?,’” Mike says. “I don’t have those worries anymore, and that feels pretty great.”

In addition to backpacking and camping trips with his family, Mike is currently learning to scuba dive – something he had always wanted to try. “It’s pure joy for me to see him doing the things that he wants to do,” says Loren.

“I’ve been given such a gift,” he affirms.

In retrospect, Mike believes that plain luck played a part in his ability to get through the first 26 years of his life as a diabetes patient without major complications. He knows that others are not as fortunate.

Recognizing the Need for Research Funding

“We have a number of friends whose children have had type 1 diabetes for a third of the time as me – and these kids eat well, exercise, and closely match food to insulin, just like I did – yet are already experiencing what I went through in my 40s in terms of volatile sugars and clinicians are scratching their heads because they can’t understand why the disease took this turn,” says Mike.

It is for this reason that he and Loren chose to establish the UCSF Diabetes Innovation Fund, which will support research for the cure. “I know that care has improved greatly, and I’m so happy about that, but I just want this disease to be cured for the next generation,” says Loren.

In giving to the Diabetes Center, the Gordons recognize that they are helping to fill a gap caused by reduced funding from traditional sources. One of the most glaring gaps, they believe, is the need to fund innovative research that is deemed too risky to qualify for grants.

“The heroes in this story are the brilliant scientists at the Diabetes Center. There are certainly other options for them in terms of their careers, yet they chose this one. But because federal grants have dried up, they must find alternative means to fund their work. That was another reason that Loren and I felt we needed to give as soon as we could because these investigators’ work is being stymied by a lack of funds and that is a real tragedy,” Mike explains.

“You don’t have to look any further than Mike if you search for inspiration to come to work and develop new strategies for combatting diabetes,” says Matthias Hebrok, PhD, director of the Diabetes Center. “I have known Mike and Loren for more than a decade now. They are among the most generous and supportive people I have ever met. We are thrilled about their gift to our Center and will use the funds to push forward as hard as we can.”

“The investigators at the Diabetes Center are the best in the world at what they do. We truly

believe they are going to make an impact.”–Mike Gordon

News from the Diabetes Center at UCSF 5

Launched in conjunction with our new visual identity in February 2014, the revamped Diabetes Center website enables our virtual visitors and patients to find what they need quickly. A central goal of the redesign project was to make it easier for newly diagnosed patients and their families to locate relevant and trustworthy information about the disease.

We are thrilled to report that the site has been well received and has even won an “Outstanding Site” award from the UCSF community.

We hope you will visit us online often, as we will continue to update our site with details about our progress toward a cure.

New Website Emphasizes Collaboration Between Research, Patient Care, and Education

Please visit our recently redesigned website: diabetes.ucsf.edu

Key features of the site include:■■ Engaging, easy-to-understand educational videos about diabetes research and patient care

■■ Basic educational information about diabetes and how to manage it

■■ News about our latest research and clinical trials

■■ Easy-to-find information about our pediatric and adult diabetes clinics

■■ Profiles and contact information for our world-renowned experts in diabetes

6 News from the Diabetes Center at UCSF

In thinking about how to define a cure for T1D, we consider different stages for possible intervention.

■■ Relatives of people with T1D are at increased risk of developing the disease. We have the means to screen and identify those at risk and offer a series of promising prevention trials to delay or prevent progression to overt T1D.

■■ Those with recent onset T1D often have a very functional remnant of beta cells. In these individuals, we are trying to preserve the existing beta cells with various immunotherapies.

■■ A person with long-standing T1D has virtually no insulin-producing cells, or at least not enough to circumvent the need for supplemental insulin injections.

The ultimate biological cure will be more beta cells (either from a donor whole pancreas transplant, islets purified from a donor pancreas, or beta cells produced from stem cells), and the cells will need to be protected from immune attack, either with immune therapies or a protective wrapping. All T1D research today will benefit the entire T1D community by enabling us to more fully understand the autoimmune destruction process.

Understanding the Development of Type 1 Diabetes (T1D) and How YOU Can Contribute to Research That is Moving Us Closer to a Cure

For families and individuals affected by T1D, there are several ways to enter the research pipeline. UCSF has multiple clinical research studies in the following areas:

SCREENING: If you are a family member of someone with T1D, your risk for developing T1D is 10 times greater than the general population. Get tested for T1D autoantibodies and determine your risk level for developing T1D. You may be eligible for one of several prevention studies if you are found to be at risk.

PREVENTION: If you are found to have T1D auto-antibodies, you may be eligible to participate in one of several studies geared toward preventing or delaying T1D. These prevention studies build upon successful trials conducted previously in new onset T1D.

NEW AND RECENT ONSET T1D: UCSF currently has several “intervention” studies for people within two years of diagnosis. The goal of these studies is to preserve remaining insulin production for as long as possible, thus further protecting the body from long-term complications.

ESTABLISHED T1D: For people with T1D for longer than two years, we are conducting and developing trials to test novel ways to restore insulin-producing cells in the pancreas and/or increase beta cell regeneration.

For a current list of clinical trials please:

■■ Visit www.diabetes.ucsf.edu/clinical_trials

■■ Email the Type 1 Diabetes Clinical Research Team at clinicalresearch@diabetes.ucsf.edu

■■ Call toll free 844-813-8273

To sign up for information about future research opportunities, please visit http://tiny.ucsf.edu/trials.

If you want to learn more about upcoming local community events at which UCSF will be present, or for opportunities to participate in clinical trials, subscribe to our e-newsletter at http://tinyurl.com/ucsf-dc.

Development of Type 1 Diabetes

GENETIC PREDISPOSITION

INFLAMMATION BETA CELL INJURY

Development of autoantibodies

Loss of insulin production but still normal glucose levels

Loss of insulin production and abnormal glucose levels

Newly diagnosed type 1 diabetes

Established type 1 diabetes

“PRE-DIABETES” DIABETES

News from the Diabetes Center at UCSF 7

Nonprofit Organization

U.S. Postage

PAIDSacramento, CA

Permit No. 333

Diabetes Center at UCSFUniversity of California, San FranciscoUCSF Box 0248San Francisco, CA 94143-0248

ADDRESS SERVICE REQUESTED

For more information, please contact Hayley Burner at 415-502-8302 or Hayley.Burner@ucsf.eduFollow the Diabetes Center online at diabetes.ucsf.edu and on Twitter @UCSFDC

Diabetes Center Investigators Receive AwardsMichael McManus, PhD, the Vincent and Stella Coates Endowed Chair in Diabetes Research, recently received the 2014 Transformative Research Award from the National Institutes of Health. The award – which supports the work of exceptionally creative scientists pursuing bold ideas – will provide the McManus lab $1.8 million over the next five years to develop technology that will track the ancestry of individual cells. This work will help us to understand pathogenic cells in diabetes, cancer, and other diseases.

Recognized for his groundbreaking efforts to engineer brown fat cells to fight obesity, Shingo Kajimura, PhD, received the Novo Nordisk Helmholtz Young Investigator Diabetes (HeIDi) Award at the second annual Helmholtz-Nature Medicine Diabetes Conference in Munich, Germany, this fall. The award honors outstanding young scientists. Earlier in the year, Kajimura was one of 102 recipients nationwide to receive the Presidential Early Career Award for Scientists and Engineers, the highest honor bestowed by the United States government to science and engineering professionals in the early stages of their independent research careers.

A history of innovation.A vision of a cure.

Michael McManus, PhD Shingo Kajimura, PhD

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News from the Diabetes Center at UCSF is produced by the UCSF Office of University Development and Alumni RelationsManaging Editor: Susan GodstoneWriters: Jeanette Anders, Kathleen Jay, Tracy Rodriguez, MA, CCRPPhotography: Peter DaSilva, Elisabeth Fall, Kathleen JayDesign: Laura Myers Design © 2014 The Regents of the University of California