to diabetes research and clinical care has. resulted in a steady stream of historical of diabetes to the first clinical tests of. synthetic human insulin …
Millennium Milestones:
Diabetes Center Achievements
a history of innovationa vision for a cure
UCSFs
eighty year commitment to diabetes research and clinical care has resulted in a steady stream of historical milestones in the understanding and treatment of diabetes Our record spans all levels of diabetes research, from the discovery of genes thought to play a precipitous role in the development of diabetes to the first clinical tests of synthetic human insulin that has brought relief to millions Today, these milestones make the UCSF commitment to the eventual cure of diabetes stronger than ever Since the year 2000, the Diabetes Center has rapidly accelerated the pace of research and clinical care in diabetes –realizing a number of significant scientific and clinical achievements Among the highlights are the following twelve 12 advances
embraced by private industry–the first exclusively type 1 diabetes treatment that has progressed this far in drug development Not only is this drug a potential prevention therapy for type 1 diabetes, it may also help those individuals who are currently living with the disease–especially if further progress is made in stem cell research, beta
cell regeneration and islet transplantation
milestone 2
Leader in Type 1 Diabetes Prevention Consortium, TrialNet
UCSF has been playing a significant leadership role in TrialNet, a NIH funded research program created in 2003 and dedicated to the discovery of new therapies to delay, or prevent, the onset of type 1 diabetes in at risk individuals TrialNet is a consortium of investigators from 18 of the leading diabetes institutions around the world Stephen Gitelman, MD serves as the study director for TrialNet at UCSF with Stephen Rosenthal, MD and Mark Anderson, MD, PhD serving as coinvestigators Since TrialNets inception in 2003, nearly a dozen studies have been pursued Recently, TrialNet launched a clinical study of oral insulin to prevent or delay diabetes in a group at intermediate risk for the disease Another pilot study, The Nutritional Intervention to Prevent Type 1 Diabetes NIP Trial, is looking at omega-3 fatty acids to see if they have anti-inflammatory benefits that prevent development of the autoimmunity that leads to type 1 diabetes
milestone 1
Anti-CD3, A Breakthrough Drug in Type 1 Diabetes
In 2002, the New England Journal of Medicine NEJM published the results of a
promising type 1 diabetes prevention study conducted by UCSFs Jeffrey Bluestone, PhD and Stephen Gitelman, MD, and Kevan Herold, MD, of Columbia University This study involving a monoclonal antibody known as Anti-CD3 or hOKT3y1 Ala-Ala proved that the autoimmune destruction of beta cells could be halted Further confirmation of this research breakthrough occurred in 2005 when NEJM published a related study led by French and Belgian researchers Today, Anti-CD3 is in Phase III clinical trials and has been
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Since the year 2000, the Diabetes Center has rapidly accelerated the pace of research and clinical care in diabetes –realizing a number of significant scientific and clinical achievements
milestone 3
Immune Tolerance Network
The Immune Tolerance Network ITN, a NIH-funded international consortium of over 80 of the worlds leading researchers and clinicians and headquartered at UCSF, is dedicated to studying novel immune tolerance strategies in numerous immunologic conditions including type 1 diabetes After seven years of research progress, the NIH renewed its support of the ITN with 220 million in funding The ITN is currently conducting clinical trials worldwide to help evaluate
new potential treatments for autoimmune diseases Many of these trials are being conducted here at UCSF One of these national, multi-center clinical trials is being spearheaded by Stephen Gitelman, MD This early phase II trial involving newly diagnosed type 1 patients uses Thymoglobulin, a polyclonal antibody that suppresses certain types of immune cells responsible for acute organ rejection in transplant patients Dr Gitelman hopes Thymoglobulin therapy will induce tolerance and help protect remaining beta cells from autoimmune destruction
the body tolerate these cells and halt the autoimmune attack Mark Anderson, MD, PhD is examining the genetic control of autoimmune disease to understand how the body recognizes self from non-self, and how the mechanisms of tolerance are broken Dr Anderson discovered the function of a protein, Aire, that helps immune cells learn how to recognize and avoid attacking its own tissue Aire works in the thymus gland by activating the production of self-proteins including insulin, and helping to remove self-reactive T cells If Aire is removed, an autoimmune attack occurs in the pancreas Further research is exploring how other genes may interact with the
Aire gene to protect against or worsen autoimmunity
milestone 5
Islet Transplantation Program Launched
In 2002, UCSF built one of the first state-of-the-art, cGMP islet transplantation facilities in the country This FDA approved facility is the cornerstone of UCSFs islet transplantation program, designated as a JDRF Center for Islet Transplantation at UCSF/University of Minnesota Andrew Posselt, MD, PhD heads the Pancreatic Islet Transplantation Program, and partners closely with Peter Stock, MD, PhD, Chair of the Pancreas Transplant Program By collaborating with fellow faculty members in the Diabetes Center and the Department of Surgery, Drs Posselt and Stock are focused on finding new sources of islet cells, new methods of islet preparation, less toxic antirejection therapies, new approaches for inducing tolerance, and other techniques designed to extend the reach of islet
milestone 4
Tolerance Research Advances
The UCSF Diabetes Center has become a world leader in tolerance research– an important factor in preventing and curing type 1 diabetes–in large part due to the strength of UCSFs internationally recognized immunology program By learning how the autoimmune process
causes beta cell destruction, innovative therapies can then be developed to help
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The UCSF Diabetes Center has become a world leader in tolerance research– an important factor in preventing and curing type 1 diabetes
transplantation Currently, Drs Posselt and Stock are spearheading a clinical trial, Prevention of Autoimmune Destruction and Rejection of Human Pancreatic Islets Following Transplantation for Insulin Dependent Diabetes Mellitus This study aims to improve islet transplantation as a treatment for type I diabetes by using a new combination of immunosuppressive drugs that have been successful in treating other autoimmune diseases and in preventing kidney transplant rejection
milestone 7
Talented, Young Researchers Making Their Mark in Diabetes
Thanks to an aggressive recruitment effort, a number of brilliant young minds are focused on diabetes research Feroz Papa, MD, PhD has been awarded a New Innovator Award, one of only 29 investigators nationwide who received this award Dr Papa is developing new therapies for diabetes using molecular tools to prevent the buildup of malfunctioning proteins in beta cells Dr Papa is an investigator in the California Institute for
Quantitative Biosciences QB3 and also treats patients with diabetes at San Francisco General Hospital Another rising star is Kaveh Ashrafi, PhD, a trained geneticist and molecular biologist who received a 2004 Searle Scholar Award Dr Ashrafi has become an expert in fat regulation– an important factor in obesity and type 2 diabetes Another research star recently recognized by the WM Keck Foundation is Michael McManus, PhD Dr McManus is known as an expert in microRNAs–the so called dark matter of the genome These very small pieces of genetic material control most of the genes we express, creating new biotechnology tools that may lead to cures for diseases including diabetes Other new talents recruited include Allison Xu, PhD who is studying how the hormones leptin and insulin act on specific bra 
in neurons to inhibit food intake and increase energy expenditure, and Eric Rulifson, PhD who is studying how endocrine cells produce insulin
milestone 6
The Identification of the Obesity Genes
Christian Vaisse, MD, PhD has identified several mutated genes that are responsible for extreme obesity that can lead to insulin resistance and type 2 diabetes Much of DrVaisses research focuses on
the fat secreted, weight regulating hormone, leptin, which signals the brain to match food intake and energy output The brain target of leptin, the receptor known as MC4R, is often defective in the severely obese–explaining why it is difficult for these individuals to suppress their appetite Research by DrVaisse shows that 25 percent of the severely obese have MC4R mutations, far more than the number caused by other gene mutations thought to control appetite Hence, MC4R has become a prime target in efforts to develop drugs to combat obesity By finding other defective genes downstream from the leptin pathway, Dr Vaisse hopes to learn how these mutations also help to contribute to obesity–and the resulting insulin resistance and type 2 diabetes, eventually leading to new therapies to combat these related conditions
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UCSF researchers are studying several mutated genes responsible for extreme obesity that can lead to insulin resistance and type 2 diabetes
milestone 8
Protein Involved in Insulin Resistance and Type 2 Diabetes
Insulin resistance syndrome is caused by the bodys inability to use insulin efficiently, often leading to obesity, high blood pressure, high cholesterol, and
type 2 diabetes It is a serious health problem–approximately 40 of all money spent on adult medications in this country is focused on combating this syndrome Back in 1995, Ira Goldfine, MD discovered a protein, known as PC-1, in abnormally high amounts in patients with diabetes In a 2005 study, Dr Goldfine reported that mice overexpressing the human version of PC-1 in their livers have significantly elevated blood glucose levels, hyperinsulinema and impaired glucose tolerance–all hallmark signs of insulin resistance and the related type 2 diabetes It appears that the PC-1 protein binds to the insulin receptor and impairs the cells ability to utilize insulin While this study examined PC-1 expression in the livers of mice, PC-1 is generally expressed in muscle and adipose fat tissue in humans Dr Goldfine and his colleagues are continuing to conduct research examining the effects of PC-1 in human muscle cells–to further establish the link to human insulin resistance and type 2 diabetes It is hoped that this discovery will lead to new drugs to prevent or reverse insulin resistance, and ultimately treat type 2 diabetes
milestone 9
Generating Beta Cells from Human Embryonic Stem
Cells
Michael German, MD and Matthias Hebrok, PhD have made significant contributions to the fields of beta cell development, pancreas development, and stem cell research Dr German is seeking to understand the molecular mechanisms underlying the formation of beta cells and to apply this knowledge to growing beta cells for individuals with type 1 diabetes In particular, he hopes to identify the genes involved in directing stem cells to begin the process of beta cell differentiation By studying how beta cells develop in the embryonic pancreas, Dr Hebrok is identifying new approaches to regenerating these cells Dr Hebrok is also developing new methods for coaxing embryonic stem cells to differentiate into fully functional beta cells By replicating the signaling events during pancreas development in cell culture, he hopes to optimize the formation of definitive endoderm–the germ layer that gives rise to beta cells from embryonic stem cells–ultimately generating fully functional beta cells Through his work with one particular embryonic signaling pathway called Hedgehog, Dr Hebrok was responsible for a breakthrough discovery in pancreatic cancer in 2003 –demonstrating the important
research linkages between diabetes, cancer and other diseases
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UCSF researchers have reported they have improved a technique for genetically reprogramming stem cells to their embryonic state
milestone 10
Reprogramming Stem Cells to their Embryonic State
Embryonic stem cells reside in the early mammalian embryo and have the ability to give rise to all cell types in the body, hence they are called pluripotent Miguel Ramalho-Santos, PhD is studying how the pluripotent nature of embryonic stem cells is genetically regulated, and how it might be possible to tailor the differentiation of these cells to particular cell types such as beta cells In 2007, Dr Santos and his colleagues reported an improved technique for genetically reprogramming mouse cells to become embryonic stem cells By over-expressing a combination of genes in mouse skin cells, the mouse cells began to lose their adult functions and function like they did in their embryonic state The next step– perfecting cell reprogramming in human cells–will help in the study of human disease development and may lead to the creation of patient-specific stem cell based therapies Once patient-matched embryonic stem cells can be
generated, the risk for rejection upon transplantation is much reduced
mast cells of the immune system, are actually driving the processes of cancer development By eliminating MMP9, the incidence of fullblown cancer is dramatically reduced, proving that the immune system is contributing to the development of cancer Dr Hanahan continues to focus on the genetics of both cancer and autoimmunity By studying the process of inflammation, he will better understand how this process plays a role in the autoimmune attack of the beta cells Additionally, inflammation has been known to disrupt the bodys ability to process insulin, contributing to the onset of type 2 diabetes
milestone 12
Diabetes Teaching Center Launches Educational Website
As one of the countrys oldest diabetes education programs and a pioneer in the development of intensive selfmanagement regimens, the Diabetes Teaching Centers DTC clinical team, led by Martha Nolte MD, was concerned that they could not effectively support the masses of individuals living with diabetes by restricting their offerings to a classroom setting at the UC Medical Center In 2007, thanks to the generous support of a number of Bay Area individuals
and foundations, the type 1 section of UCSF Diabetes Education Online DEO was launched at wwwdtcucsfedu/, and a section dedicated to type 2 diabetes will follow The project was led by Dr Nolte and DTC Program Coordinator Marlene Bedrich, and included an interdisciplinary team composed of representatives from the Medical Center, Department of Nutrition, School of Pharmacy, and Public Affairs
milestone 11
The Role of Inflammation
Inflammation is a biological process driven by the immune system to help the body react to infection, irritation or other injury–and help the body to repair itself In 2000, Douglas Hanahan, PhD and his colleagues discovered that chronic tissue inflammation may paradoxically serve to fuel rather than reduce tumor growth in cancer He believes MMP9, a protein secreted by inflammatory
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UCSF is home to one of the countrys oldest diabetes education programs, the Diabetes Teaching Center–a pioneer in the development of intensive self-management regimens and the creator of UCSF Diabetes Education Online DEO: wwwdtcucsfedu
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Pediatric Diabetes Program 415-353-7337 UCSF Adult Diabetes Program 415-353-2350 UCSF Diabetes Teaching Center 415-353-2266 wwwdiabetesucsfedu/diabetesteachingcenter UCSF Clinical Trials in Diabetes 415-353-9084 wwwdiabetesucsfedu/clinical_trials To sign up for our electronic newsletter wwwdiabetesucsfedu/eUpdate To learn how you can support the Diabetes Center 415-476-3627 kmcateer@supportucsfedu
