The Naomi Berrie
Diabetes Center at 10

A unique, family-centered clinical care program and its diabetes research laboratories mark special anniversary

By Robin Eisner
Eli Bunzel, 17, first came to the Naomi Berrie Diabetes Center for treatment when he was 10 years old, soon after being diagnosed with type 1 diabetes. He toured the center’s research laboratories on the second and sixth floors of

photo credit: Robert Bean
Pre-med student Lindsay Knable, left, and first-year medical student Diana Arnold Miller began their association with the Naomi Berrie Diabetes Center as patients but also completed internships in Berrie Center labs.
Pre-med student Lindsay Knable, left, and first-year medical student Diana Arnold Miller began their association with the Naomi Berrie Diabetes Center as patients but also completed internships in Berrie Center labs. Ms. Knable, a sophomore at Cornell, worked in the Berrie labs this summer. Ms. Miller, a student at UMDNJ’s Robert Wood Johnson Medical School, interned in the labs two summers ago while attending Columbia’s engineering school. She also spent the past year in a full-time research position at the Berrie Center while waiting to begin medical school. Like many patients who have taken their turns at research benches studying a disease they have, Ms. Knable and Ms. Miller could use their experiences as patients and researchers to help others.

the Russell Berrie Medical Science Pavilion on the east side of St. Nicholas Avenue and 168th Street, as many other Berrie Center patients and family members do. “I remember thinking it would be cool to work here,” Eli says.
   This past summer the junior at Riverdale Country School in the Bronx had the opportunity to intern for a month and a half at a Berrie Center laboratory. He is one of several high school and college students who have worked in the Berrie labs, including the women pictured at left and on the cover, Lindsay Knable and Diana Arnold Miller. During his internship, Eli analyzed DNA and looked at brain cells with fluorescence microscopy in the laboratory of Lori Zeltser, assistant professor of clinical pathology.
   Dr. Zeltser studies in mouse models how a pregnant woman who is obese increases the likelihood that her child may become overweight and develop type 2 diabetes. She and her students also are characterizing in mice the cells and molecular circuitry in a brain region called the arcuate nucleus of the hypothalamus that controls appetite, energy metabolism, fertility, fat deposition, and lactation. A related area in human brains regulates similar functions.
   “The experience of working in the laboratory was eye-opening, and by the end I could work independently,” Eli says. “It was great to see how the biology I learned in school was really being used in the real world. I discovered that I love research [and] I may want to pursue medicine and to help patients one day.”
   For the past 10 years, the Naomi Berrie Diabetes Center has been inspiring patients living with diabetes, like Eli Bunzel, to live life to the fullest while keeping diabetes under optimal control and staying healthy. Both type 1 and type 2 diabetes are chronic conditions requiring life-long treatment, so the unique, family-oriented care provided at the Berrie Center has allowed more than 10,000 patients to not let their condition get in the way of school, good food, sports, love, having babies, work, vacations, and life. With more than 40 clinical staff members, the center in its location on the second floor of the Berrie Pavilion offers its patients the medical care they need: adult and pediatric endocrinologists, dieticians, nurse educators, social workers, psychologists, and ophthalmologists.
   The center also is dedicated to researching better ways to prevent and treat diabetes with an ultimate goal of
 Eli Bunzel “I remember thinking it would be cool to work here.”
— Eli Bunzel
photo credit: Karl Crutchfield
curing diabetes. More than 50 scientists in Berrie Center laboratories investigate the causes and consequences of diabetes. The NIH-funded Diabetes and Endocrinology Research Center at Columbia University supports Berrie Center and collaborating scientists doing related research throughout Columbia University. Through the center’s Program in Cellular Therapies for Diabetes and the Naomi Berrie Award for Outstanding Achievement in Diabetes Research, the Berrie Center also funds research outside Columbia.
   Opened in October 1998, the center is named for Naomi Berrie, the mother of Russ Berrie, a philanthropist and founder of Russ Berrie and Company Inc., a toy and gift manufacturer. In the late 1990s, Mr. Berrie donated $13.5 million to partially fund the building where the center is housed and to help launch the clinical and research programs of the Naomi Berrie Diabetes Center. Both mother and son (Russ Berrie died in 2002) had diabetes. The Russell Berrie Foundation has provided more than $63 million to support the Berrie Center’s clinical and research programs.


“Care the way it is supposed to be”

Lab day during the
Lab day during the Summer Fun Program
Strong philanthropic support from the Berrie Foundation and other donors has been critical for the center’s success in meeting the challenge of caring for diabetes, says Robin Goland, M.D., founding co-director of the center and professor of clinical medicine. “We can provide clinical care without completely relying on the often inadequate reimbursement from insurance companies,” she says.
   A significant amount of time in caring for people with diabetes involves education about the disease and communication to patients over the telephone and through email and fax about blood sugar levels and how to match insulin and other medications to blood sugars, food, exercise and level of stress, all services that are not compensated. But health care providers at the center spend as much time with patients and their family members as necessary. “Diabetes management can be improved dramatically if those who live with and support the patient understand diabetes and its management too,” Dr. Goland says.
   Berrie Center clinicians have particular expertise in the care of children. A diagnosis of diabetes is life-changing for an adult, but it can be overwhelming for a youngster. Children want to be like their peers; a chronic disease can be alienating and isolating. Pediatric diabetes nurse educators and nutritionists explain the disease in age-appropriate ways, while social workers work with the young person and their families to talk about their feelings.
   “I felt that the nurse educator who talked to me really understood what I was going through and spoke to me in a way I could understand,” says Eli Bunzel, recalling his earliest experiences at the center. Berrie Center staff members also may visit a patient’s school to educate nurses, teachers, coaches, and classmates about diabetes.
   To help underserved children with diabetes, the Berrie Center in 2001 began offering a free week-long Summer Fun Program each summer for 20 youngsters with type 1 diabetes. Participants have traditional activities but also tour Berrie Center laboratories.
   “The center provides humanistic medical care the way it is supposed to be,” says Angelica Berrie, Russell Berrie Foundation president and widow of Russ Berrie. “When you walk into the center, it is a happy environment, where kids are playing and parents and adults are smiling.”
   Having clinical facilities near research laboratories also was part of the center’s design. “People with diabetes can see the laboratories where research is going on that can and will help them,” says Rudolph Leibel, M.D., co-director of the center and professor of pediatrics and medicine. “Scientists also regularly meet patients.” Proximity also allows scientists to interact routinely with clinicians, “with the goal of getting the basic research results into the clinic as quickly as possible,” he says, and to study in more detail promising clinical findings.

Access to the latest clinical research
Ultimately, Dr. Goland says, the goal of the Berrie Center is to put itself out of business. Toward that end, the Berrie Center offers opportunities for patients to participate in clinical trials that aim to prevent or delay onset of disease or prevent the disease’s complications.
   One international trial involving Berrie patients is testing whether the drug, abatacept, can reduce the immune destruction of beta cells and preserve insulin production in people recently diagnosed with type 1 diabetes. The trial is placebo-controlled, randomized, and masked so neither patient nor staff know which participants are taking the
Strong philanthropic support from the Berrie Foundation and other donors has been critical for the center’s success in meeting the challenge of caring for diabetes
drug (approved by the FDA in 2005 for rheumatoid arthritis, another autoimmune disease) or the placebo.
   “The trial requires quite a commitment because subjects receive 27 intravenous drug infusions during a two-year period and are followed for two more years,” explains Ellen Greenberg, type 1 diabetes research coordinator. “We get to know the patients extremely well.”
   The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial seeks the best ways to decrease the high rates of heart attack and stroke in patients with type 2 diabetes. The eight-year NIH-funded study involves more than 10,000 patients between 40 and 79 years old who either have cardiovascular disease or are at very high risk for it. Because study results in June 2008 revealed that extreme levels of glucose control increased the risk of death in this population, the trial investigators stopped that aspect of the trial but are continuing to test moderate glucose control and other parameters: cholesterol-lowering medications, lipid-lowering agents, and blood pressure control drugs. This unexpected finding of adverse consequences associated with extremely “tight” glucose control emphasizes the importance of such studies and of the Berrie Center as a major venue.
   “A mission of the Berrie Center is to give the best care to the patients and improve their lives,” says Pat Kringas, clinical research nurse coordinator for type 2 diabetes. “One way to do that is give them the opportunity to take advantage of research.”

Moving from the laboratory to the clinic
Berrie Center scientists are leaders in uncovering the mysteries of diabetes and routinely collaborate with scientists at Columbia University and at other institutions so that promising findings can benefit patients.
   Husband and wife team Paul Harris, Ph.D., and Antonella Maffei, Ph.D., research scientists at the Berrie Center, have been studying PET imaging as a way to directly monitor the loss of insulin-producing cells that occurs in type 1 and type 2 diabetes. “A method to quantify the change in number of pancreatic beta cells would help assess the progression of diabetes and the effects of interventions such as beta cell transplants, a drug, or a lifestyle change,” says Dr. Harris. Beta cell mass is now indirectly inferred by measuring glucose and insulin in the blood.
   PET produces three-dimensional images of the pancreas by detecting radiation released from a radioactively labeled tracer that binds to VMAT-2, a protein Dr. Harris found is a marker for beta cells of the pancreas. “The marker had already been identified in the brain and used to study the brain. We now point the PET camera to a person’s abdomen and use the same brain tracers.” After performing PET studies in animal models, he is validating the work in humans. “We have to make sure what we are seeing over time really reflects real changes in beta cell mass,” says Dr. Harris.
   Ten years ago, beta cell loss seemed an inevitable consequence of diabetes. But during that time clinicians at the

A mission of the Berrie Center is to give the best care to the patients and improve their lives. One way to do that is give them the opportunity to take advantage of research.
Berrie Center and elsewhere had some success in reducing insulin dependence in patients with type 1 diabetes who received a transplant of donor islet cells from pancreases of recently deceased donors. (Islets include insulin-producing beta cells.) In time, though, the need for insulin administration returned. However, even if the procedure were more successful, expanding its application would have been difficult: Each patient would need two to four donor pancreases, which are in short supply.
   With advances in stem cell technology, scientists have started to try to create beta cells de novo, from adult stem cells, from embryonic stems cells, or by reprogramming other cells in the body to become a stem cell and then a beta cell. “With stem cell technology you could potentially have an unlimited source of beta cells,” says Lori Sussel, Ph.D., associate professor of genetics & development, who studies the molecules that guide the formation of the different cells in the pancreas during mouse development. Her research goal: to identify beta cell-promoting regulatory factors for colleagues who can use them to turn stem cells into beta cells for treatment of diabetic patients.
   Although the pancreas is a major organ involved in diabetes, it is not the only organ affected, says Domenico Accili, M.D., professor of medicine and director of the NIH-funded Diabetes and Endocrinology Research Center that is part of the Naomi Berrie Diabetes Center. “Diabetes is a miscommunication among different organs. To understand the disease you have to understand which organ(s) are the main offenders in any particular person. There can be insulin resistance in the liver, fat cells, brain, and pancreatic beta cells. Each individual might be more insulin-resistant in one of different organs, and in an individual, the disease may change. Therefore, we need different treatments for different people.”
   Dr. Accili hopes his laboratory’s research will lead to a drug that targets the liver in diabetes. For the past 10 years, his research focused on the protein FOX01, which regulates insulin shut-down of liver glucose production. “We think drugs targeting FOX01 would be beneficial for people with diabetes because they have too much glucose production in their liver,” he says. FOX01, however, was not amenable to usual small-molecule pharmaceutical approach. Now, he is using RNA interference technology, involving small pieces of RNA, to dampen the activity of the FOX01 gene.
   Currently, diagnosing the involvement of the different organs in diabetes is not possible, but Dr. Accili notes that
Moving from the laboratory to the clinic
photo credit: Karl Crutchfield
Dr. Harris’s PET studies may allow clinicians to monitor pancreatic beta loss and response to interventions.
   Dr. Accili likens diabetes treatment today to cancer treatment 40 years ago, when the same cocktail of chemotherapeutic agents was given to people who had breast or colon cancer. “Today different drugs are given to treat specific cancers in different organs,” Dr. Accili says. “In the future, we will have better drugs to treat the different organ systems affected in diabetes.”
   Because obesity is a significant risk factor for type 2 diabetes, Berrie scientists also study the biological mechanisms that regulate body weight, appetite, and energy metabolism. Reduction in body weight can prevent and even reverse type 2 diabetes and today represents the most effective means of preventing and ameliorating the disease. However, sustained weight reduction is very difficult to achieve.
   Dr. Leibel, Berrie Center co-director, has studied obesity for more than 25 years. He and his associates cloned the gene for leptin, a hormone that regulates body weight, and they continue to identify and study other genes involved in obesity and type 2 diabetes. Understanding how these genes and their protein products act and interact with environmental factors may lead to new interventions that could prevent obesity. Dr. Leibel and his associate Michael Rosenbaum (see more about Dr. Rosenbaum below) are investigating use of the protein leptin to help people who have lost weight to maintain their weight loss.
   Research is ongoing about leptin and its role in the neural circuitry of the brain’s hypothalamus. Dr. Zeltser is making significant progress in mapping the neurons in the arcuate nucleus of the hypothalamus which regulates body weight and energy metabolism. She also is studying in animal models how these neurons might be affected in utero because they are probably involved in the physiological mechanism that leads to the increased risk of obesity in the offspring of obese pregnant women.
   The increasing body weight of pregnant women in recent years may be partially responsible for the increased rates of obesity now seen in children. This so-called “maternal effect” might be due to insulin resistance associated with obesity and an exaggerated inflammatory response, which occurs in the placenta during the pregnancy of obese mothers. Dr. Zeltser and her students are studying in mice how these biological phenomena might be communicated to offspring. Her findings could be extended to pregnant women to try to prevent the maternal effect.
   That a cell -- the macrophage -- is partially causing the inflammation associated with obesity was discovered in 2003 by Berrie Center scientist Anthony Ferrante, M.D., Ph.D., assistant professor of medicine. He found that the numbers of macrophages, cells that fight infection and help to stimulate the immune or inflammatory response, increase in adipose tissue with increasing obesity. Dr. Ferrante also has shown in animal models of diabetes that tamping down the macrophage inflammatory response can reduce blood sugar levels and fat accumulation in the liver, another diabetes complication. Dr. Ferrante is working with pharmaceutical companies to develop agents to counter the macrophage action because such drugs might reduce diabetes complications.
   While more is learned about obesity and its role in diabetes, other researchers are studying the effect of educational programs in helping to prevent type 2 diabetes. Michael Rosenbaum, M.D., associate professor of clinical pediatrics and medicine, collaborates with other medical centers in New York to assess the effectiveness of a nutrition and exercise curriculum in reducing type 2 diabetes in metropolitan area youngsters. The five-year initiative, called ROAD (Reduce Obesity And Diabetes), is targeted to children in the sixth through eighth grades (before type 2 diabetes usually shows up).
   Dr. Rosenbaum has developed a unique method to monitor both ability to make insulin and insulin sensitivity and is coupling this method to multiple biochemical, historical, and clinical measures to characterize who is at risk for type 2 diabetes and how the interventions help. These uniquely detailed assessments are already providing valuable insights into how diabetes develops and what can be done in school to reduce fatness and diabetes risk in all students.

The future
As the Berrie Center looks forward, it plans to continue to provide the best care for its patients and to do the most exciting research, training the next generation of clinicians and scientists. “If I cannot execute all the ideas in my professional lifetime, there needs to be bright young people in academic medicine to focus on diabetes in the future,” says Dr. Accili.
   Ten years ago, Dr. Ferrante was just starting his career at the Berrie Center, says Dr. Accili. “Look what Tony [Ferrante] has accomplished.” Perhaps someday, Eli Bunzel, Diana Arnold Miller, or Lindsay Knable as physician-scientists will return to the Berrie Center and help to transform the lives of others through medicine or research, as their own lives were transformed by the dedicated staff at the Naomi Berrie Diabetes Center.

The Power of Philanthropy

The Naomi Berrie Diabetes Center became New York City’s only comprehensive diabetes center after other diabetes centers closed because of the financial burdens of treating the disease.
    A concept for a multidisciplinary center with clinical and basic research components was developed by Robin Goland, M.D., who would become the center’s founding director. Russell Berrie, a philanthropist and toy manufacturer, and others donated funds to build the second building in the Audubon Research Park in Berrie’s name, which would house a diabetes center. Mr. Berrie, who had type 2 diabetes and was Dr. Goland’s patient, provided resources to help establish the Naomi Berrie Diabetes Center in honor of his mother, who died of complications of type 1 diabetes. Other donors who helped and continue to help are honored with plaques at the entrance to the center on the second floor of the building and throughout the facility.
   “We raised a lot of money then, and knew we would continue to have to do so because of the clinical and research needs of the center,” says Joseph M. Murphy, emeritus co-chair of the Berrie Diabetes Advisory Committee with his wife, JoAnn. Mr. Murphy, who has type 2 diabetes, served on an advisory committee during the center’s planning stages in the mid-1990s. In 2007, he established the Christopher J. Murphy Professorship in Diabetes Research to honor his son who died in 2001 from cardiovascular complications of type 1 diabetes. The Murphys’ daughter also has type 1 diabetes. The Murphy family has given $3.5 million to date and pledged an additional $1 million in support for clinical and research needs.
   John and Josephine (Jodie) Eastman, current co-chairs of the Berrie Diabetes Advisory Committee, decided to get involved after their granddaughter, Merrill, was diagnosed with type 1 diabetes. “We knew she was going to be able to get good care, but we wanted to make sure others also get good care,” says Mr. Eastman. “Diabetes hasn’t slowed Merrill down a bit; it shouldn’t slow anyone else down either. As we looked at the various diabetes efforts, we concluded that a cure was scientifically a most complex undertaking, which possibly was decades away. In the meantime, increasingly sophisticated advances in care and related research are critical and we felt were underfunded. This led us as a family, including Merrill’s parents, uncles and aunts and cousins, to support Robin and Rudy’s extraordinary efforts at the Berrie Center, beginning with funding the J. Merrill Eastman Professorship in Diabetes, designated for the clinical co-director of the Berrie Center.”
   To further support the center, the Russell Berrie Foundation donated $21 million to Columbia University and $7 million to New York-Presbyterian Hospital/Columbia in March 2008. The funding to the University goes toward non-reimbursed clinical care, a new professorship, new pilot research, the Berrie Center’s endowment, and a continuation of the Berrie Program in Cellular Therapies of Diabetes, started in 2003, to use cell biology, molecular genetics, and stem cells to develop means of treating and preventing diabetes. The hospital’s funding will establish a heart center to focus on the disease’s cardiovascular complications.

 

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