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Department of Diabetes and Metabolic Diseases Research

The City of Hope has a long and impressive history of groundbreaking discoveries in the field of diabetes. It spans more than four decades of intense investigation since Rachmiel Levine, M.D., who discovered the role of insulin in glucose transport, launched diabetes research at City of Hope.
Arthur D. Riggs, Ph.D., chairs
the Department of Diabetes
and Metabolic Diseases Research.

The Department of Diabetes and Metabolic Diseases Research is now chaired by Arthur D. Riggs, Ph.D., another renowned researcher and pioneer in the field.

Riggs is recognized for his work on the synthesis of the first man-made gene and the use of synthetic genes for the production of human insulin. This first practical source of human insulin has largely replaced porcine- or bovine-derived insulin and has become the standard of care for diabetes worldwide.
 
Riggs continues to break ground in the battle against cancer, particularly in the area of epigenetics.
 
Read interviews with Riggs on the story behind synthetic human insulin and his thoughts on the future of diabetes research on City of Hope’s Breakthroughs blog.
 
 
 
 
Two divisions
 
The department headed by Riggs encompasses two divisions, which interface between diabetes research and translational medicine:
 
 
Goals

The Department of Diabetes and Metabolic Diseases Research includes as its primary goals:
 
  • Understanding the genetic and molecular signaling mechanisms that lead to diabetes and its complications
  • Advancing islet cell transplantation and related treatments for type 1 diabetes by developing better methods to prevent rejection and cure autoimmunity and by developing improved sources of islets or insulin-producing beta cells
  • Developing drugs that precisely target the receptor molecules responsible for diabetes
  • Studying the relationship between diabetes and cancer in order to better understand cancer etiology (and interplay at the metabolic level between these complex diseases). Specifically, developing systems biology data analysis framework to quantify and model diabetes and cancer molecular pathways
  • Designing interventions that address molecular targets common to both diabetes and cancer, through targeted, personalized pharmacotherapy.
 

An Overview of Diabetes Basic Research

City of Hope has one of the most influential diabetes research programs in the world.  Our scientists’ work has revolutionized the understanding and treatment of the disease and continues today with exciting developments in cell transplantation, gene regulation, immune tolerance, and gaining systemic understanding of diabetes as a complex, multifaceted disease.

Within Diabetes Research is the Department of Diabetes and Metabolic Diseases Research. Scientists in that department work in two divisions:
 
 
Landmark contributions

City of Hope’s leadership in diabetes began decades ago when the “father of endocrinology,” Rachmiel Levine, M.D., launched diabetes research at City of Hope. Levine had, in the 1940s, identified the principal cause of the illness: a reduction in our body’s ability to stimulate glucose entry in the cells, directly linked to the insulin production. 
City of Hope researchers, such as Rama Natarajan, Ph.D., are making landmark contributions to the fight against diabetes.
Today, City of Hope researchers continue to make landmark contributions to the fight against diabetes. Recognized nationwide for our innovative biomedical research, we are home to some of the most creative minds in science. Our strength lies in collaboration – leveraging the talents of investigators across departments and across the institution and rapidly translating scientific discoveries into new treatments. By working together and sharing results, researchers and clinicians are able to put theories into practice. As a result, excellence in one area fuels advancements in all areas.
 
City of Hope’s mission in diabetes research is to improve the quality of life for patients, prevent complications from the disease, and ultimately, establish a cure. At City of Hope, we’ve achieved many milestones in the field and are now pursuing the next generation of diabetes treatments in our efforts to end the devastation of the disease and usher in a new era of healing and hope.
 
Diabetes basic research is housed in the Leslie & Susan Gonda (Goldschmied) Diabetes & Genetic Research Center, which was recently expanded to provide urgently needed laboratory space. City of Hope researchers are using this lab space in their race to find ways to understand, control and cure diabetes, which continues to grow as a major public health threat.

An epidemic reaching pandemic proportions
 
Diabetes is rapidly progressing from epidemic to pandemic. The Centers for Disease Control and Prevention predicts that by the year 2050, if current epidemiological trends continue, one in every three people in the U.S. could suffer from diabetes at some point in their life. Diabetes is a global issue as well, as one of the world’s leading causes of death, disability and lost economic growth. Worldwide, health expenditures to treat and prevent the disease and its complications continue to grow, with $465 billion spent in 2011 alone.
 
To learn more about diabetes, go to the About Diabetes page.

Scientists in basic research provide the foundation for new therapies and approaches to battling diabetes. Our work touches on all aspects of the disease, including heart and kidney complications. Read more about our current projects and the work of each division by clicking on the tabs above.
 
Our clinical program and translational research
 
At City of Hope, our experience in the area of diabetes, including established analytic, molecular and clinical resources, have enabled us to rapidly translate emerging scientific concepts into new treatments. Our mission is to ensure that breakthroughs from the basic research of scientists in the Department of Diabetes and Metabolic Diseases Research are then rapidly translated into clinical settings where they can impact patients. The Department of Clinical Diabetes, Endocrinology & Metabolism is currently conducting a number of important clinical research programs to help put our basic and clinical biomedical research into practice.
 
To search for a trial, go to our clinical trials page.
               
 

Division of Developmental and Translational Diabetes and Endocrine Research


The Division of Developmental and Translational Diabetes and Endocrine Research, directed by Fouad Kandeel, M.D., Ph.D., has translated landmark scientific discoveries into treatments that have improved the lives of diabetic patients around the world.  The expansion of the Leslie & Susan Gonda (Goldschmied) Diabetes & Genetic Research Center has enabled us to bolster our efforts in the fight against diabetes simultaneously on multiple fronts:  from developmental research starting in our state-of-the-art laboratories to clinical investigations leading to innovative patient care. 
Fouad Kandeel, M.D., Ph.D., directs
the Division of Developmental and
Translational Diabetes and
Endocrine Research.

Our approach
 
Our goal is to bring the latest scientific findings into medical practice as quickly as possible. Researchers in our division conduct  laboratory, translational and clinical research with the goal of improving our understanding of the disease process and guiding the development of new diagnostic, prognostic, and therapeutic interventions.
 
Here, we focus on stem cell biology and development, translational immunology, islet isolation and distribution, islet quality assessment, islet imaging, islet encapsulation and isolation, and new drug discoveries.
 
We are also developing a mobile device that combines a live glucose monitor with an automatic insulin delivery pump system. This “artificial pancreas” will free patients from periodic self-monitoring, as well as allow more accurate control of blood glucose levels. City of Hope researchers are working with the device manufacturer to optimize performance, and preparations are being made to test the device in newly transplanted islet recipients in order to provide maximum protection of islets from the harmful effects of high blood sugar.

Imaging islet cells within the body is greatly needed to elucidate the mechanisms underlying type 1 diabetes development and monitor islet cells following transplant. New cell-imaging approaches developed at City of Hope have been used to track islet cell survival and function in animal models and have been successfully applied in a human case of pancreatic tumor.
 
 
 
 
City of Hope Islet Cell Transplant Program
City of Hope is studying the
safety and effectiveness of
transplanting islet cells
as a treatment for
type 1 diabetes.
 
City of Hope is conducting clinical trials to study the safety and effectiveness of  islet transplantation as a treatment for type 1 diabetes. City of Hope performed its first islet transplantation in 2004 and performed dozens more in the Islet Transplantation Alone and Islet After Kidney Transplantation trials. The current T cell-depleting trial will help answer the question of whether temporarily reducing or eliminating the recipient’s T cells at the time of islet transplantation will improve short- and long-term transplant results in patients with type 1 diabetes. The study also includes an assessment for changes in the quality of life after islet transplantation.
 
To qualify for the study, candidates must have type 1 diabetes, be between the ages of 18 and 68, and have the ability and willingness to comply with a post-transplant regimen that includes taking immunosuppression medications, frequent clinic visits and laboratory testing, using reliable contraception, maintaining detailed records of blood glucose levels, insulin doses, medications and completing detailed follow-up studies for up to five years.
 
Candidates who have received a prior kidney transplant for diabetic kidney failure may also participate in the study, if they have a stable kidney transplant for at least three months on specific commonly used anti-rejection medications. 

For clinical transplant matters you may contact us by calling (866) 44 ISLET (47538) or email us at islets@coh.org.
 
Global diabetes health initiative

There is a global need for a cost-effective solution to simplify diabetes management and minimize time spent on expensive and unstructured treatment plans. This solution must simultaneously improve patient participation in behavior modification and medication regimes. 
 
The center's physicians and scientists, led by Fouad Kandeel, M.D., are collaborating with diabetes scientists and clinicians in Europe to develop a fully automated patient-management system that can be utilized on a global scale. 
 
The ADAMS (Adaptive Diabetes Algorithm Managements System) platform is software that is designed to generate an automated, interventional treatment plan tailored to each patient.  It takes into account culturally relevant dietary and behavioral issues and has the potential to streamline the efficiency of diabetes care around the world.
 
 
 
Each year, City of Hope hosts an annual diabetes and obesity symposium in memory of the late Dr. Rachmiel Levine, the scientist responsible for clarifying the nature of insulin action.
 
The 15th Annual Rachmiel Levine Symposium will cover recent scientific advances in diabetes and will highlight results of recent diabetes clinical trials.  It will also include poster sessions where promising trainees can present their work, and debate sessions with world leaders in areas of controversy in diabetes research and clinical care.
 
City of Hope researchers including  Rama Natarajan, Ph.D., director of the Division of Molecular Diabetes Research, have been selected to speak at the symposium.
 
The event is scheduled for March 1 to 4, 2015 in San Diego, California.
 
 
Team members

Researchers and clinicians at City of Hope are engaged in ongoing communication and interaction to bring work from the lab to the bedside. Meet the researchers in the Division of Developmental & Translational Diabetes and Endocrine Research:
 
Fouad Kandeel , M.D., Ph.D. -  division director and professor
Islet cell transplantation

Ismail Al-Abdullah , Ph.D. - research professor
Islet cell isolation

Sanjay Awasthi , M.D. - professor
Diabetes and cancer

Kevin Ferreri , Ph.D. - associate research professor
Islet cell transplantation, epigenetics, and diabetic biomarkers

H. Teresa Ku , Ph.D. - associate professor
Stem cell therapy for type 1 diabetes; in vitro differentiation of human and mouse embryonic stem cells towards pancreatic lineage cells; identification, purification and characterization of embryonic and adult pancreatic stem/progenitor cells

Yoko Mullen , M.D., Ph.D. - research professor
Extrahepatic islet transplantation; prevention of islet loss for transplantation
 
 

Division of Molecular Diabetes Research

The Division of Molecular Diabetes Research, directed by Rama Natarajan, Ph.D., is at the forefront of research on the complications of diabetes and was the first to study epigenetic changes in diabetic complications.
Rama Natarajan, Ph.D., directs the Division
of Molecular Diabetes Research.

Research leading to new therapies

Basic science research in molecular biology, biochemistry and immunology provides the foundation that drives the development of new therapies for diabetes and related complications. City of Hope scientists in this division are performing cutting-edge research in these areas.

Battling the complications of diabetes

Diabetes is the leading cause of kidney failure and a significant risk factor for the development of vascular complications like atherosclerosis. Our researchers are working to determine molecular mechanisms and factors mediating these complications and to develop strategies to prevent and reverse these complications. The researchers' study of atherosclerosis and kidney disease includes both diabetic animal models and humans.

Scientists in this division are examining the molecular links between diabetes, obesity, metabolism, cancer and aging, including the role of various nuclear receptors.

Gene and cell-based therapies

Translational approaches using small molecules are also being investigated. Researchers are using potential gene therapy and RNA interference translational approaches to inhibit key genes associated with diabetic complications. They are also developing synthetic small molecules to target genes that promote obesity and related metabolic changes.

Our researchers have identified a molecular link between physical activity and insulin sensitivity. They are using animal models to characterize key mechanisms in exercise's effects on skeletal muscle's energy metabolism and growth.

In addition, our researchers are performing important studies to develop novel methods to induce immune tolerance for the treatment of type 1 diabetes and also identify new cellular targets that can lead to cell-based therapies for diabetes. The results of these studies with immune cells can lead to more effective approaches in the treatment diabetes and to improved success of islet-cell transplantation.
 
Our approach

Overall, this division within the Department of Diabetes and Metabolic Research uses several state-of-the-art computational and systems biology data-analysis methods; genomic and epigenomic profiling approaches; novel transgenic mouse models; and translational approaches with small molecules, antibody and cell-based therapies in animal models and humans in its quest to advance the field of diabetes research.

The division's investigators also work closely with the clinical researchers in the Department of Clinical Diabetes, Endocrinology and Metabolism as well as other multidisciplinary teams throughout City of Hope.
 
 
Each year the City of Hope hosts a meeting involving a consortium of laboratories in the Southern California region with a shared interest in related fields of gene regulation and nuclear receptor function and mechanism.  Topics span an array of biological area, including development, metabolism, diabetes, and cancer.
 
The MoLAR meeting provides a venue for investigators and scientists, post-doctoral fellows and graduate trainees to present progress on current research projects in their laboratories.  The agenda includes an invited keynote speaker with the rest of the meeting left for participating laboratories to feature their work in short talks (15-25 minutes in length).  The gathering aims to provide a local, small and collegial environment to discuss projects, interact and foster collaborations between laboratories.

Team members
 
Rama Natarajan , Ph.D., F.A.H.A., F.A.S.N. - division director and professor
Identification of the molecular mechanisms underlying the accelerated cardiovascular and renal disease observed in diabetic patients and in obese subjects; role of epigenetics, microRNAs and other non-coding  RNAs; and inflammatory responses in islet destruction
 
Wendong Huang , Ph.D. - associate professor
Genetic and epigenetic regulation of diabetes; stem cell and drug development for diabetes
 
Janice Huss , Ph.D. – associate professor
Characterization of transcriptional mechanisms regulating skeletal muscle metabolic adaptations during growth and differentiation and in response to physiologic stress; the etiologic role of orphan nuclear receptors in obesity and type 2 diabetes
 
Chih-Pin Liu , Ph.D. – professor
Development of methods to induce immune tolerance; identification of novel cellular and molecular targets to improve cell-based therapy for diabetes
 
Defu Zeng , M.D. - professor
Induction of mixed chimerism for reversal of autoimmunity, beta cell regeneration, and transplantation immune tolerance
 

Accomplishments in Diabetes Research

City of Hope researchers have built the foundation of scientific knowledge upon which the understanding and treatment of diabetes are based.
 
Engineering synthetic insulin

In the late 1970s,  Arthur Riggs , Ph.D., and Keiichi Itakura, Ph.D., produced synthetic human insulin using bacteria. It became the first genetically engineered product approved by the Food and Drug Administration and today is used worldwide by millions of people with diabetes. The breakthrough made insulin more available and affordable and helped launch the biotechnology industry.
City of Hope researchers have made numerous breakthoughs, including in islet-cell transplantation and in the understanding of islet dysfunction.
 
Perfecting islet transplantation protocols

Fouad Kandeel , M.D., Ph.D., perfected clinical islet-cell transplantation protocols and has developed imaging methods that enable physicians to more monitor in real time the health of islets after transplantation.
 
Targeting diabetic complications

Rama Natarajan , Ph.D., and Jerry Nadler, M.D., conducted research dealing with diabetic complications and islet dysfunction. Their work has led to the identification of novel therapeutic targets and agents for the treatment of diabetic complications. Natarajan was also the first to demonstrate the role of epigenetics in diabetic vascular inflammation and in the metabolic memory phenomenon.

Her laboratory was also the first to demonstrate how microRNAs (small, non-coding RNAs) can cause the overproduction of collagen, which creates damage that can lead to kidney abnormalities and renal dysfunction. She used therapeutic interventions to block these microRNAs, slowing the cells’ harmful overproduction of collagen and other proteins and kidney damage.
 
 
Diagnosing type 1 diabetes sooner

Kevin Ferreri , Ph.D., has developed a new method of diagnosing type 1 diabetes. His research team detected unique markings on the DNA of insulin-producing cells. When these cells die during the progression of type 1 diabetes, the markings can be detected on DNA that circulates in the blood. This method can be used to diagnose type 1 diabetes before complications and can be used to test the effectiveness of new treatments.

To read about more of City of Hope researchers’ accomplishments, including the 1940s discovery by Rachmiel Levine, M.D., of insulin’s role in processing sugars, read our Diabetes Program History page. 
 

Current Projects in the Department of Diabetes and Metabolic Diseases Research

 
Using computer science-based approaches to create individualized treatment plans
 
City of Hope researchers are developing a high-tech analytic tool that promises to revolutionize the way diabetes is treated. The treatment platform uses the combination of both data-driven and expert-based algorithms to generate validated individualized treatment plans. Advanced Diabetes Algorithm Management System, or ADAMS, starts by gathering information on the patient’s health, treatment preferences and other epidemiological and cultural factors. The data is processed using the model-fitting software that gives the physicians not only a basic “overview” of how a patient’s body is metabolizing glucose, but also the results of in silico simulations showing a specific intervention’s likely impact on a patient’s metabolic footprint. Thus, the patient is armed with a comprehensive treatment plan and continued feedback on diet, exercise and medication.
 
Fouad R. Kandeel , M.D., Ph.D., director of the Division of Developmental & Translational Diabetes and Endocrine Research, who is leading this project, believes the program can vastly improve long-time clinical outcomes for large populations of diabetic patients across the globe. Kandeel is directly collaborating with  Andrei Rodin , Ph.D., a leader in the field of developing systems biology data analysis methodology, who is working on adapting his secondary data analysis tools to clinical data.
 

Identifying mechanisms and drug targets for diabetic complications

Diabetes is the leading cause of kidney failure and a significant risk factor for the development of vascular complications like atherosclerosis.  Rama Natarajan , Ph.D., director of the Division of Molecular Diabetes Research, is studying mechanisms of atherosclerosis and kidney disease in diabetes. She is using cell, animal and human models to demonstrate how diabetes leads to increased inflammation in blood and kidney cells and is devising approaches to interfere with the production of these inflammatory molecules to slow down diabetic vascular complications

Her team has also studied a gene-control mechanism called RNA silencing, which may play a key role in diabetic kidney disease. In it, cells employ pieces of genetic material called microRNA, or miRNA, to turn genes off. The researchers have identified a key miRNA that creates an overproduction of collagen, which causes damage that can lead to kidney disease and renal dysfunction.  By controlling key miRNAs in the kidney, the researchers seek to slow down the cells’ overproduction of collagen and similar proteins and potentially control diabetic kidney disease. They are also similarly examining miRNAs and related molecules that promote inflammation in blood cells and blood vessels under diabetic conditions and approaches to interfere with their actions to control cardiovascular complications of diabetes.
City of Hope researchers are investigating
new ways to generate insulin-producing
cells from stem cells.

Generating insulin-producing cells from stem cells

One of the major roadblocks to translating stem cell research from the lab to the clinic is the low yield of insulin-producing cells from stem cells.  Arthur Riggs , Ph.D., the department chair, is collaborating with   Hsun Teresa Ku , Ph.D., on ways to generate insulin-producing cells from stem cells.
 
The team is creating new technologies to accomplish this, including synthetic extracellular matrices, structures found in the connective tissues of animals, and genetically reprogram them to adopt a new identity and function.
 
 
 
 Targeting a key to metabolic syndrome
 
Sanjay Awasthi , M.D., is studying the role of glutathione metabolism in the development of cancer and type 2 diabetes. He silenced the gene that expresses the protein RLIP76, increasing resistance to the development of chemically induced cancers in animal models. Furthermore, the models showed reduced blood sugar, cholesterol and triglycerides despite a high-fat diet. These findings are expected to lead to the development of novel drugs that targets RLIP76 in order to treat obesity, metabolic syndrome and cancer.
 
 
Creating a drug to mimic the benefits of exercise

In order to develop treatments that slow or prevent the development of type 2 diabetes, researchers must understand the ways in which various insulin responsive tissues respond to fluctuations in diet and energy demand. The laboratory of  Janice Huss , Ph.D., investigates mechanisms governing mitochondrial energy metabolism and growth of skeletal muscle in healthy and diseased states. The capacity of skeletal muscle to regulate whole body energy balance, glucose and lipid utilization and to prevent the development of obesity and insulin resistance is determined by its oxidative capacity and it overall mass.  Her group has discovered that the Estrogen-related Receptors (ERRs) control interrelated programs of muscle energy metabolism and growth.  ERRs control levels of proteins needed for energy metabolism and muscle contraction. These factors are essential for directing metabolic enhancements caused by endurance exercise. Her laboratory is investigating whether targeting ERR genetically and novel drugs could prevent diet-induced obesity or mimic the beneficial effects of exercise on whole body glucose control. 
 
T cells are the focus of
investigations by
Chih-Pin Liu, Ph.D.
Suppressing a patient’s immune imbalance
 
Chih-Pin Liu , Ph.D., is developing a new method to correct immune imbalance that may cause diabetes by taking a patient’s own regulatory T cells, which help to maintain balance in the immune system, and expanding them in the laboratory, then re-administering the cells to the diabetic patient. Liu’s promising research has already shown that Treg cells fortified in this way are as potent as normal Treg cells in suppressing the pathogenic immune imbalance that leads to a patient’s inability to produce insulin. 
 
 
From nature, a potential treatment for diabetes

The lab of  Wendong Huang , Ph.D., recently discovered that a chemical derivative of the barbary plant, berberine, may block diabetes by activating a receptor that increases the body’s sensitivity to insulin and helps maintain glucose balance. Berberine, which is approved by the Food and Drug Administration to treat other conditions, could be tested in humans for its potential effect on diabetes. Huang is also interested in small RNAs known as microRNAs (miRNAs), which have emerged as key regulators of genes related to metabolism and diabetes. He discovered a specific miRNA that, when overproduced in animal models, improves insulin sensitivity and prevents obesity-related metabolic complications. That miRNA is now a potential target for type 2 diabetes therapies.
 
 
Real-time imaging of islet cells after transplant
 
Fouad Kandeel , M.D., Ph.D., is also developing methods to directly monitor islet survival and function after transplantation into the liver using a radio-labeled protein developed at City of Hope that binds to human islet cells, an approach that has been successful in mouse models. Real-time imaging of the transplanted islet graft will provide critical information about cell health and dysfunction and help to ensure graft survival. It could also be used to monitor native islet cells in patients newly diagnosed with type 1 diabetes.  This leading-edge technology will allow physicians to assess the success of islet cell translation with more accuracy and timeliness than traditional assessment methods.
Defu Zeng, M.D., front, pictured with former post-doctoral student Dong-Chang Zhao, is investigating a non-toxic method of inducing mixed chimerism as part of a cure for type 1 diabetes. 
 
Developing a curative therapy for overt type 1 diabetes

Autoimmune type 1 diabetes is caused by autoimmune destruction of insulin-producing cells. Cure of overt type 1 diabetes requires the simultaneous stoppage of autoimmunity and regeneration of insulin-producing cells. At this time, the only therapy with the potential to do this is the combination of induction of mixed chimerism and administration of growth factors that has been recently developed by the laboratory of  Defu Zeng , M.D. Mixed chimerism is the co-existence of donor and recipient hematopoiesis and immune system that can cure autoimmunity. Once autoimmunity is stopped, injection of growth factors can augment the regeneration of insulin-producing cells and subsequently cure the disease. 
 
Mixed chimerism can be established by hematopoietic cell transplantation (HCT), but the classical HCT procedure requiring total body irradiation or high-dose chemotherapy has strong toxicity and the potential to cause graft versus host disease (GvHD).  Zeng’s lab has found that anti-CD3 monoclonal antibodies can replace total body irradiation or high dose chemotherapy for induction of mixed chimerism. This new procedure is non-toxic and avoids the side effect of GvHD. Now, in collaboration with  Arthur Riggs , Ph.D., the department chairman, Zeng’s lab is working on translating this novel therapy into clinical application by making antibodies that can be used in patients and by conducting experiments with large animal models.
 
 
Exploring the epigenetic and genetic underpinnings of obesity and diabetic complications

Rama Natarajan , Ph.D., is leading examinations into the role of epigenetics in diabetes and its complications, as well as genetic variations that make some people more susceptible to obesity and metabolic disease. Susceptibility to both obesity and diabetes depends on genetics and environmental factors (like high calorie and high fat diets) that affect our epigenes or epigenetics. Epigenetics refers to changes that are made to our genes and can be passed on to future generations — but are not written into our DNA. Dr. Natarajan’s laboratory is using state-of-the-art epigenome profiling to decipher epigenetic changes that promote inflammation and metabolic memory in diabetes, and also predispose to diabetic vascular and kidney disease in animal and human subjects. Because epigenetic changes are reversible, this research could lead to the development of epigenetic drugs to treat diabetes and its debilitating complications.

Furthermore, in collaboration with other researchers, Natarajan is using novel animal models to map specific genome regions that become active when the subjects consume a diet high in fat and sugar. The goal is to discover unique genes and develop therapies to turn them on or off to give a patient the same genetic protection that some members of the general population have against obesity, regardless of diet.

More projects

Read more about City of Hope projects on each researcher’s individual page.
 

The Connection Between Diabetes and Cancer

City of Hope is one of a few elite institutions in the United States with expertise in both diabetes and cancer research and treatment. Our leading-edge diabetes and cancer research programs benefit from, and build on, each other's discoveries.
 
A dual diagnosis
 
Researchers are finding that cancer and diabetes often occur together; as many as one in six cancer patients also has diabetes. The two diseases are diagnosed within the same patient more often than could be ascribed solely to chance.
 
In fact, people with type 2 diabetes are at an increased risk of various cancers. The risks appear to be greatest for cancers of the liver, pancreas and endometrium, and slightly less so for cancers of the colon, bladder and breast.  Some studies indicate that diabetes also may significantly increase mortality in cancer patients.  And some studies suggest that breast cancer survivors are more likely to develop diabetes than other women.
 
Researchers are trying to determine whether diabetes and pre-diabetic conditions might influence the cancer processes through hyperinsulinemia, hyperglycemia, chronic inflammation or other mechanisms; whether diabetes is a marker, and consequence, of biologic causative factors that affect the risk of cancer; or whether the diabetes-cancer link is based on common risk factors.
 

Shared risk factors
 
Type 2 diabetes and many cancers share numerous risk factors, including smoking, obesity, age, excessive alcohol consumption, poor diet and sedentary lifestyle.
 
Studies strongly indicate that being overweight and not getting sufficient physical activity are risk factors for cancers of the prostate, colon, kidney, breast, uterus and esophagus. Both of these factors are key risk indicators for not just developing diabetes, but also for a younger age of onset.
Strikingly, a growing body of evidence also indicates that waist circumference or waist-to-hip ratio are directly associated with increased risk of both type 2 diabetes and colon cancer.
 

Drugs and the two diseases
 
Some drugs used to treat cancer may worsen diabetes. Chemotherapy can adversely affect blood sugar levels. Glucocorticoids, which are often given to cancer patients to ease nausea, are believed to increase insulin resistance.
 
And certain types of anti-diabetic drugs can modify the risk of cancers. Researchers are investigating how treatment for diabetes should be modified for patients with increased cancer risk.
 
But there may be good cancer news about a drug commonly used to treat type 2 diabetes. Diabetic patients prescribed metformin have been shown to develop cancer less frequently that patients taking other drugs. It appears that the medicine inhibits cell growth and tumor formation as well as lower blood-glucose levels. Some studies show that the drug may aid in the treatment of breast cancer by killing cancer stem cells.

A protein linked to cancer, diabetes and obesity
 
One protein, RLIP76, has been linked to diabetes, cancer and obesity.

“It’s always present in every type of cancer, and it’s increased in multiple diseases, including diabetes and obesity," says City of Hope's  Sanjay Awasthi , M.D. "Cancer, diabetes and obesity are linked to about 80 percent of all adult mortalities."
 
Studies by Awasthi and colleagues have shown that cancer cells produce excessive amounts of RLIP76, which makes the cancerous cells resistant to radiation and chemotherapy. He's also found in animal studies that mice engineered without the protein "have a greater metabolism and they have lower blood sugars and lower triglycerides and cholesterol and they're very resistant to carcinogens." 
 
Now Awasthi is investigating a compound called 2-hydroxyflavanone, present in high quantities in orange rind, which appears to inhibit the protein.
 
"Not only does it inhibit RLIP76, but it reduces the amount of this protein in cells, particularly cancer cells," Awasthi says. "We think that taking this compound could prevent a variety of cancers and perhaps reduce obesity as well."
 
A molecular approach to treating cancer and diabetes
 
Wendong Huang , Ph.D., is another City of Hope researcher finding answers in both the cancer and diabetes fields.
 
He had discovered that chemical derivatives from the barberry plant kill melanoma cells. And more recently, he found that one of those analogs — berberine — may also block diabetes.
 
It activates a receptor that increases the body's sensitivity to insulin and helps to maintain glucose balance.
 
 
 
For more information on diabetes basic research at City of Hope, click on the CURRENT PROJECTS tab above.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

Diabetes and Metabolic Diseases Research

Department of Diabetes and Metabolic Diseases Research

The City of Hope has a long and impressive history of groundbreaking discoveries in the field of diabetes. It spans more than four decades of intense investigation since Rachmiel Levine, M.D., who discovered the role of insulin in glucose transport, launched diabetes research at City of Hope.
Arthur D. Riggs, Ph.D., chairs
the Department of Diabetes
and Metabolic Diseases Research.

The Department of Diabetes and Metabolic Diseases Research is now chaired by Arthur D. Riggs, Ph.D., another renowned researcher and pioneer in the field.

Riggs is recognized for his work on the synthesis of the first man-made gene and the use of synthetic genes for the production of human insulin. This first practical source of human insulin has largely replaced porcine- or bovine-derived insulin and has become the standard of care for diabetes worldwide.
 
Riggs continues to break ground in the battle against cancer, particularly in the area of epigenetics.
 
Read interviews with Riggs on the story behind synthetic human insulin and his thoughts on the future of diabetes research on City of Hope’s Breakthroughs blog.
 
 
 
 
Two divisions
 
The department headed by Riggs encompasses two divisions, which interface between diabetes research and translational medicine:
 
 
Goals

The Department of Diabetes and Metabolic Diseases Research includes as its primary goals:
 
  • Understanding the genetic and molecular signaling mechanisms that lead to diabetes and its complications
  • Advancing islet cell transplantation and related treatments for type 1 diabetes by developing better methods to prevent rejection and cure autoimmunity and by developing improved sources of islets or insulin-producing beta cells
  • Developing drugs that precisely target the receptor molecules responsible for diabetes
  • Studying the relationship between diabetes and cancer in order to better understand cancer etiology (and interplay at the metabolic level between these complex diseases). Specifically, developing systems biology data analysis framework to quantify and model diabetes and cancer molecular pathways
  • Designing interventions that address molecular targets common to both diabetes and cancer, through targeted, personalized pharmacotherapy.
 

Overview of Diabetes Basic Research

An Overview of Diabetes Basic Research

City of Hope has one of the most influential diabetes research programs in the world.  Our scientists’ work has revolutionized the understanding and treatment of the disease and continues today with exciting developments in cell transplantation, gene regulation, immune tolerance, and gaining systemic understanding of diabetes as a complex, multifaceted disease.

Within Diabetes Research is the Department of Diabetes and Metabolic Diseases Research. Scientists in that department work in two divisions:
 
 
Landmark contributions

City of Hope’s leadership in diabetes began decades ago when the “father of endocrinology,” Rachmiel Levine, M.D., launched diabetes research at City of Hope. Levine had, in the 1940s, identified the principal cause of the illness: a reduction in our body’s ability to stimulate glucose entry in the cells, directly linked to the insulin production. 
City of Hope researchers, such as Rama Natarajan, Ph.D., are making landmark contributions to the fight against diabetes.
Today, City of Hope researchers continue to make landmark contributions to the fight against diabetes. Recognized nationwide for our innovative biomedical research, we are home to some of the most creative minds in science. Our strength lies in collaboration – leveraging the talents of investigators across departments and across the institution and rapidly translating scientific discoveries into new treatments. By working together and sharing results, researchers and clinicians are able to put theories into practice. As a result, excellence in one area fuels advancements in all areas.
 
City of Hope’s mission in diabetes research is to improve the quality of life for patients, prevent complications from the disease, and ultimately, establish a cure. At City of Hope, we’ve achieved many milestones in the field and are now pursuing the next generation of diabetes treatments in our efforts to end the devastation of the disease and usher in a new era of healing and hope.
 
Diabetes basic research is housed in the Leslie & Susan Gonda (Goldschmied) Diabetes & Genetic Research Center, which was recently expanded to provide urgently needed laboratory space. City of Hope researchers are using this lab space in their race to find ways to understand, control and cure diabetes, which continues to grow as a major public health threat.

An epidemic reaching pandemic proportions
 
Diabetes is rapidly progressing from epidemic to pandemic. The Centers for Disease Control and Prevention predicts that by the year 2050, if current epidemiological trends continue, one in every three people in the U.S. could suffer from diabetes at some point in their life. Diabetes is a global issue as well, as one of the world’s leading causes of death, disability and lost economic growth. Worldwide, health expenditures to treat and prevent the disease and its complications continue to grow, with $465 billion spent in 2011 alone.
 
To learn more about diabetes, go to the About Diabetes page.

Scientists in basic research provide the foundation for new therapies and approaches to battling diabetes. Our work touches on all aspects of the disease, including heart and kidney complications. Read more about our current projects and the work of each division by clicking on the tabs above.
 
Our clinical program and translational research
 
At City of Hope, our experience in the area of diabetes, including established analytic, molecular and clinical resources, have enabled us to rapidly translate emerging scientific concepts into new treatments. Our mission is to ensure that breakthroughs from the basic research of scientists in the Department of Diabetes and Metabolic Diseases Research are then rapidly translated into clinical settings where they can impact patients. The Department of Clinical Diabetes, Endocrinology & Metabolism is currently conducting a number of important clinical research programs to help put our basic and clinical biomedical research into practice.
 
To search for a trial, go to our clinical trials page.
               
 

Division of Translational Research

Division of Developmental and Translational Diabetes and Endocrine Research


The Division of Developmental and Translational Diabetes and Endocrine Research, directed by Fouad Kandeel, M.D., Ph.D., has translated landmark scientific discoveries into treatments that have improved the lives of diabetic patients around the world.  The expansion of the Leslie & Susan Gonda (Goldschmied) Diabetes & Genetic Research Center has enabled us to bolster our efforts in the fight against diabetes simultaneously on multiple fronts:  from developmental research starting in our state-of-the-art laboratories to clinical investigations leading to innovative patient care. 
Fouad Kandeel, M.D., Ph.D., directs
the Division of Developmental and
Translational Diabetes and
Endocrine Research.

Our approach
 
Our goal is to bring the latest scientific findings into medical practice as quickly as possible. Researchers in our division conduct  laboratory, translational and clinical research with the goal of improving our understanding of the disease process and guiding the development of new diagnostic, prognostic, and therapeutic interventions.
 
Here, we focus on stem cell biology and development, translational immunology, islet isolation and distribution, islet quality assessment, islet imaging, islet encapsulation and isolation, and new drug discoveries.
 
We are also developing a mobile device that combines a live glucose monitor with an automatic insulin delivery pump system. This “artificial pancreas” will free patients from periodic self-monitoring, as well as allow more accurate control of blood glucose levels. City of Hope researchers are working with the device manufacturer to optimize performance, and preparations are being made to test the device in newly transplanted islet recipients in order to provide maximum protection of islets from the harmful effects of high blood sugar.

Imaging islet cells within the body is greatly needed to elucidate the mechanisms underlying type 1 diabetes development and monitor islet cells following transplant. New cell-imaging approaches developed at City of Hope have been used to track islet cell survival and function in animal models and have been successfully applied in a human case of pancreatic tumor.
 
 
 
 
City of Hope Islet Cell Transplant Program
City of Hope is studying the
safety and effectiveness of
transplanting islet cells
as a treatment for
type 1 diabetes.
 
City of Hope is conducting clinical trials to study the safety and effectiveness of  islet transplantation as a treatment for type 1 diabetes. City of Hope performed its first islet transplantation in 2004 and performed dozens more in the Islet Transplantation Alone and Islet After Kidney Transplantation trials. The current T cell-depleting trial will help answer the question of whether temporarily reducing or eliminating the recipient’s T cells at the time of islet transplantation will improve short- and long-term transplant results in patients with type 1 diabetes. The study also includes an assessment for changes in the quality of life after islet transplantation.
 
To qualify for the study, candidates must have type 1 diabetes, be between the ages of 18 and 68, and have the ability and willingness to comply with a post-transplant regimen that includes taking immunosuppression medications, frequent clinic visits and laboratory testing, using reliable contraception, maintaining detailed records of blood glucose levels, insulin doses, medications and completing detailed follow-up studies for up to five years.
 
Candidates who have received a prior kidney transplant for diabetic kidney failure may also participate in the study, if they have a stable kidney transplant for at least three months on specific commonly used anti-rejection medications. 

For clinical transplant matters you may contact us by calling (866) 44 ISLET (47538) or email us at islets@coh.org.
 
Global diabetes health initiative

There is a global need for a cost-effective solution to simplify diabetes management and minimize time spent on expensive and unstructured treatment plans. This solution must simultaneously improve patient participation in behavior modification and medication regimes. 
 
The center's physicians and scientists, led by Fouad Kandeel, M.D., are collaborating with diabetes scientists and clinicians in Europe to develop a fully automated patient-management system that can be utilized on a global scale. 
 
The ADAMS (Adaptive Diabetes Algorithm Managements System) platform is software that is designed to generate an automated, interventional treatment plan tailored to each patient.  It takes into account culturally relevant dietary and behavioral issues and has the potential to streamline the efficiency of diabetes care around the world.
 
 
 
Each year, City of Hope hosts an annual diabetes and obesity symposium in memory of the late Dr. Rachmiel Levine, the scientist responsible for clarifying the nature of insulin action.
 
The 15th Annual Rachmiel Levine Symposium will cover recent scientific advances in diabetes and will highlight results of recent diabetes clinical trials.  It will also include poster sessions where promising trainees can present their work, and debate sessions with world leaders in areas of controversy in diabetes research and clinical care.
 
City of Hope researchers including  Rama Natarajan, Ph.D., director of the Division of Molecular Diabetes Research, have been selected to speak at the symposium.
 
The event is scheduled for March 1 to 4, 2015 in San Diego, California.
 
 
Team members

Researchers and clinicians at City of Hope are engaged in ongoing communication and interaction to bring work from the lab to the bedside. Meet the researchers in the Division of Developmental & Translational Diabetes and Endocrine Research:
 
Fouad Kandeel , M.D., Ph.D. -  division director and professor
Islet cell transplantation

Ismail Al-Abdullah , Ph.D. - research professor
Islet cell isolation

Sanjay Awasthi , M.D. - professor
Diabetes and cancer

Kevin Ferreri , Ph.D. - associate research professor
Islet cell transplantation, epigenetics, and diabetic biomarkers

H. Teresa Ku , Ph.D. - associate professor
Stem cell therapy for type 1 diabetes; in vitro differentiation of human and mouse embryonic stem cells towards pancreatic lineage cells; identification, purification and characterization of embryonic and adult pancreatic stem/progenitor cells

Yoko Mullen , M.D., Ph.D. - research professor
Extrahepatic islet transplantation; prevention of islet loss for transplantation
 
 

Division of Molecular Diabetes Research

Division of Molecular Diabetes Research

The Division of Molecular Diabetes Research, directed by Rama Natarajan, Ph.D., is at the forefront of research on the complications of diabetes and was the first to study epigenetic changes in diabetic complications.
Rama Natarajan, Ph.D., directs the Division
of Molecular Diabetes Research.

Research leading to new therapies

Basic science research in molecular biology, biochemistry and immunology provides the foundation that drives the development of new therapies for diabetes and related complications. City of Hope scientists in this division are performing cutting-edge research in these areas.

Battling the complications of diabetes

Diabetes is the leading cause of kidney failure and a significant risk factor for the development of vascular complications like atherosclerosis. Our researchers are working to determine molecular mechanisms and factors mediating these complications and to develop strategies to prevent and reverse these complications. The researchers' study of atherosclerosis and kidney disease includes both diabetic animal models and humans.

Scientists in this division are examining the molecular links between diabetes, obesity, metabolism, cancer and aging, including the role of various nuclear receptors.

Gene and cell-based therapies

Translational approaches using small molecules are also being investigated. Researchers are using potential gene therapy and RNA interference translational approaches to inhibit key genes associated with diabetic complications. They are also developing synthetic small molecules to target genes that promote obesity and related metabolic changes.

Our researchers have identified a molecular link between physical activity and insulin sensitivity. They are using animal models to characterize key mechanisms in exercise's effects on skeletal muscle's energy metabolism and growth.

In addition, our researchers are performing important studies to develop novel methods to induce immune tolerance for the treatment of type 1 diabetes and also identify new cellular targets that can lead to cell-based therapies for diabetes. The results of these studies with immune cells can lead to more effective approaches in the treatment diabetes and to improved success of islet-cell transplantation.
 
Our approach

Overall, this division within the Department of Diabetes and Metabolic Research uses several state-of-the-art computational and systems biology data-analysis methods; genomic and epigenomic profiling approaches; novel transgenic mouse models; and translational approaches with small molecules, antibody and cell-based therapies in animal models and humans in its quest to advance the field of diabetes research.

The division's investigators also work closely with the clinical researchers in the Department of Clinical Diabetes, Endocrinology and Metabolism as well as other multidisciplinary teams throughout City of Hope.
 
 
Each year the City of Hope hosts a meeting involving a consortium of laboratories in the Southern California region with a shared interest in related fields of gene regulation and nuclear receptor function and mechanism.  Topics span an array of biological area, including development, metabolism, diabetes, and cancer.
 
The MoLAR meeting provides a venue for investigators and scientists, post-doctoral fellows and graduate trainees to present progress on current research projects in their laboratories.  The agenda includes an invited keynote speaker with the rest of the meeting left for participating laboratories to feature their work in short talks (15-25 minutes in length).  The gathering aims to provide a local, small and collegial environment to discuss projects, interact and foster collaborations between laboratories.

Team members
 
Rama Natarajan , Ph.D., F.A.H.A., F.A.S.N. - division director and professor
Identification of the molecular mechanisms underlying the accelerated cardiovascular and renal disease observed in diabetic patients and in obese subjects; role of epigenetics, microRNAs and other non-coding  RNAs; and inflammatory responses in islet destruction
 
Wendong Huang , Ph.D. - associate professor
Genetic and epigenetic regulation of diabetes; stem cell and drug development for diabetes
 
Janice Huss , Ph.D. – associate professor
Characterization of transcriptional mechanisms regulating skeletal muscle metabolic adaptations during growth and differentiation and in response to physiologic stress; the etiologic role of orphan nuclear receptors in obesity and type 2 diabetes
 
Chih-Pin Liu , Ph.D. – professor
Development of methods to induce immune tolerance; identification of novel cellular and molecular targets to improve cell-based therapy for diabetes
 
Defu Zeng , M.D. - professor
Induction of mixed chimerism for reversal of autoimmunity, beta cell regeneration, and transplantation immune tolerance
 

Accomplishments

Accomplishments in Diabetes Research

City of Hope researchers have built the foundation of scientific knowledge upon which the understanding and treatment of diabetes are based.
 
Engineering synthetic insulin

In the late 1970s,  Arthur Riggs , Ph.D., and Keiichi Itakura, Ph.D., produced synthetic human insulin using bacteria. It became the first genetically engineered product approved by the Food and Drug Administration and today is used worldwide by millions of people with diabetes. The breakthrough made insulin more available and affordable and helped launch the biotechnology industry.
City of Hope researchers have made numerous breakthoughs, including in islet-cell transplantation and in the understanding of islet dysfunction.
 
Perfecting islet transplantation protocols

Fouad Kandeel , M.D., Ph.D., perfected clinical islet-cell transplantation protocols and has developed imaging methods that enable physicians to more monitor in real time the health of islets after transplantation.
 
Targeting diabetic complications

Rama Natarajan , Ph.D., and Jerry Nadler, M.D., conducted research dealing with diabetic complications and islet dysfunction. Their work has led to the identification of novel therapeutic targets and agents for the treatment of diabetic complications. Natarajan was also the first to demonstrate the role of epigenetics in diabetic vascular inflammation and in the metabolic memory phenomenon.

Her laboratory was also the first to demonstrate how microRNAs (small, non-coding RNAs) can cause the overproduction of collagen, which creates damage that can lead to kidney abnormalities and renal dysfunction. She used therapeutic interventions to block these microRNAs, slowing the cells’ harmful overproduction of collagen and other proteins and kidney damage.
 
 
Diagnosing type 1 diabetes sooner

Kevin Ferreri , Ph.D., has developed a new method of diagnosing type 1 diabetes. His research team detected unique markings on the DNA of insulin-producing cells. When these cells die during the progression of type 1 diabetes, the markings can be detected on DNA that circulates in the blood. This method can be used to diagnose type 1 diabetes before complications and can be used to test the effectiveness of new treatments.

To read about more of City of Hope researchers’ accomplishments, including the 1940s discovery by Rachmiel Levine, M.D., of insulin’s role in processing sugars, read our Diabetes Program History page. 
 

Current Projects

Current Projects in the Department of Diabetes and Metabolic Diseases Research

 
Using computer science-based approaches to create individualized treatment plans
 
City of Hope researchers are developing a high-tech analytic tool that promises to revolutionize the way diabetes is treated. The treatment platform uses the combination of both data-driven and expert-based algorithms to generate validated individualized treatment plans. Advanced Diabetes Algorithm Management System, or ADAMS, starts by gathering information on the patient’s health, treatment preferences and other epidemiological and cultural factors. The data is processed using the model-fitting software that gives the physicians not only a basic “overview” of how a patient’s body is metabolizing glucose, but also the results of in silico simulations showing a specific intervention’s likely impact on a patient’s metabolic footprint. Thus, the patient is armed with a comprehensive treatment plan and continued feedback on diet, exercise and medication.
 
Fouad R. Kandeel , M.D., Ph.D., director of the Division of Developmental & Translational Diabetes and Endocrine Research, who is leading this project, believes the program can vastly improve long-time clinical outcomes for large populations of diabetic patients across the globe. Kandeel is directly collaborating with  Andrei Rodin , Ph.D., a leader in the field of developing systems biology data analysis methodology, who is working on adapting his secondary data analysis tools to clinical data.
 

Identifying mechanisms and drug targets for diabetic complications

Diabetes is the leading cause of kidney failure and a significant risk factor for the development of vascular complications like atherosclerosis.  Rama Natarajan , Ph.D., director of the Division of Molecular Diabetes Research, is studying mechanisms of atherosclerosis and kidney disease in diabetes. She is using cell, animal and human models to demonstrate how diabetes leads to increased inflammation in blood and kidney cells and is devising approaches to interfere with the production of these inflammatory molecules to slow down diabetic vascular complications

Her team has also studied a gene-control mechanism called RNA silencing, which may play a key role in diabetic kidney disease. In it, cells employ pieces of genetic material called microRNA, or miRNA, to turn genes off. The researchers have identified a key miRNA that creates an overproduction of collagen, which causes damage that can lead to kidney disease and renal dysfunction.  By controlling key miRNAs in the kidney, the researchers seek to slow down the cells’ overproduction of collagen and similar proteins and potentially control diabetic kidney disease. They are also similarly examining miRNAs and related molecules that promote inflammation in blood cells and blood vessels under diabetic conditions and approaches to interfere with their actions to control cardiovascular complications of diabetes.
City of Hope researchers are investigating
new ways to generate insulin-producing
cells from stem cells.

Generating insulin-producing cells from stem cells

One of the major roadblocks to translating stem cell research from the lab to the clinic is the low yield of insulin-producing cells from stem cells.  Arthur Riggs , Ph.D., the department chair, is collaborating with   Hsun Teresa Ku , Ph.D., on ways to generate insulin-producing cells from stem cells.
 
The team is creating new technologies to accomplish this, including synthetic extracellular matrices, structures found in the connective tissues of animals, and genetically reprogram them to adopt a new identity and function.
 
 
 
 Targeting a key to metabolic syndrome
 
Sanjay Awasthi , M.D., is studying the role of glutathione metabolism in the development of cancer and type 2 diabetes. He silenced the gene that expresses the protein RLIP76, increasing resistance to the development of chemically induced cancers in animal models. Furthermore, the models showed reduced blood sugar, cholesterol and triglycerides despite a high-fat diet. These findings are expected to lead to the development of novel drugs that targets RLIP76 in order to treat obesity, metabolic syndrome and cancer.
 
 
Creating a drug to mimic the benefits of exercise

In order to develop treatments that slow or prevent the development of type 2 diabetes, researchers must understand the ways in which various insulin responsive tissues respond to fluctuations in diet and energy demand. The laboratory of  Janice Huss , Ph.D., investigates mechanisms governing mitochondrial energy metabolism and growth of skeletal muscle in healthy and diseased states. The capacity of skeletal muscle to regulate whole body energy balance, glucose and lipid utilization and to prevent the development of obesity and insulin resistance is determined by its oxidative capacity and it overall mass.  Her group has discovered that the Estrogen-related Receptors (ERRs) control interrelated programs of muscle energy metabolism and growth.  ERRs control levels of proteins needed for energy metabolism and muscle contraction. These factors are essential for directing metabolic enhancements caused by endurance exercise. Her laboratory is investigating whether targeting ERR genetically and novel drugs could prevent diet-induced obesity or mimic the beneficial effects of exercise on whole body glucose control. 
 
T cells are the focus of
investigations by
Chih-Pin Liu, Ph.D.
Suppressing a patient’s immune imbalance
 
Chih-Pin Liu , Ph.D., is developing a new method to correct immune imbalance that may cause diabetes by taking a patient’s own regulatory T cells, which help to maintain balance in the immune system, and expanding them in the laboratory, then re-administering the cells to the diabetic patient. Liu’s promising research has already shown that Treg cells fortified in this way are as potent as normal Treg cells in suppressing the pathogenic immune imbalance that leads to a patient’s inability to produce insulin. 
 
 
From nature, a potential treatment for diabetes

The lab of  Wendong Huang , Ph.D., recently discovered that a chemical derivative of the barbary plant, berberine, may block diabetes by activating a receptor that increases the body’s sensitivity to insulin and helps maintain glucose balance. Berberine, which is approved by the Food and Drug Administration to treat other conditions, could be tested in humans for its potential effect on diabetes. Huang is also interested in small RNAs known as microRNAs (miRNAs), which have emerged as key regulators of genes related to metabolism and diabetes. He discovered a specific miRNA that, when overproduced in animal models, improves insulin sensitivity and prevents obesity-related metabolic complications. That miRNA is now a potential target for type 2 diabetes therapies.
 
 
Real-time imaging of islet cells after transplant
 
Fouad Kandeel , M.D., Ph.D., is also developing methods to directly monitor islet survival and function after transplantation into the liver using a radio-labeled protein developed at City of Hope that binds to human islet cells, an approach that has been successful in mouse models. Real-time imaging of the transplanted islet graft will provide critical information about cell health and dysfunction and help to ensure graft survival. It could also be used to monitor native islet cells in patients newly diagnosed with type 1 diabetes.  This leading-edge technology will allow physicians to assess the success of islet cell translation with more accuracy and timeliness than traditional assessment methods.
Defu Zeng, M.D., front, pictured with former post-doctoral student Dong-Chang Zhao, is investigating a non-toxic method of inducing mixed chimerism as part of a cure for type 1 diabetes. 
 
Developing a curative therapy for overt type 1 diabetes

Autoimmune type 1 diabetes is caused by autoimmune destruction of insulin-producing cells. Cure of overt type 1 diabetes requires the simultaneous stoppage of autoimmunity and regeneration of insulin-producing cells. At this time, the only therapy with the potential to do this is the combination of induction of mixed chimerism and administration of growth factors that has been recently developed by the laboratory of  Defu Zeng , M.D. Mixed chimerism is the co-existence of donor and recipient hematopoiesis and immune system that can cure autoimmunity. Once autoimmunity is stopped, injection of growth factors can augment the regeneration of insulin-producing cells and subsequently cure the disease. 
 
Mixed chimerism can be established by hematopoietic cell transplantation (HCT), but the classical HCT procedure requiring total body irradiation or high-dose chemotherapy has strong toxicity and the potential to cause graft versus host disease (GvHD).  Zeng’s lab has found that anti-CD3 monoclonal antibodies can replace total body irradiation or high dose chemotherapy for induction of mixed chimerism. This new procedure is non-toxic and avoids the side effect of GvHD. Now, in collaboration with  Arthur Riggs , Ph.D., the department chairman, Zeng’s lab is working on translating this novel therapy into clinical application by making antibodies that can be used in patients and by conducting experiments with large animal models.
 
 
Exploring the epigenetic and genetic underpinnings of obesity and diabetic complications

Rama Natarajan , Ph.D., is leading examinations into the role of epigenetics in diabetes and its complications, as well as genetic variations that make some people more susceptible to obesity and metabolic disease. Susceptibility to both obesity and diabetes depends on genetics and environmental factors (like high calorie and high fat diets) that affect our epigenes or epigenetics. Epigenetics refers to changes that are made to our genes and can be passed on to future generations — but are not written into our DNA. Dr. Natarajan’s laboratory is using state-of-the-art epigenome profiling to decipher epigenetic changes that promote inflammation and metabolic memory in diabetes, and also predispose to diabetic vascular and kidney disease in animal and human subjects. Because epigenetic changes are reversible, this research could lead to the development of epigenetic drugs to treat diabetes and its debilitating complications.

Furthermore, in collaboration with other researchers, Natarajan is using novel animal models to map specific genome regions that become active when the subjects consume a diet high in fat and sugar. The goal is to discover unique genes and develop therapies to turn them on or off to give a patient the same genetic protection that some members of the general population have against obesity, regardless of diet.

More projects

Read more about City of Hope projects on each researcher’s individual page.
 

Cancer Connection

The Connection Between Diabetes and Cancer

City of Hope is one of a few elite institutions in the United States with expertise in both diabetes and cancer research and treatment. Our leading-edge diabetes and cancer research programs benefit from, and build on, each other's discoveries.
 
A dual diagnosis
 
Researchers are finding that cancer and diabetes often occur together; as many as one in six cancer patients also has diabetes. The two diseases are diagnosed within the same patient more often than could be ascribed solely to chance.
 
In fact, people with type 2 diabetes are at an increased risk of various cancers. The risks appear to be greatest for cancers of the liver, pancreas and endometrium, and slightly less so for cancers of the colon, bladder and breast.  Some studies indicate that diabetes also may significantly increase mortality in cancer patients.  And some studies suggest that breast cancer survivors are more likely to develop diabetes than other women.
 
Researchers are trying to determine whether diabetes and pre-diabetic conditions might influence the cancer processes through hyperinsulinemia, hyperglycemia, chronic inflammation or other mechanisms; whether diabetes is a marker, and consequence, of biologic causative factors that affect the risk of cancer; or whether the diabetes-cancer link is based on common risk factors.
 

Shared risk factors
 
Type 2 diabetes and many cancers share numerous risk factors, including smoking, obesity, age, excessive alcohol consumption, poor diet and sedentary lifestyle.
 
Studies strongly indicate that being overweight and not getting sufficient physical activity are risk factors for cancers of the prostate, colon, kidney, breast, uterus and esophagus. Both of these factors are key risk indicators for not just developing diabetes, but also for a younger age of onset.
Strikingly, a growing body of evidence also indicates that waist circumference or waist-to-hip ratio are directly associated with increased risk of both type 2 diabetes and colon cancer.
 

Drugs and the two diseases
 
Some drugs used to treat cancer may worsen diabetes. Chemotherapy can adversely affect blood sugar levels. Glucocorticoids, which are often given to cancer patients to ease nausea, are believed to increase insulin resistance.
 
And certain types of anti-diabetic drugs can modify the risk of cancers. Researchers are investigating how treatment for diabetes should be modified for patients with increased cancer risk.
 
But there may be good cancer news about a drug commonly used to treat type 2 diabetes. Diabetic patients prescribed metformin have been shown to develop cancer less frequently that patients taking other drugs. It appears that the medicine inhibits cell growth and tumor formation as well as lower blood-glucose levels. Some studies show that the drug may aid in the treatment of breast cancer by killing cancer stem cells.

A protein linked to cancer, diabetes and obesity
 
One protein, RLIP76, has been linked to diabetes, cancer and obesity.

“It’s always present in every type of cancer, and it’s increased in multiple diseases, including diabetes and obesity," says City of Hope's  Sanjay Awasthi , M.D. "Cancer, diabetes and obesity are linked to about 80 percent of all adult mortalities."
 
Studies by Awasthi and colleagues have shown that cancer cells produce excessive amounts of RLIP76, which makes the cancerous cells resistant to radiation and chemotherapy. He's also found in animal studies that mice engineered without the protein "have a greater metabolism and they have lower blood sugars and lower triglycerides and cholesterol and they're very resistant to carcinogens." 
 
Now Awasthi is investigating a compound called 2-hydroxyflavanone, present in high quantities in orange rind, which appears to inhibit the protein.
 
"Not only does it inhibit RLIP76, but it reduces the amount of this protein in cells, particularly cancer cells," Awasthi says. "We think that taking this compound could prevent a variety of cancers and perhaps reduce obesity as well."
 
A molecular approach to treating cancer and diabetes
 
Wendong Huang , Ph.D., is another City of Hope researcher finding answers in both the cancer and diabetes fields.
 
He had discovered that chemical derivatives from the barberry plant kill melanoma cells. And more recently, he found that one of those analogs — berberine — may also block diabetes.
 
It activates a receptor that increases the body's sensitivity to insulin and helps to maintain glucose balance.
 
 
 
For more information on diabetes basic research at City of Hope, click on the CURRENT PROJECTS tab above.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Overview
Beckman Research Institute of City of Hope is responsible for fundamentally expanding the world’s understanding of how biology affects diseases such as cancer, HIV/AIDS and diabetes.
 
 
Research Departments/Divisions

City of Hope is a leader in translational research - integrating basic science, clinical research and patient care.
 

Research Shared Services

City of Hope embodies the spirit of scientific collaboration by sharing services and core facilities with colleagues here and around the world.
 

Our Scientists

Our research laboratories are led by the best and brightest minds in scientific research.
 

City of Hope’s Irell & Manella Graduate School of Biological Sciences equips students with the skills and strategies to transform the future of modern medicine.
Develop new therapies, diagnostics and preventions in the fight against cancer and other life-threatening diseases.
 
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