Diabetes research: From epigenetics to metabolic disease
Improved diabetes treatments and new cures for millions of people across the globe – that’s the singular focus of the Diabetes Research Center at City of Hope. One of the most influential diabetes research programs in the world, the center fosters diverse and collaborative research across a wide range of disciplines. Here are some of the recent developments:
Leading the way
Arthur Riggs, Ph.D., director emeritus of Beckman Research Institute of City of Hope and the chair of the Department of Diabetes and Metabolic Diseases Research, was a pioneer in diabetes and cancer research. He still is.
Riggs was the first to use organic chemistry and recombinant DNA technology to produce human insulin. He then went on to help found the modern field of epigenetics, which has revolutionized our understanding of the molecular nature of normal development and disease.
Epigenetics refers to stable changes in the way our genes function, some of which can be passed on to future generations — but are not written into our genetic code. Mistakes in the epigenetic program are not mutations and thus have the potential to be corrected through medical intervention.
Currently, Riggs' lab is focusing on epigenetic changes in diabetes, with much work devoted to developing new methods for epigenetic intervention, for example, to improve the production of mature insulin producing cells for the treatment of type 1 diabetes. He is also studying new methods to “reawaken” epigenetically-silenced genes, a project that could ultimately lead to new treatments for both diabetes and cancer.
Discovering novel molecular approaches to diabetes treatment
One of the scientists in the Diabetes Research Center is turning to nature to find answers to cancer as well as diabetes.
In October’s issue of Molecular Oncology, Wendong Huang, Ph.D., associate professor in the Division of Gene Regulation and Drug Discovery, and other City of Hope colleagues reported that chemical derivatives from the barbary plant kill melanoma cells. Huang recently found that one of those chemical derivatives called berberine may also block diabetes by activating a receptor that increases the body’s sensitivity to insulin and helps maintain glucose balance.
Berberine already has Food and Drug Administration-approval as a treatment for other conditions. Thus, it could be rapidly 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 a mouse model, improves insulin sensitivity and prevents obesity-related metabolic complications. That miRNA is now a potential target for type 2 diabetes therapies.
Developing novel diagnostics
As the toll of diabetes continues to rise, more people are developing the illness, and an alarming number of people in the United States have diabetes and are unaware that they have it.
Researchers at City of Hope are looking for more accurate methods to detect and predict diabetes and its complications. John Termini, Ph.D., professor of molecular medicine, is asking whether glycated forms of DNA, known as DNA-AGEs (for advanced glycation endproducts), could serve as next-generation disease indicators.
Glycation occurs when sugar molecules in the body bond to other molecules; this process is implicated in diabetes as well as many age-related disorders. Termini discovered that one DNA-AGE, called CEdG, is excreted in urine and therefore readily detectable. He is collaborating with City of Hope clinicians to determine whether CEdG levels can predict diabetic complications.
Kevin Ferreri, Ph.D., an associate research professor in the Division of Diabetes, Endocrinology & Metabolism, is studying a different DNA-based marker to detect diabetes. He found that in type 1 diabetes patients, dying islet cells release into the blood DNA that has been chemically modified by a process known as methylation. He has now shown that those modifications are detectable in circulation before blood sugar levels increase, potentially providing a very early diagnostic tool.
Testing this hypothesis, he is currently using the DNA-based assays to monitor islet health in transplantation patients and in patients with early stage type 1 diabetes.
Minimizing diabetes complications
Diabetes causes many serious health problems, such as kidney damage, nerve damage and cardiovascular disease. In hope of identifying new therapies, Rama Natarajan, Ph.D., National Office Products Industry Professor in Diabetes Research and the director of the Division of Molecular Diabetes Research, is studying the body’s inflammatory response, which is believed to play a significant role in the development of kidney and vascular complications.
One line of inquiry focuses on TGF-beta, a protein that controls growth, differentiation and other functions in cells. Natarajan was the first to show that TGF-beta activates specific miRNAs that promote diabetic kidney damage.
Last year, she reported in the Journal of the American Society for Nephrology that, when mice exhibiting diabetic kidney damage were administered a drug that neutralizes one such miRNA, they showed fewer symptoms and their TGF-beta levels were lower. This research suggests that similar approaches can be applied to possibly treat or prevent the development of kidney complications in humans.
In the May issue of the Journal of Biological Chemistry, Natarajan also reported for the first time that epigenetic changes occur at specific genetic locations on a chromosome that are active in type 1 diabetes. That work, which was a collaborative effort with the Biomedical Informatics Core headed by Yate-Ching Yuan, Ph.D., suggests that drugs which control those kinds of genomic changes might be used to treat people predisposed to type 1 diabetes — potentially providing an important new and highly focused means to prevent the disease from developing.
Genome-wide studies identify a new player
Natarajan is collaborating with Dustin Schones, Ph.D., assistant professor in the Department of Cancer Biology, and with Aldons Lusis, Ph.D., a professor at University of California, Los Angeles, to examine genetic variations that make some people more susceptible to obesity and metabolic disease.
Using a novel genomic resource known as the Hybrid Mouse Diversity Panel, they are mapping specific chromosomal regions that become active when mice consume a high fat/sugar diet. Specifically, Natarajan and Schones, along with post-doctoral fellow Amy Leung, are working to identify genes that either promote or protect against diet-induced obesity. They also want to determine how changes in these genes are affected by a patient’s genetic background.
If they can discover unique gene candidates, it could be possible to use small-interfering RNA, or siRNA, technology to turn those specific genes on or off and give a patient the same genetic protection that some members of the general population have against obesity, regardless of a high fat/sugar diet.
Natarajan, Schones and Leung are also collaborating to better understand and discover new treatment approaches for cardiovascular disease.
They are analyzing gene expression over the entire genome in vascular smooth muscle cells, which surround blood vessels and directly regulate blood pressure. Their aim is to pinpoint genes that become active in response to a hormone, known as angiotensin II, which is overproduced in cardiovascular disease — and to use those genes to control the harmful effects of angiotensin II in vascular smooth muscle cells, thereby stemming or even reversing the harmful cardiovascular complications of diabetes.
Age and type 2 diabetes
Ivan Todorov, Ph.D., is investigating age-related changes in the pancreas and how these changes contribute to the development of type 2 diabetes.
By studying pancreas tissue from patients of different ages, he has identified several markers that increase significantly in older patients compared to patients under the age of 30 years. Todorov is continuing this study to understand how these markers are connected to the development of type 2 diabetes as patients age.
He has submitted this research for publication.
Inﬂammation: The missing link between diabetes and cancer?
It has long been established that obesity is a major cause of type 2 diabetes, due in part to specific cells in fat tissue that promote pathogenic T cells and blunt the activity of insulin.
Hua Yu, Ph.D., co-director of the Cancer Immunotherapeutics Program, is a pioneer in research involving a gene called STAT3 and the role it plays in the dysregulation of the immune system. Yu has also been exploring the connection between STAT3 and the development of diabetes.
In efforts to learn more about this potential link, her lab has used genetically-engineered mice whose T cells lack the STAT3 gene. When these mice became obese through forced consumption of a fatty diet, they showed improved glucose tolerance compared with comparably overfed normal mice, as well as a shift in the balance of pathogenic T cells toward regulatory T cells.
These intriguing findings suggest that STAT3 is common to both cancer and diabetes and suggest that anti-STAT3 therapies, which have thus far been considered primarily for cancer, might also be effective against type 2 and perhaps type 1 diabetes.
Fat metabolism also interests Robert Whitson, Ph.D., associate research scientist in the Department of Molecular and Cellular Biology. He previously found that mice genetically engineered to lack a protein called ARID5B remained lean, even when fed a high-fat diet. Last year, he discovered that ARID5B likely activates genes essential for fat tissue development. The goal is now to design drugs targeting ARID5B to counteract devastating metabolic consequences of obesity, which is linked to both cancer and diabetes.
Research by Zuoming Sun, Ph.D., associate professor in the Department of Immunology, also suggests important molecular links between STAT3, diabetes and cancer. He previously showed that a signaling protein called PKC-q increases production of pro-inflammatory Th17 cells — when they are produced in excess these pro-inflammatory cells promote the development of diabetes.
In a June study published in the Journal of Immunology, Sun reported a novel connection between the PKC-q protein and STAT3: These proteins work together to cause the proliferation of the harmful pro-inflammatory cells. This connection is of intense interest due to the dual role of Th17 cells: Too few allow infection, while too many likely create an inflammatory environment encouraging autoimmunity and cancer.
Connecting the dots between diabetes and cancer
Sanjay Awasthi, M.D., professor of diabetes, is conducting research that elucidates a possible target to treat metabolic syndrome.
This condition is characterized by hypertension, obesity and insulin resistance. He recently published a study in which mice with the gene RALBP1, which encodes the RLIP76 protein, was genetically deleted, and found that the mice experienced very low blood sugar, cholesterol and triglycerides.
Awasthi conducted further studies in the same genetically altered mice, testing the effect of several drugs, including the anti-diabetic drug metformin, on blood sugar and lipid levels. These drugs had no effect, suggesting that the RALBP1 gene plays a crucial role in the development of metabolic syndrome, and that common drugs to treat metabolic syndrome may work through the RLIP76 protein. This finding could lead to a novel drug that targets RLIP76 to treat metabolic syndrome.
In other studies aimed at stopping and reversing metabolic syndrome, the Rahbar laboratory is investigating a drug called COH-SR4. The drug slows fat cell development by activating an enzyme called AMPK at low concentrations.
In the August issue of Biochemical Pharmacology, Rahbar and Awasthi reported that COH-SR4 blocked the growth of cultured melanoma cells. Currently, the Rahbar laboratory is testing the efficacy of COH-SR4 in mouse models of diabetes to explore the potential for this drug, developed by Samuel Rahbar here at City of Hope, to treat cancer.
Exercising control over metabolic disease
In order to develop treatments that slow — and even stop — the progression of type 2 diabetes, researchers must first understand the ways in which the body works to properly metabolize insulin.
In one effort, Janice Huss, Ph.D., an assistant professor in the Division of Gene Regulation and Drug Discovery, seeks to determine the role estrogen-related receptors (ERRs) play in regulating and forming skeletal muscle tissue. A well-recognized molecular benefit of exercise is that it activates the protein AMPK. Through exercise, AMPK works with ERRs to enhance the beneficial effects of exercise, as well as enhance the way skeletal muscle metabolizes insulin.
In Huss’ studies, she identified this molecular link between physical activity and insulin sensitivity and suggests that ERRs could be therapeutically boosted to enhance AMPK sensitivity in skeletal muscle. Huss is now engineering mice in which the expression of ERRs can be “turned on” at defined times. With this, she can then pinpoint the best time for administration of ERR-based therapies.
She hopes that this study will result in potent drug interventions that can delay the onset of obesity-related type 2 diabetes in patients faced with this disease.
Edited from the Diabetes Research Center Impact Report, February 2013.