DUARTE, Calif. — Bart Roep, Ph.D., City of Hope’s Chan Soon-Shiong Shapiro Distinguished Chair in Diabetes, professor/founding chair of the Department of Diabetes Immunology and director of The Wanek Family Project for Type 1 Diabetes, continues to break new ground in revealing the relationship between type 1 diabetes and the body’s natural defenses.
Roep was invited to speak about his research at the American Diabetes Association’s (ADA’s) 79th Scientific Sessions, held June 7-11, 2019 in San Francisco. Roep and several City of Hope colleagues highlighted research successes and presented recent findings.
Nearly 15,000 leading physicians, scientists and health-care professionals gathered at the conference to unveil leading-edge research, treatment recommendations and advances toward a cure for diabetes, which is associated with significant increases in inflammation and debilitating vascular complications that can lead to blindness and heart and kidney failure.
The root of type 1 diabetes
Roep spoke on a featured symposium titled “The Complicit Beta Cell in Type 1 Diabetes.” His talk, “Antigenic Peptides Are Generated Through Beta-Cell Translational Errors,” centers on an important revelation that came out of Roep’s laboratory in 2017: Type 1 diabetes (T1D) results from a mistake in the insulin-producing beta cells of the pancreas, not an error of the immune system, the previously accepted explanation for how the disease begins.
According to Roep’s findings, beta cells in T1D seem to produce abnormal proteins from the insulin gene that provoke immune responses. This is because of a “wrong read” of the insulin gene — a mechanism similar to what happens in some tumors. In addition to shedding light upon why some cancer patients develop T1D after successful immunotherapy, this discovery suggests new directions for treatments for T1D. Roep and his collaborators have built upon those investigations to explore a potential diabetes vaccine.
Rama Natarajan, Ph.D., City of Hope’s National Business Products Industry Professor in Diabetes Research and professor/chair of the Department of Diabetes Complications & Metabolism, gave a talk titled “Epigenetics of Inflammation and Diabetic Vascular Complications” as part of a featured symposium. Discussing her research into diabetes and epigenetics, or the changes that are made to genes by external or environmental factors, she underlined data collected by her lab that shows many inflammatory and fibrotic genes associated with diabetic complications are regulated by epigenetic mechanisms, and highlighted a clinical trial that elucidated the importance of strict glycemic control to prevent progression of diabetes-related complications.
Natarajan reviewed epigenetics data that her lab has generated with samples obtained from subjects enrolled in the Diabetes Control and Complications Trial (DCCT), which ran from 1983 to 1993, and from the current, long-term follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, which also demonstrated the phenomenon of metabolic memory that results in long-term malfunction of genes and sustained complications even after patients with diabetes bring their blood sugar under control.
“Building on that knowledge, we have used epigenomic approaches with samples from DCCT/EDIC type 1 diabetes patients to demonstrate a role for epigenetic mechanisms in this intriguing phenomenon of metabolic memory,” Natarajan said. “It shows that DNA is not your destiny: Despite being born with ‘good’ genes, your lifestyle can change things for the worse and vice versa via epigenetics.”
Another important part of Natarajan’s research is focused on the role of noncoding RNAs that form another epigenetic layer. These different epigenetic layers can cross talk and amplify pathological genes in diabetes.
“In the future, precision medicine with genetic, epigenetic and clinical information will help in more effective diagnosis and treatment of diabetes and its complications,” Natarajan said. “Furthermore, epigenetic variations are reversible and therefore provide an additional opportunity for therapeutic intervention.”
At the ADA conference, two postdoctoral scholars from Natarajan’s lab, Maryam Abdollahi, Ph.D., and Ragadeepthi Tunduguru, Ph.D., also presented their work with noncoding RNA. The three women worked together on both projects, along with Mitsuo Kato, Ph.D., an associate research professor in the Natarajan lab, and additional collaborators.
Beta cell diversity
Sangeeta Dhawan, Ph.D., City of Hope assistant professor of translational research and cellular therapeutics, delivered a talk on “Beta cell heterogeneity: a neuronal story” in a session entitled “Will the Real Beta Cell Please Stand Up?” Her research focuses on beta cells, the cells in the pancreas that produce insulin. A deficit of functioning beta cells is behind the symptoms of both type 1 and type 2 diabetes.
Dhawan’s work adds to a growing body of evidence indicating that not all beta cells are the same. Her presentation concerned two novel subpopulations of beta cells that exhibit molecular features similar to neurons (cells of the brain and nervous system). She discussed the changes that occur in these distinct sub-types during beta cell growth and in diabetes, and presented the epigenetic mechanisms that drive these differences in beta cells.
Qiong “Annabel” Wang, Ph.D., City of Hope assistant professor of molecular and cellular endocrinology, gave a presentation titled “315-OR – Two brown adipocyte subpopulations with distinct thermogenic activity coexist and undergo dynamic interconversions upon changes in environmental temperature.” In this research, she investigates brown fat, a type of darker-colored and richly veined fat that plays a role in warming up the body. Brown fat actually seems to have beneficial effects upon obesity and the insulin resistance seen in diabetes.
The previous understanding was that brown fat cells are more or less similar. Wang presented a discovery from her lab: a subtype of brown fat cells with distinct qualities, including low thermogenic activity — that is, they generate less heat.
Furthermore, she described how the two groups of brown fat cells convert from one to the other. Under normal circumstances, highly thermogenic brown fat cells are recruited to turn into the newly described subtype that have lower thermogenic activity. When ambient temperatures become cold, the opposite happens, with the newly described brown fat cells changing into brown fat cells that create more warmth.
# # #
About City of Hope
City of Hope is an independent biomedical research and treatment center for cancer, diabetes and other life-threatening diseases. Founded in 1913, City of Hope is a leader in bone marrow transplantation and immunotherapy such as CAR T cell therapy. City of Hope’s translational research and personalized treatment protocols advance care throughout the world. Human synthetic insulin and numerous breakthrough cancer drugs are based on technology developed at the institution. A National Cancer Institute-designated comprehensive cancer center and a founding member of the National Comprehensive Cancer Network, City of Hope is ranked one of America's "Best Hospitals" in cancer by U.S. News & World Report. Its main campus is located near Los Angeles, with additional locations throughout Southern California. For more information about City of Hope, follow us on Facebook, Twitter, YouTube or Instagram.