City of Hope Experts Present Pioneering Research at 2025 American Diabetes Association Conference

New Discoveries Offer Innovative Targets to Improve Beta Bell Function, Develop Potential Therapies and Prevent Prediabetes Progression

Scientists with City of Hope^®, one of the largest and most advanced cancer research and treatment organizations in the United States, and a leading research center for diabetes and other life-threatening illnesses, presented their latest research findings at the American Diabetes Association’s 85th Scientific Sessions, June 20-23, 2025, at the McCormick Place Convention Center in Chicago.

“City of Hope studies featured at this year’s ADA meeting offer remarkable new insights that help demystify the molecular and cellular mechanisms of diabetes, pointing to new translational approaches and innovative therapies to prevent and treat the disease,” said Rama Natarajan, Ph.D., deputy director of the Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope. “The breadth of our research reflects City of Hope’s legacy of excellence in breakthrough diabetes science.”

Guarding Beta Cells from Autoimmune Attacks

Beta cells are specialized endocrine cells in the pancreas that make and release insulin. Protection by internal energy factories called mitochondria enables each cell to produce the perfect dose of insulin to maintain normal blood glucose levels.

When mitochondrial performance goes awry, however, the malfunction may trigger inflammation and immune response, leading to disease.

Now, a City of Hope study led by Geming Lu, M.D., assistant research professor, discovered that a protein called BNIP3 plays a critical role in preserving mitochondrial health and reducing the organisms’ ability to induce immune responses in type 1 diabetes.

Using a preclinical model, Dr. Lu and his colleagues found that BNIP3 declines as diabetes worsens, disrupting beta cells’ ability to make insulin and damaging cellular regions linked to inflammation. Various tests showed a drop in insulin and related proteins that support beta cell development and function.

When the researchers treated the beta cell with a substance that mimicked cellular signals, it elevated proteins that invoked an immune response.

Boosting BNIP3 quieted the body’s immune response to the treatment. Conversely, reducing BNIP3 in the beta cells activated signaling pathways that help fight infections.

“When BNIP3 drops or goes missing in the beta cells, they start sending out a strong SOS that can trigger autoimmune attacks,” said Dr. Lu. “Restoring BNIP3 helps calm these distress signals down.”

That balance could prove critical in preventing or slowing cellular destruction in type 1 diabetes, he observed.

“Our research suggests that BNIP3 acts like a guardian for beta cells, preventing them from attracting unwanted attention from the immune system,” said Dr. Lu.

The findings open up exciting possibilities for future therapies.

“If we can figure out how to boost BNIP3 activity — or imitate its protective effects — we may be able to preserve beta cell function longer or even prevent the onset of type 1 diabetes in people at risk,” he said. “Our research offers a new path for scientists to explore how to make beta cells more resilient in an autoimmune environment.”

Dr. Lu shared the findings of his study, “BNIP3-mediated Mitophagy Protects Human Beta Cells by Regulating Mitochondrial Integrity and Immunogenicity in Type 1 Diabetes,” during an oral presentation on June 20 from 2 to 2:15 p.m. CT.

Special Note: Dr. Lu earned the Young Investigator Award from the American Diabetes Association for his top-scoring work above. He works in the lab of Adolfo Garcia-Ocaña, Ph.D., City of Hope’s Ruth B. and Robert K. Lanman Chair in Gene Regulation & Drug Discovery Research and chair of the Department of Molecular & Cellular Endocrinology.

Interferons Influence RNA Activity in Beta Cells

Two type-1 interferons, IFN-alpha and IFN-gamma, promote inflammation and play a key role in the early development of type 1 diabetes. Until now, how these signaling molecules shape the way insulin-producing cells read and use their genetic information had not been tested.

“We aimed to investigate how exposure of different pro-inflammatory cytokines alters the RNA epitranscriptome in human pancreatic islets and how these modifications affect protein synthesis under conditions of cellular stress,” explained City of Hope’s Farooq Syed, Ph.D., assistant professor in the Department of Diabetes Immunology at the Arthur Riggs Diabetes & Metabolism Research Institute.

To mimic early disease, Dr. Syed and colleagues treated human pancreatic islet cells — clusters of hormone producing cells that includes insulin secreting β cells — with IFN-alpha and IFN-gamma for eight and 24 hours and subjected them to RNA sequencing.

Using a variety of techniques, the lab discovered different cytokines have selective impacts on RNA modifications and activated the integrated stress response (ISR) pathway. Scientists also pinpointed time- and cytokine-specific changes in RNA modifications.

IFN-alpha treatment induced widespread m6A methylation changes, affecting 1,688 of 4,006 unique sites at eight hours and 14 of 936 sites at 24 hours. IFN-gamma similarly altered 639 of 2,527 sites at eight hours and 65 of 664 at 24 hours. Notably, 95 sites were consistently modified across all treatment conditions, many of which were linked to activation of the cellular stress response.

“We identified epitranscriptomic alterations in genes activated during defective messenger RNA translation, as well as in genes involved in beta-cell dysfunction and immune response,” Dr. Syed said.

In a preclinical model, treatment with a drug that inhibited the cellular stress response led to a 70% reduction compared to the vehicle treated control group. Importantly, the treatment also restored mRNA translation in the pancreatic beta cells.

“Our findings show how inflammation activates the integrated stress response that drives RNA changes and disrupts messenger RNA translation in the beta cells. The process happens over time and selective cytokine specific manner,” said Dr. Syed. “The results suggest that targeting the ISR pathway may hold promise as a therapeutic approach for type 1 diabetes.”

He presented his abstract, “Temporal Dynamics of RNA Modifications and Translation in Type I Interferon Stimulated Human,” during an oral presentation on June 20 from 1:15 to 1:30 p.m. CT.

Why Tolerating Cold Is Harder as We Age

Recent advances in single-cell technologies have uncovered complex cellular heterogeneity, yet it remains unclear whether this translates into functional diversity and how it affects tissue activity.

A City of Hope preclinical study led by staff scientist Anying Song explored how distinct populations of brown fat cells contribute to heat production and energy regulation. The research focused on uncovering why thermogenic activity declines over time, revealing an immune-neural mechanism that drives this process and becomes impaired with aging.

Song and associates had previously identified a subgroup of brown fat cells that express low levels of uncoupling protein 1 (UCP1), coexist with typical brown fat cells exhibiting high UCP1 levels.

“The UCP1 generates heat by burning fat,” said Song, who works in the lab of Qiong (Annabel) Wang, Ph.D., associate professor in the Department of Molecular & Cellular Endocrinology, Diabetes and Metabolism Research Institute. “Brown fat cells burn energy, while white fat cells store it.”

The team discovered a population of immune cells that secrete interleukin-1 beta (IL-1β), which acts locally to lower the heat production in adjacent brown fat cells. IL-1β protects a protein called H6PD from breaking down; this enhances local glucocorticoid activation, which in turn signals hormone receptors to suppress the expression of the uncoupling protein 1.

Cold temperatures reduced IL-1β levels and speeds up activity in brown fat cells to generate heat.

“When we removed the hormone receptor during cold exposure, the brown fat cells couldn’t slow their activity as it grew warmer,” explained Song. “This kept heat production going.”

“As we age, IL-1β levels rise, leading to a lower ratio of active to inactive brown fat cells and making it harder to tolerate the cold,” explained Song.

Reducing the hormone receptor signaling in older mice helped restore the balance between active and inactive brown fat and boosted heat production.

“Our findings demonstrate how different types of brown fat cells work together over time and space to control heat production in the body,” said Song. “This mechanism integrates neural and immune signals and becomes dysregulated with age, contributing to the aging of brown fat tissue Understanding this process opens new avenues for improving metabolic health and could lead to better strategies for preventing or treating conditions like type 2 diabetes.”

Song discussed the study, titled “Bistable Regulation of Cellular Heterogeneity Governs Thermogenic Activity,” during an oral presentation on June 21 from 2:45 to 3 p.m. CT.

How Prediabetes Develops into Type 2 Diabetes

More than 35% of the U.S. population over age 18 has prediabetes, the precursor to type 2 diabetes (T2D). Exactly how prediabetes advances to T2D is unclear, but scientists suspect a disruption of how the body metabolizes food for energy plays a role. This metabolic dysfunction creates toxic byproducts that attach to DNA, RNA and proteins, altering how they work.

Research, led by Kassandra Lopez, a Ph.D. candidate, scrutinized how MG-adducts, a metabolic byproduct made from methylglyoxal, change the function of insulin-producing beta cells in the pancreas.

“We suspect MG-adducts build up during pre-diabetes and drive progression to type 2 diabetes by damaging DNA and blocking beta cells’ ability to release insulin when needed,” said Lopez, who works in the laboratory of Sarah Shuck, Ph.D., assistant professor, Department of Diabetes & Cancer Metabolism, Arthur Riggs Diabetes & Metabolism Institute

The researchers utilized a novel liquid chromatography tandem mass spectrometry method to measure MG-adducts in cells, tissues, urine and blood. The team also examined DNA breakage and monitored the production of destructive molecules.

Their early findings link high blood sugar to the accumulation of MG-adducts in pancreatic beta cells, especially in people diagnosed with prediabetes and T2D. The combination of high blood sugar and MG-adducts also increased DNA damage to beta cells, undermining their ability to secrete insulin.

“Our study is the first to measure methylglyoxal and its harmful byproducts in people with prediabetes,” said Lopez. “We believe our novel approach offers a unique opportunity to decipher how MG-adducts are linked to the progression of type 2 diabetes.”

Lopez will present her research poster, “Elucidating the Role of Reactive Metabolic By-Products as Predictors and Drivers of Type 2 Diabetes,” on June 23 from 1:30 to 2:30 pm.

Additional presentations by City of Hope scientists at the meeting include those listed below.

• Alberto Pugliese, M.D. — the Samuel Rahbar Chair in Diabetes & Drug Discovery, chair, Department of Diabetes Immunology, Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope — lead an advisory panel on viral T-cell responses on June 21 from 3:55 – 4:05 p.m. CT. Location: W192 A-C.
• Poster presentation sessions on June 23 from 12:30 to 1:30 p.m. CT will include:
  • Human Alpha-cell Heterogeneity and Trajectory Inference Analyses of Human Islets Reveal SMOC1 as a Beta-Cell Dedifferentiation Gene [Board No. 1846] by Randy Kang, senior research associate
  • Dual Roles of Renal Tubular Mitochondrial AKT1 in Improving Whole Body Glucose Metabolism and Protecting Against Diabetic Nephropathy [Board No. 380] by Esam Salem, postdoctoral fellow
  • Selective Induction of Spliced XBP1 in Pancreatic Islet Beta Cells Causes Reversible Diabetes [Board No. 1831] by Yingfeng Deng, Ph.D. assistant professor, Department of Diabetes, & Cancer Metabolism

About City of Hope

City of Hope's mission is to make hope a reality for all touched by cancer and diabetes. Founded in 1913, City of Hope has grown into one of the largest and most advanced cancer research and treatment organizations in the United States, and one of the leading research centers for diabetes and other life-threatening illnesses. City of Hope research has been the basis for numerous breakthrough cancer medicines, as well as human synthetic insulin and monoclonal antibodies. With an independent, National Cancer Institute-designated comprehensive cancer center that is ranked a Top 5 “Best Hospital” in the nation for cancer care by U.S. News & World Report at its core, City of Hope’s uniquely integrated model spans cancer care, research and development, academics and training, and a broad philanthropy program that powers its work. City of Hope’s growing national system includes its Los Angeles campus, a network of clinical care locations across Southern California, a new cancer center in Orange County, California, and cancer treatment centers and outpatient facilities in the Atlanta, Chicago and Phoenix areas. City of Hope’s affiliated group of organizations includes Translational Genomics Research Institute and AccessHope^TM. For more information about City of Hope, follow us on Facebook, X, YouTube, Instagram and LinkedIn.

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Scientists with City of Hope presented their latest research findings at the American Diabetes Association’s 85th Scientific Sessions, June 20-23, 2025, at the McCormick Place Convention Center in Chicago.