Research focused on potentially reducing hypoglycemic episodes, why more men might have diabetes than women, and targeting glucose control

Researchers with City of Hope^®, one of the largest cancer research and treatment organizations in the United States and a leading research center for diabetes and other life-threatening illnesses, presented novel study results at the 84th Scientific Sessions of ADA held June 21 to 24 in Orlando, Florida.

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Debbie Thurmond, Ph.D., director of the Arthur Riggs Diabetes & Metabolism Research Institute, leads ARDMRI, whose researchers presented at the annual American Diabetes Association (ADA) conference (Photo: City of Hope)

“City of Hope studies featured at this year’s ADA demonstrate the expertise, innovation and strength of our diabetes research from the essential preclinical stages all the way through to translational and clinical applications,” said Debbie C. Thurmond, Ph.D., director of the Arthur Riggs Diabetes & Metabolism Research Institute and Chan Soon-Shiong Shapiro Distinguished Chair in Diabetes. “City of Hope research speaks to our legacy of excellence in breakthrough diabetes science and our current research focus on islet cells, which are the crux of insulin production in diabetes.”

Reducing Hypoglycemic Episodes

Low blood sugar, or hypoglycemia, is managed by the release of a hormone called glucagon from pancreatic alpha cells. However, for people with type 1 diabetes (T1D), these cells are dysfunctional, leading to a loss of the ability to defend against low blood sugar, which can be life-threatening.

Julia Panzer, Ph.D., a staff scientist in the lab of Alberto Pugliese, M.D., City of Hope’s Samuel Rahbar Chair in Diabetes & Drug Discovery, chair of the Department of Diabetes Immunology and director of The Wanek Family Project for Type 1 Diabetes within the Arthur Riggs Diabetes & Metabolism Research Institute, explored how to restore proper alpha cell function in T1D.

Panzer presented the team’s findings from experiments using isolated islets and pancreatic tissue slices from both nondiabetic organ donors and donors with T1D. The study indicated that alpha cells respond very differently to glucose levels compared to beta cells. Furthermore, they are highly dependent on signals released from their neighboring cells.

“Alpha cells require inhibitory signals as a reset to function properly,” Panzer said. “When beta cells are lost, as observed in type 1 diabetes, the alpha cells become dysfunctional. We found that by restoring these inhibitory signals, we can reactivate the alpha cell and restore their function.”

She said the findings emphasize the critical role of alpha cells, which have long been neglected, and could significantly impact patients with T1D by reducing life-threatening hypoglycemic episodes. The team found that restoring alpha cell responses can be achieved by reactivating glucagon secretion through pharmacological receptor manipulation and plans to initiate a clinical trial using Food and Drug Administration-approved drugs to do just that.

“To develop effective treatments for diabetes, we need to understand the complex interactions and signals among all the different cell types within the islet, not just the beta cells,” Panzer said. “This research highlights the importance of the interactions among individual cells within the islet, demonstrating that their collective function is essential for overall islet health.”

Gender Differences in Diabetes Susceptibility

Worldwide, millions more men have diabetes than women. Biological sex is an important factor that affects beta cell physiology independent of insulin sensitivity in adults and also affects beta cell function differentially with aging. Researchers have found that one potential reason is that resilience to cellular stress in beta cells is different between male and female animal models.

To test beta cell response to one particular type of cellular stress called endoplasmic reticulum (ER) stress, Yingfeng Deng, Ph.D., assistant professor in City of Hope’s Department of Diabetes & Cancer Metabolism, and a group of researchers investigated something called the unfolded protein response (UPR). UPR is activated by beta cells to resolve ER stress.

Deng reported that when a protein that helps activate UPR was removed from mouse models, the female mice retained normal blood sugar levels while male mice developed early onset diabetes. They also confirmed that the protein plays a role in the early development of pancreatic islets in young mice.

“If we can relay our findings in animal models to humans, it indicates a candidate gene has been identified by us to understand the molecular mechanism of the differential risk for diabetes in men and women,” said Deng. “This information will help screen for the causes of diabetes in patients according to their biological sex.”

She said that while the UPR had been previously identified as a mechanism for better resilience to ER stress in beta cells of females, the significance of UPR in beta cell biology remains largely unexplored in the postnatal period when male and female differences have not fully unfolded, and beta cells are still immature.

“Our study fills this gap by demonstrating that while a specific UPR-activating protein is critical for beta cell function in both postnatal and adult states, it is indispensable to males, but females can stay healthy without it,” said Deng. “Males appear to be less tolerant to the disruption of UPR when it comes to diabetogenesis.”

A New Target for Improving Glucose Control

Learning more about how molecular mechanisms in the body regulate glucose-stimulated insulin secretion and help beta cells grow is essential to developing new approaches to diabetes therapies. Recently, researchers in the labs of Thurmond and 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, showed that a novel gene called zinc finger protein 385D, ZNF385D, is specifically expressed in human beta cells, but they were unsure of its role.

According to Geming Lu, M.D., a City of Hope assistant research professor working in Garcia-Ocaña’s lab, the team has now found that ZNF385D has a negative impact in beta cells because it decreases insulin expression and secretion. ZNF385D plays an active role in the development of type 2 diabetes (T2D) and can be therapeutically targeted.

“Treatment approaches to reduce ZNF385D levels in human beta cells can normalize blood glucose in patients with type 2 diabetes,” Lu said. “Therefore, developing strategies towards this goal could improve the life of the millions of patients with T2D.”

The researchers used single cell RNA-sequencing data from human islets of nondiabetic and T2D donors to analyze the relationship between ZNF385D and glucose control and beta cell survival. Expression of the gene significantly enhanced beta cell death and features of diabetes.

“Since diabetes results from insulin resistance or insufficient insulin production to reduce blood glucose levels, efforts to modulate ZNF385D to stop its detrimental effects will be explored for the development of new treatments for T2D,” Lu said.

Imaging Functional Beta Cells for Better Decision Making

One of the major obstacles in translating successful animal studies of diabetes therapies to people with T1D is the inability to detect functional beta cells in the body. Restoring function in beta cells, which are insulin-producing cells found in pancreatic islets, is the key to effective treatments. But taking a biopsy from the pancreas is currently the only way to assess beta cells and the procedure carries too high a risk to justify its use.

Now, Junfeng Li, Ph.D., assistant research professor in City of Hope’s Department of Translational Research & Cellular Therapeutics, believes that he has found a workaround to detecting beta cell function that could aid in early therapeutic development and clinical decision-making for T1D patients.

Li reported on findings from study by a team of City of Hope researchers that used positron emission tomography (PET) imaging to track a zinc ion called Zn²⁺ that is an excellent biomarker of beta cell insulin release in the body. By using a highly specific fluorine 18 radiotracer (small amounts of radioactive materials used in PET scans), the researchers demonstrated that PET imaging could efficiently detect Zn²⁺ being released from beta cells, which reflects a capacity for insulin secretion.

“To our knowledge, this is the first report utilizing a fluorine 18-labeled zinc PET probe for detecting functional beta cells,” said Li. “Our initial results showed that this technology could be valuable for tracking in vivo beta cell function in future T1D treatment strategies.”

He said that further validation studies are ongoing, but if clear visualizations of functional beta cells in the pancreas are observed, it could significantly benefit clinical decision-making regarding treatment assignment or adaptation for advancing diabetic therapies.

“Reliably detecting functional beta cells directly is imperative to demonstrating therapy efficacy in humans,” Li said. “PET imaging technology shows great promise as a tool to advance and validate T1D treatment strategies for clinical application or integration into clinical processes in humans.”

The Wanek Family Project for Type One Diabetes supported this research.

The Importance of Cholesterol in Islets

While cholesterol often gets a bad reputation for clogging arteries, it is also necessary for building and repairing cells, including islets. In fact, Wilma Tixi, Ph.D., a postdoctoral researcher in the lab of Ben Shih, Ph.D., associate professor in City of Hope’s Department of Translational Research & Cellular Therapeutics, announced that she, along with Shih and a team of researchers from the department, recently discovered that cholesterol production is essential for keeping the structure and function of pancreatic islets intact.

More specifically, the researchers found that functionality and clustering of islets — needed to regulate glucose and insulin — depends on strong cellular junctions. Furthermore, a cell adhesion protein called alpha-catenin is critical to the structural integrity of a particular type of junction, called a tight junction, and relies on cholesterol to do its job.

“The connection between cell adhesion and cholesterol production is crucial for the health of pancreatic islets,” said Tixi. “Targeting cholesterol synthesis in these cell connections could lead to new treatments that improve how pancreatic islets work, offering better options for managing diabetes.”

The findings could help improve stem cell techniques and advance beta cell replacement therapies for diabetes and point to a new focus for therapeutic research.

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 cancer research and treatment organizations in the U.S. 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 at its core, City of Hope brings a uniquely integrated model to patients spanning cancer care, research and development, academics and training, and innovation initiatives. 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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