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 AccessHopeTM. For more information about City of Hope, follow
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Letisia Marquez 626-476-7593 lemarquez@coh.org