Neonatal diabetes model provides insights on how condition develops

At left, an islet, or cluster of pancreatic cells, from a typical mouse is full of insulin-producing cells (red). At right, there are far fewer insulin-producing cells in an islet from a mouse carrying the mutation that causes neonatal diabetes.

DALLAS – April 08, 2025 – A preclinical model developed at UT Southwestern Medical Center that recapitulates a rare infant-onset form of diabetes suggests the condition stems from gradual damage to the pancreas through misregulation of a molecular pathway called the unfolded protein response (UPR). The findings, published in Molecular Metabolism, could one day lead to new ways to treat more common subsets of diabetes, including Types 1 and 2, which affect hundreds of millions worldwide.

Amanda Casey, Ph.D., is Assistant Professor of Molecular Biology at UT Southwestern.

“Our findings from this model, which carries the same genetic mutation as in human disease, provide insights into how beta cells may become dysfunctional during diabetes,” said Amanda Casey, Ph.D., Assistant Professor of Molecular Biology at UT Southwestern. Dr. Casey co-led the study with Kim Orth, Ph.D., Professor of Molecular Biology and Biochemistry and a Howard Hughes Medical Institute Investigator, and Jun Wu, Ph.D., Associate Professor of Molecular Biology. Drs. Orth and Wu are members of the Harold C. Simmons Comprehensive Cancer Center at UTSW.

Neonatal diabetes affects an estimated 1 in 90,000-to-160,000 live births worldwide. Researchers have identified several single-gene mutations that cause this condition. One such mutation occurs in the gene encoding FicD, an enzyme that regulates the activity of BiP, a protein that helps fold other proteins into the shapes they need to function.

Under normal conditions, FicD precisely controls BiP by switching it between active and inactive states, allowing cells to respond to changing demands. When FicD is mutated, it loses this regulatory activity, resulting in permanent inactivation of BiP. This persistent BiP inactivation leads to the buildup of unfolded proteins inside cells, chronically activating the UPR.

Kim Orth, Ph.D., is Professor of Molecular Biology and Biochemistry at UT Southwestern and a member of the Harold C. Simmons Comprehensive Cancer Center. She is a Howard Hughes Medical Institute Investigator, holds the Earl A. Forsythe Chair in Biomedical Science, and is a W.W. Caruth, Jr. Scholar in Biomedical Research.

To determine how mutated FicD causes neonatal diabetes, Drs. Casey and Orth worked with the Wu Lab to develop a mouse line that carries the same genetic mutation as humans with this disease. Surprisingly, the mice appeared normal at birth, Dr. Orth said. But by 5 weeks of age, the mice developed high blood sugar and low levels of circulating insulin – hallmarks of diabetes.

When the researchers searched for signs of UPR throughout tissues in the rodents’ bodies, they saw hyperactivation of this molecular pathway in both the liver and pancreas, with pancreatic function significantly more affected. A closer look at mice with the mutation showed that pancreatic cells gradually lost the organized structure typical of healthy tissue. Although the insulin-producing pancreatic beta cells didn’t die, they appeared to lose the gene expression necessary to produce insulin, leading to a gradual decrease in levels of this critical blood sugar-regulating hormone over time.

Jun Wu, Ph.D., is Associate Professor of Molecular Biology at UT Southwestern and a member of the Harold C. Simmons Comprehensive Cancer Center. He is a Virginia Murchison Linthicum Scholar in Medical Research.

Dr. Casey noted that a misregulated UPR has been found to play a role in both Type 1 and Type 2 diabetes. It’s unclear why the pancreas is unusually susceptible to damage from glitches in this molecular pathway. But if scientists can find a way to protect the pancreas from UPR-related damage, she said, they might be able to protect this organ from progressive damage in patients with diabetes, allowing its beta cells to continue producing insulin.

Other UTSW researchers who contributed to this study are Bret Evers, M.D., Ph.D., Assistant Professor of Pathology and Ophthalmology; Nathan Stewart, B.S., and Naqi Zaidi, B.S., Research Technicians; Hillery Gray, B.A., Orth Lab Manager; Hazel A. Fields, Registered Histotechnologist, Lab Technical Assistant; Masahiro Sakurai, Ph.D., Research Scientist; and Carlos Pinzon-Arteaga, D.V.M., Ph.D., Research Associate.

This study was funded by grants from The Welch Foundation (I-1561), Once Upon a Time Foundation, the National Institutes of Health (R35 GM134945, R21 1R21EY034597-01A1, GM138565-01A1, and HD103627-01A), UTSW Nutrition & Obesity Research Center (under National Institute of Diabetes and Digestive and Kidney Diseases/NIH award number P30DK127984), and New York Stem Cell Foundation.

Dr. Orth holds the Earl A. Forsythe Chair in Biomedical Science and is a W.W. Caruth, Jr. Scholar in Biomedical Research. Dr. Wu is a Virginia Murchison Linthicum Scholar in Medical Research.

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.