Neonatal Diabetes Linked to Unfolded Protein Response (UPR)

The UT Southwestern researchers study findings pave way for new treatment prospects in Type 1 and Type 2 Diabetes

Neonatal Diabetes - Rare form of diabetes in neonates, developed after few weeks of birth, which can lead to lifelong medications if not treated properly during early stagesRepresentational image - Unsplash

Published on:

21 Apr 2025, 6:30 pm

UT Southwestern Medical Center has developed a preclinical model which elucidate the progress of a rare condition known as neonatal diabetes. This is a progressive disease, characterized by the gradual damage to the pancreatic beta cells caused due to disruption in the normal molecular cascade of Unfolded Protein Response (UPR). This disturbance leads to decreased insulin production thereby increasing the blood glucose levels in neonates. The study finding published in Molecular Metabolism¹, could be a way forward for the new treatment options, for a numerous people who are suffering from different forms of diabetes such as Type 1 and Type 2

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

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

Neonatal Diabetes - Gene mutation

1 in 90,000-to-160,000 live births worldwide is affected by this rare condition called neonatal diabetes. Researchers found that, among the several single-gene mutations that causes neonatal diabetes, this one mutation that happens in an enzyme FicD, that regulates BiP, which has the key responsibility in folding the proteins into shapes for their intended function, plays a pivotal role in the progress of the disease

Molecular Cascade of UPR

In normal neonates, the FicD regulates the BiP, by activating and deactivating BiP, to fold the proteins and unfold the proteins for different functions respectively. The FicD enzyme activates the BiP by deAMPylating and inactivates it by AMPylating (BiP-Amp)

In neonatal diabetes, the FicD is mutated, that permanantly deactivates the BiP which leads to accumulation of unfolded proteins inside the cells, resulting in activation of UPR

The Mice Model of Neonatal Diabetes

In order to verify this molecular cascade misregulation, Drs. Casey and Orth developed a preclinical study on genetically mutated mice model that represents the human mutation in Wu Lab²

Surprisingly, the mice appeared normal at birth

Dr. Kim Orth, Ph.D., Professor of Molecular Biology and Biochemistry, Howard Hughes Medical Institute Investigator

But developed high blood sugar and had low levels of circulating insulin by the 5th week which are the markers for diabetes. The researchers were able to find the signs of UPR and found the hyperactivity of molecular dysregulations mainly in liver and predominantly in pancreas of the mutated mice. With a closer look at the mutated mice pancreas, the organ lost the organized structure of insulin producing beta cells. Even though the beta cells didn't die, the disorganized beta cells lost the genetic makeup to produce enough circulating insulin

Future Prospects in UPR

Dr. Casey states that the UPR dysregulation not only contributes to neonatal diabetes, but also for Type 1 and Type 2 diabetes. Even though it is unclear why the pancreas is greatly affected with the slight disturbance in this molecular pathway, further research on UPR dysregulations and its correction through genetic modifications will make way for new ways to protect the pancreas. Extended research in UPR mechanisms could lead to crucial breakthrough in the early diagnosis and targeted therapies for neonatal, Type 1 and Type 2 diabetes.

Reference:

1. https://www.sciencedirect.com/science/article/pii/S2212877825000274?via%3Dihub

2. https://labs.utsouthwestern.edu/wu-jun-lab

(Newswise/AE)

Andhra Pradesh's Medtech Zone Launches Nation's First Monkeypox RT-PCR Kit

Diabetes