Faculty of Medicine

A step towards personalized diabetes treatment

Research at UiB and Haukeland gives insight into a particular form of diabetes that can be treated with alternative drugs.

Bilde som er som en mini vitenskapelig poster med masse tegninger, piler og figurer
In a healthy pancreatic β-cell, HNF4A expression is regulated by the transcription factor HNF-1A. When genetic mutations occur in either of the two genes, patients can develop MODY diabetes. Researchers at the Mohn Center for Diabetes Precision Medicine investigated the effects of HNF4A promoter mutations on a molecular and clinical level.
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The epidemic rise in diabetes cases is a global health threat.

"Patients with diabetes have a mis-balanced glucose metabolism due to functional changes in the glucose-insulin signaling pathway in the pancreas and/or insulin action in the peripheral tissues", says Laura Kind, PhD at the Mohn Research Center for Diabetes Precision Medicine, UiB, and Haukeland University Hospital.

In diabetes, the body struggles to respond properly with insulin to meals, leading to abnormally high blood glucose levels:

"In the long-term, this condition leads to increased risk for micro- and macrovascular diseases, for example stroke, coronary heart disease, retinopathy, neuropathy, and kidney failure", Kind explains.

A deep dive into the molecular mechanisms of the disease.

According to the researchers at Mohn Research Center for Diabetes Precision Medicine there are different kinds of the disease.

Kind has been researching a specific form of diabetes that occurs during adolescence and young adulthood, "Maturity-onset diabetes of the young" (MODY).

To increase the knowledge of MODY, Kind has studied the genes involved, more specifically the interplay between the transcription factors HNF-1A and HNF-4A:

"They are crucial regulators of the insulin-producing β-cells in the pancreas. Variants in the HNF1A and HNF4A genes are associated with MODY", Kind explains.

"I wanted to dive deep into the molecular mechanisms of the disease. I took out the magnifying glass and looked at individual molecules to understand how they cooperate in the pancreatic cells".

In vitro techniques can help explain some of the cellular defects occurring in MODY patients.

Guided by her supervisors, Prof. Thomas Arnesen and Prof. Petri Kursula, at the Department of Biomedicine, UiB, she utilized different in vitro techniques to study how HNF-1A binds to the promoter region of HNF4A and thereby activates HNF4A transcription:

"We solved a crystal structure of HNF-1A bound to the promoter of HNF4A, allowing us to identify the crucial contact points between transcription factor and target promoter. Using biolayer interferometry and isothermal titration calorimetry, we were able to study the affinity and kinetics of the binding event. Finally, we performed luciferase-based reporter assays in different cell lines to investigate the transcriptional activity of HNF-1A towards the HNF4A promoter."

With her biochemical and structural biology approaches, she can explain some of the cellular defects occurring in the MODY patients:

"I found that specific mutations in the promoter region of the HNF4A gene lead to a mis-regulation of HNF-1A binding and consequently an altered HNF4A gene transcription in the insulin-producing cells", Kind explains.

International collaborations are required to study MODY diabetes.

Because MODY is a rare form of diabetes, the national patient catalogues were not sufficient to gather the required clinical information.

Professor and PI at the center, Pål Rasmus Njølstad, teamed up with clinicians across Europe to expand the data pool, allowing them to study the connection between genome mutations, the patients’ diabetes phenotype, and potential treatment options.

"International collaborations are crucial for our work", Njølstad emphasizes and adds:

"Genetic tests are conducted in numerous hospitals around the globe. If we share clinical data and results from experimental validation experiments, we can advance the field faster and henceforth improve the personalized treatment approach in diabetes medicine."


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