Scientists Uncover Novel Molecular Mechanism Underlying Monogenic Diabetes in Cell Reports Study

March 14, 2022 /BIOON/ -- Maturity-onset diabetes of the young (MODY) is a disease caused by single-gene mutations. The genes typically affected by MODY are crucial for the development and function of β-cells, which are essential for maintaining insulin and glucagon levels in the body. MODY often occurs in young people under 25 years old and is characterized by highly diverse symptoms. Some patients require dietary and pharmacological treatments, while others need insulin injections to manage disease progression.

Scientists Reveal Novel Molecular Mechanism of Monogenic Diabetes.

Image Source: King's College London

Recently, an article published in the international journalCell ReportsThe research report titled "An HNF1α truncation associated with maturity-onset diabetes of the young impairs pancreatic progenitor differentiation by antagonizing HNF1β function"Scientists from King's College London and other institutions have revealed how common MODY3 mutations in the HNF1A (hepatocyte nuclear factor 1A) gene cause diabetes in the population. Researchers were very curious about why patients carrying the same genetic mutation exhibited various MODY characteristics, even within the same family.

In Petri dishes, researchers differentiated human induced pluripotent stem cells (iPSCs) derived from MODY3 patients into the β-cell lineage in vitro. Meanwhile, they developed pancreatic organoids (simplified and microscopic "mini-organs") from both healthy and MODY3 iPSCs to understand the impact of mutations on β-cell development and function. The results showed that MODY3 mutations lead to the formation of short-chain HNF1A proteins, which impair their binding with themselves and with HNF1B, and reduce the expression of genes crucial for β-cell development. This, in turn, may cause developmental defects in MODY3 lineages and a reduction in the formation of functional pancreatic progenitor cells and β-cells in vitro.

Researcher Sancho said,Although mouse models and gene knockout models involved in monogenic diabetes contribute to understanding general aspects of the disease, this study may highlight the importance of using patient-specific mutations and human iPSC-derived pancreatic models to decipher more subtle and unknown aspects of the disease. The phenotypic diversity observed in the MODY3 patient line used in this study suggests that, depending on genetic background and other clinical factors, the mutation might result in milder or more severe effects, thereby aiding in better understanding the diversity of the body's response to MODY3.

Image Source: https://www.cell.com/cell-reports/fulltext/S2211-1247(22)00149-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124722001498%3Fshowall%3Dtrue

In addition, the researchers have also established an in vitro pancreatic progenitor organoid model, which might help reveal the impact effects of MODY3 mutations during early and late pancreatic development; therefore, the researchers believe that this novel organoid model could be used by scientists to understand other subtypes of monogenic and polygenic diabetes.

In summary,The findings of this study highlight the ability of pancreatic progenitor-derived organoids to model diseases in vitro. Meanwhile, the researchers also uncovered an HNF1β-mediated mechanism associated with HNF1α truncation, which might influence progenitor cell differentiation and could explain the clinical heterogeneity observed in MODY3 patients.. (Bioon.com)

Original Source:

Ana-Maria Cujba，Mario E. Alvarez-Fallas，Sergio Pedraza-Arevalo, et al. An HNF1α truncation associated with maturity-onset diabetes of the young impairs pancreatic progenitor differentiation by antagonizing HNF1β function, Cell Reports (2022). DOI:10.1016/j.celrep.2022.110425