How Scrambled RNA Contributes to the Development of Type 2 Diabetes

Recent research has uncovered that small-scale mutations in the gene HNF1A play a significant role in pushing millions of individuals toward developing type 2 diabetes. While mutations in this gene are known to cause MODY3, a rare early-onset form of diabetes, more subtle mutations can quietly influence the risk across a much larger population. A study published in Cell Metabolism reveals that these mutations primarily impair insulin-producing pancreatic beta cells.

Investigators at the Center for Genomic Regulation (CRG) in Barcelona demonstrated through mouse models that when HNF1A is deactivated specifically in beta cells, blood glucose regulation is disrupted, highlighting the crucial role of this gene within these cells. HNF1A functions as a transcription factor, regulating the expression of numerous genes essential for insulin synthesis and secretion.

The study further identified that deleting HNF1A also drastically reduces the levels of A1CF, a gene involved in RNA splicing – the process of editing RNA molecules before they are translated into proteins. Without functional HNF1A, A1CF levels drop significantly, leading to widespread errors in RNA splicing within beta cells — with between 1,900 and 2,300 RNA splicing mistakes observed. These errors cause a cascade of dysfunction, impairing the cells’ ability to produce and release insulin effectively.

Analysis of human pancreatic cells from donors showed a similar pattern: individuals with type 2 diabetes had a notable increase in beta cells with low activity of HNF1A and A1CF, indicating a disrupted regulatory pathway. Notably, the ratio of high-functioning to low-functioning beta cells was about one-to-eight in diabetic donors compared to a more balanced ratio in healthy individuals. This suggests that a single genetic mutation can trigger extensive tissue and organ-level malfunctions.

These findings open promising avenues for targeted therapies. Since the observed defect involves RNA splicing errors, researchers envision strategies to correct or 're-edit' these RNA messages, akin to recent treatments for conditions like spinal muscular dystrophy. Such approaches could address the root cause of the disease rather than solely managing symptoms.

Dr. Jorge Ferrer, the study's senior author, emphasizes that current diabetes treatments focus on lowering blood sugar but do not correct the underlying genetic and molecular abnormalities. The discovery of this RNA splicing disruption provides a new, druggable target, especially for MODY3 and potentially for broader cases of type 2 diabetes, affecting over 600 million people worldwide. However, he notes that type 2 diabetes is multifactorial, influenced by many genes and lifestyle factors, and this is just one piece of a complex puzzle.

Going forward, the research team aims to map the entire chain of molecular interactions involved, seeking to identify the most practical targets for innovative beta cell therapies. The ultimate goal is to translate these molecular insights into effective, targeted treatments to prevent or reverse beta cell dysfunction and diabetes progression.