Understanding the Declining Effectiveness of Common Type 2 Diabetes Medications

Recent research from the University of Barcelona and affiliated institutions sheds light on why certain widely used medications for type 2 diabetes, such as sulfonylureas, gradually lose effectiveness over time. These drugs, which have been a cornerstone of diabetes management since the 1950s, initially help lower blood sugar levels by stimulating insulin secretion from pancreatic beta (β) cells. However, the new findings reveal that prolonged use may contribute to a decline in beta cell function, not only through cell death but also via a loss of cell identity, which impairs insulin production even when cells are alive.

Diabetes is fundamentally characterized by elevated blood glucose levels, primarily due to insulin resistance and the progressive failure of β cells. In type 2 diabetes, the body's tissues become resistant to insulin, prompting β cells to produce more insulin to compensate. Over time, this overexertion can weaken β cells, leading to reduced functionality and mass, which exacerbates hyperglycemia.

The study highlights that, contrary to earlier beliefs that β cell decline was mainly caused by cell death, recent evidence shows another significant factor: the loss of beta cell identity. Dr. Eduard Montanya and colleagues confirmed that in humans, β cells not only die but can also revert to a non-functional state, losing their ability to produce and secrete insulin effectively. Importantly, they found that sulfonylureas, especially glibenclamide, can accelerate this loss of cell function by inducing stress within the endoplasmic reticulum, a subcellular structure involved in protein processing.

This stress leads to decreased expression of vital genes for insulin production, increased cell death, and diminished insulin secretion capacity. The longer the exposure to sulfonylureas, the greater the damage, which helps explain why these drugs can become less effective over time, a phenomenon known as secondary sulfonylurea failure. The findings imply that these medications may unintentionally contribute to the progression of diabetes.

Fortunately, the study also suggests that the loss of cell identity could be reversible, opening new avenues for therapies aimed at restoring β cell function. Understanding and preventing the mechanisms that cause this dedifferentiation could lead to long-term solutions for managing and potentially reversing some aspects of type 2 diabetes.

Overall, these insights emphasize the need for ongoing research into how traditional medications impact pancreatic cells and highlight the importance of developing treatments that preserve or restore β cell health, offering hope for improved management of the disease.