One of the Most Common Diabetes Treatments May Be Making the Disease Worse, Study Warns

Diabetes Paper — Drugs long used to treat type 2 diabetes may have previously unrecognized effects on the cells that produce insulin. New research suggests that sulphonylureas could gradually impair these cells’ identity and function, potentially influencing how the disease progresses. Credit: Stock

A new study suggests that one of the most common diabetes treatments may speed type 2 diabetes progression by causing insulin-producing cells to lose their functional identity.

Sulphonylureas have been used to treat type 2 diabetes since the early 1950s and remain among the most frequently prescribed medications for the disease. Common examples include glimepiride (Amaryl), glipizide (Glucotrol), and glyburide (Diabeta, Micronase). Even so, evidence shows that their effectiveness can decline with long-term use and that they may produce more side effects than several newer diabetes drugs.

New research from the University of Barcelona, the Bellvitge Biomedical Research Institute (IDIBELL), Bellvitge University Hospital, and the CIBER Area for Diabetes and Associated Metabolic Diseases (CIBERDEM) indicates that sulphonylureas may interfere with the normal function of insulin-producing cells.

The study found that these drugs can drive a loss of cellular identity in pancreatic beta cells, limiting their ability to release insulin and potentially speeding the progression of type 2 diabetes.

The findings were published in the journal Diabetes, Obesity and Metabolism and were led by Professor Eduard Montanya of the University of Barcelona’s Faculty of Medicine and Health Sciences. Montanya heads the Diabetes, Nutrition and Endocrine Diseases group at IDIBELL and also works as a physician at Bellvitge Hospital while serving as a member of CIBERDEM.

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The gears of diabetes

Diabetes is a chronic condition caused by an abnormal increase in blood glucose (hyperglycemia). This complex disease involves insulin, the hormone that regulates blood glucose levels, and the pancreatic beta (β) cells, which are responsible for producing insulin.

Type 2 diabetes is characterized by insulin resistance and a progressive loss of β-cell function to cope with it. Both β-cell death and loss of β-cell identity play an important role in these alterations, a process known in animal models and now corroborated in humans by the researchers.

“Not only do β cells die, but they also lose their functional identity and, although they are still alive, they revert to a state in which they are unable to produce and secrete insulin effectively, and it seems that sulphonylureas contribute to this loss of cell identity, increasing and enhancing their loss of function,” explains Dr. Eduard Montanya. leader of the Diabetes, nutrition and endocrine diseases group at IDIBELL, physician at the Bellvitge Hospital, researcher at CIBER and professor at the Faculty of Medicine and Health Sciences of the UB. He adds,

“And it appears that sulfonylureas contribute to this loss of cell identity, increasing and enhancing their loss of function.”

The double face of sulfonylureas

Sulfonylureas are drugs capable of interacting directly with β cells to stimulate insulin secretion. Initially, they are effective in lowering blood glucose levels, but eventually lose the ability to restore glycemic control (which is known as secondary sulfonylurea failure).

What’s more, as seen by the researchers, continued exposure to these drugs contributes to the loss of β cell function. This would explain why they are progressively less effective in reducing blood glucose, which could accelerate the progression of type II diabetes.

To understand how this happens, Dr. Montanya’s team has analyzed the effect of glibenclamide, a sulfonylurea, on healthy pancreatic β cells exposed to normal glucose conditions. The results are clear: cells exposed to the drug showed a reduction in the expression of genes essential to their function (including insulin expression itself), increased rate of cell death, and loss of insulin-secretion capacity in response to glucose.

“We have been able to confirm that glibenclamide has negative effects on β cells and accelerates the loss of functional mass, and that it does so in a time-dependent manner, since the involvement is greater the longer the exposure time,” researchers emphasize. The team has shown that the mechanism by which sulfonylureas cause the loss of identity of beta cells is, at least partially, through the induction of stress in the endoplasmic reticulum, a subcellular structure involved in the manufacture and modification of proteins.

Loss of identity, a potentially reversible phenomenon

Ultimately, these results provide a basis for understanding the loss of efficacy of sulfonylureas in the treatment of diabetes and their potential contribution to the progression of the disease, although more studies are needed to see how this finding translates into clinical practice.

However, on the other hand, knowing that in type II diabetes some beta cells do not die, but revert to a non-functional state, opens a line of research of great clinical interest: unlike cell death, the loss of identity is a potentially reversible phenomenon. Thus, understanding how it is produced is key to proposing, in the future, possible therapies that reverse the process and recover the functional identity of cells to offer long-term solutions for diabetic patients.

Reference: “Loss of β-cell identity in human islets treated with glibenclamide” by Claudia Fernández, Montserrat Nacher, Kevin Rivera, Sandra Marín-Cañas, Maria Sorribas, Gabriel Moreno-González, Elisabet Estil·les, Patricia San José, Noèlia Téllez and Eduard Montanya, 4 August 2025, Diabetes, Obesity and Metabolism.
DOI: 10.1111/dom.16632

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