Type 2 diabetes medications, such as sulfonylureas, have been a mainstay of treating the disease since they came on the market in the early 1950s. However, although they are one of the most common drugs for this condition, it is not surprising that they lose effectiveness over time and have been seen to often cause more side effects than other antidiabetic drugs.
A new study led by IDIBELL, the University of Barcelona, the Bellvitge University Hospital and the Center for Biomedical Research in Diabetes and Associated Metabolic Diseases (CIBERDEM), recently published in the journal Diabetes, Obesity and Metabolism, has delved into this problem, confirming that drugs in the sulfonylurea family can cause a loss of identity of insulin-producing cells, reducing their ability to secrete the hormone and possibly accelerating the progression of type 2 diabetes.
The gears of diabetes
Diabetes is a chronic condition caused by an abnormal increase in blood glucose (hyperglycemia). It is a complex disease with various biological actors involved, but its main protagonists are insulin and pancreatic beta (?) cells: insulin is the hormone that allows blood glucose levels to be regulated, facilitating the exit of glucose from the bloodstream and its consequent entry into the cells so that they can be nourished; and ? cells are precisely the ones responsible for producing insulin.
In type 2 diabetes, the problem lies in the appearance of insulin resistance and a progressive loss of function of the cells ? that try to cope with it. The resistance of peripheral tissues to the effect of insulin forces ? cells to produce more insulin and, over time, this overexertion leads to the loss of functional mass of ? cells. Without them, insulin production drops and blood glucose levels rise.
Beta cells don’t just die, they also change
Until now, the death of ? cells was considered the main cause of the loss of functional cell mass in type 2 diabetes, but recently it has been seen that the loss of identity of these cells also plays an important role. It was known that this happened in mouse models, but now researchers corroborate it in humans.
“Cells ? not only die but 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,” 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.
“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 ? 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 ? cell function. This would explain why they are progressively less effective in reducing blood glucose, which could accelerate the progression of type 2 diabetes.
To understand how this happens, Dr. Montanya’s team has analyzed the effect of glibenclamide, a sulfonylurea, on healthy pancreatic ? 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 lose of insulin-secretion capacity in response to glucose.
“We have been able to confirm that glibenclamide has negative effects on ? 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,” the 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 2 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.
More information:
Claudia Fernández et al, Loss of ??cell identity in human islets treated with glibenclamide, Diabetes, Obesity and Metabolism (2025). DOI: 10.1111/dom.16632
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