Glimepiride, glipizide... these common glucose-lowering drugs may be quietly damaging your body's precious insulin-producing cells.

"Just prescribed glimepiride by my doctor—should I keep taking it?" Aunt Wang anxiously came to the outpatient clinic holding the latest research report. Like her, many people with diabetes are confused and worried about these findings.

Since the 1950s, sulfonylureas have been one of the cornerstones of type 2 diabetes treatment. Drugs like glimepiride, glipizide, and glibenclamide are still widely used worldwide.

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However, the latest research from the University of Barcelona in Spain has revealed a troubling discovery: these drugs may cause damage to insulin-producing beta cells and even accelerate the progression of type 2 diabetes.

01 Commonly Used Glucose-Lowering Drugs

Sulfonylureas, one of the most commonly prescribed medications for type 2 diabetes, have a simple and direct mechanism of action—stimulating insulin secretion. This class of drugs promotes insulin release by binding to specific receptors on pancreatic beta cells, thereby helping to lower blood glucose levels.

Since their introduction in the early 1950s, sulfonylureas have become an important option in diabetes treatment. They are widely used in clinical practice due to their relatively low cost and significant blood sugar-lowering effects.

Even in the face of competition from newer glucose-lowering drugs, this class of medications still holds a significant position in the global diabetes drug market. According to data from the International Diabetes Federation, over 500 million adults worldwide have diabetes.

The vast majority of these patients have type 2 diabetes, and many rely long-term on sulfonylurea drugs to control their blood sugar.

However, as clinical experience has accumulated, doctors have gradually discovered a troubling phenomenon with this class of drugs: secondary failure of sulfonylurea therapy.

That is, in patients who initially responded well to the drugs with good blood sugar control, the drug's effectiveness gradually diminishes over time, eventually becoming unable to effectively manage blood glucose levels. The biological mechanisms behind this phenomenon have not been fully elucidated.

02 Cellular Identity Crisis

A research team led by Professor Montanya from the University of Barcelona discovered that sulfonylurea drugs may interfere with the normal function of insulin-secreting cells. This research, published in the journal *Diabetes, Obesity and Metabolism*, reveals the potential risks associated with this class of medications.

The research team observed in experiments that in healthy pancreatic beta cells exposed to glibenclamide, the expression of genes critical to cell function decreased. These genes include the insulin gene itself. Cell mortality increased, while the cells' ability to secrete insulin in response to glucose stimulation was significantly weakened.

More concerningly, the study found that sulfonylureas can cause pancreatic beta cells to "lose their cellular identity." This means that these cells, specialized for insulin production, may gradually lose their professional functions.

This transition aligns with the natural progression of type 2 diabetes. During the development of diabetes, some beta cells do not die immediately but instead enter a "non-functional state"—they remain alive but are unable to effectively produce and secrete insulin.

Professor Montana explained, "We have confirmed that sulfonylureas have a negative impact on beta cells, accelerating the loss of functional beta cells, and this effect is time-dependent." In other words, the longer patients use this type of medication, the greater the potential damage to beta cells may be.

03 The Source of Insulin

Pancreatic β-cells, located in the pancreas, are the only cell type in the human body capable of producing insulin. In healthy individuals, these tiny yet precise cells can sensitively detect changes in blood glucose levels and accurately regulate insulin secretion.

When blood glucose rises, β-cells rapidly increase insulin secretion, prompting muscle, liver, and adipose tissues to absorb and utilize glucose. When blood glucose returns to normal, insulin secretion decreases accordingly. This precise balancing mechanism maintains the stability of human blood glucose levels.

However, in patients with type 2 diabetes, this balance is disrupted. First, insulin resistance occurs, meaning the body's cells have a weakened response to insulin. To compensate for this resistance, β-cells are forced to secrete more insulin.

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This long-term state of overload ultimately leads to the gradual functional decline of β-cells. A research team from the University of Barcelona discovered that during this process, β-cells not only undergo cell death but, more importantly, experience a "loss of cellular identity."

These "identity-lost" beta cells remain alive but lose their ability to efficiently produce and secrete insulin. Sulfonylurea drugs may exacerbate this process, causing more normally functioning beta cells to transform into dysfunctional cells.

04 The Dual-Faced Diabetes Medication

Sulfonylureas play a paradoxical role in diabetes treatment. On one hand, they directly interact with beta cells, stimulating insulin secretion and effectively lowering blood glucose in the short term; on the other hand, studies indicate that long-term use may accelerate the loss of beta cell function.

This dual effect can explain the clinically common phenomenon of "secondary sulfonylurea failure" — where patients initially experience good glycemic control with the medication, but over time, the drug's effectiveness gradually diminishes, ultimately failing to control blood glucose effectively.

To gain deeper insight into the mechanism behind this phenomenon, Professor Montanya’s team investigated how sulfonylureas affect beta cells. They discovered that the mechanism by which these drugs lead to beta cell function loss is, at least in part, achieved by inducing endoplasmic reticulum stress.

The endoplasmic reticulum is a key structure in cells responsible for protein synthesis and modification. When β-cells are forced to continuously secrete insulin under normal blood glucose conditions (such as under drug stimulation), the endoplasmic reticulum becomes overloaded, ultimately triggering a stress response and impairing cellular function.

This finding provides a biological basis for understanding the long-term efficacy decline of sulfonylureas. The study also suggests that longer drug exposure leads to greater negative impacts on beta cells, prompting doctors and patients to reevaluate the long-term use strategies of such medications.

05 New Directions in Treatment

Although the findings are concerning, Professor Montanya’s team’s research also brings new hope for diabetes treatment. They observed that in type 2 diabetes, some beta cells do not die but rather enter a "non-functional state."

Unlike cell death, this functional impairment may be a reversible phenomenon. This means that if scientists can identify mechanisms to reverse this process, there is hope for restoring the function of these beta cells.

This discovery opens a highly clinically significant research direction. Professor Montana stated: "Understanding its underlying mechanism is crucial for future efforts to propose therapies that reverse this process and restore cellular functional characteristics, thereby offering long-term solutions for people with diabetes."

If researchers can develop treatments that help β-cells regain function, it could potentially transform the landscape of type 2 diabetes management. This type of therapy not only holds promise for restoring patients' own insulin production capacity but may also reduce reliance on exogenous insulin or insulin secretagogues.

This research direction also prompts us to reconsider the overall strategy for diabetes management. Beyond simply lowering blood glucose levels, protecting and restoring β-cell function could become one of the key objectives in future diabetes treatment.

"Doctor, should I stop taking sulfonylureas immediately?" Faced with Aunt Wang's question, the doctor patiently explained, "Any medication adjustments must be made under medical supervision; never discontinue medication on your own. This study reminds us to pay more attention to the long-term effects of drugs, but it does not mean that patients currently using these medications need to stop taking them right away."

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The doctor added, "Each individual's situation is different. Whether to adjust medication and how to do so must be considered comprehensively based on blood glucose control, the risk of complications, and overall health status."

The significance of this study may lie more in promoting more personalized and precise diabetes treatment strategies, as well as in spurring the development of a new generation of drugs that can both control blood sugar levels and protect or even repair β-cells.