In Vitro Study shows glibenclamide reduces pancreatic beta cell function and increases cell death — Evidence Review
Published in Diabetes, Obesity and Metabolism, by researchers from University of Barcelona, Bellvitge Biomedical Research Institute (IDIBELL), Bellvitge University Hospital, CIBER Area for Diabetes and Associated Metabolic Diseases (CIBERDEM)
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Table of Contents
A new study suggests that sulfonylurea drugs, commonly used for type 2 diabetes, may worsen disease progression by causing insulin-producing cells to lose their functional identity. Most related research supports these findings, showing negative long-term effects of sulfonylureas on beta-cell function, though some evidence suggests these effects could be partially reversible (see original source).
- Several related studies have shown that chronic exposure to sulfonylureas, such as glibenclamide, increases beta-cell apoptosis and impairs insulin secretion, aligning with the new study’s findings that these drugs induce both cell death and loss of function 1 3 5.
- Some studies indicate that beta-cell dysfunction caused by sulfonylureas may be partially reversible after discontinuation, suggesting that not all detrimental effects are permanent 6.
- Comparative trials with other diabetes treatments, such as GLP-1 analogs or early insulin therapy, consistently demonstrate better preservation or improvement of beta-cell function compared to sulfonylureas, further supporting concerns about the long-term use of sulfonylureas in type 2 diabetes management 2 12.
Study Overview and Key Findings
Sulfonylureas have been a mainstay in type 2 diabetes treatment for decades, yet their long-term impact on pancreatic beta cells has remained a subject of concern. This new study, conducted by researchers at the University of Barcelona and affiliated institutions, addresses an important gap: whether sulfonylureas contribute to the decline of beta-cell function by altering cellular identity rather than causing outright cell death. Their findings may have significant implications for the clinical management of diabetes and the development of future therapeutic strategies.
| Property | Value |
|---|---|
| Study Year | 2025 |
| Organization | University of Barcelona, Bellvitge Biomedical Research Institute (IDIBELL), Bellvitge University Hospital, CIBER Area for Diabetes and Associated Metabolic Diseases (CIBERDEM) |
| Journal Name | Diabetes, Obesity and Metabolism |
| Authors | Claudia Fernández, Montserrat Nacher, Kevin Rivera, Sandra Marín-Cañas, Maria Sorribas, Gabriel Moreno-González, Elisabet Estil·les, Patricia San José, Noèlia Téllez, Eduard Montanya |
| Population | Pancreatic beta cells |
| Methods | In Vitro Study |
| Outcome | Loss of cellular identity, insulin secretion capacity |
| Results | Glibenclamide reduces beta cell function and increases cell death. |
Literature Review: Related Studies
To contextualize these findings, we searched the Consensus database of over 200 million research papers for relevant literature. The following queries were used:
- glibenclamide beta cell function effects
- diabetes treatment glibenclamide cell death
- glibenclamide long-term diabetes outcomes
Summary Table of Related Research
| Topic | Key Findings |
|---|---|
| What are the long-term effects of sulfonylureas on beta-cell function? | - Chronic sulfonylurea exposure increases beta-cell apoptosis and reduces insulin content, leading to progressive loss of function 1 3 5. - Some studies find that beta-cell dysfunction induced by sulfonylureas can be rapidly reversed after discontinuation, suggesting the absence of permanent cell loss in certain models 6. |
| How do sulfonylureas compare to other therapies for preserving beta-cell function? | - GLP-1 analogs (e.g., exenatide) and early insulin therapy better preserve or improve beta-cell function compared to sulfonylureas, and also reduce inflammation and body weight 2 12. - Metformin and newer agents are associated with fewer side effects and less weight gain than sulfonylureas, though all have similar short-term glycemic efficacy 9 10. |
| What mechanisms underlie sulfonylurea-induced beta-cell impairment? | - Sulfonylureas reduce K(ATP) channel activity, increase cytosolic calcium, and induce ER stress, all contributing to beta-cell apoptosis and loss of function 1 3 4 5 7. - GLP-1 analogs like exendin-4 can protect beta cells from sulfonylurea-induced apoptosis by modulating ER stress and restoring SERCA expression 7. |
| Are the adverse effects of sulfonylureas on beta cells reversible? | - In animal models, withdrawal of sulfonylureas can restore insulin secretory capacity, indicating that loss of function may be reversible if cell death has not occurred 6. - Some studies suggest that loss of beta-cell identity, as opposed to cell death, may allow for future therapeutic interventions to reverse dysfunction [6, new study]. |
What are the long-term effects of sulfonylureas on beta-cell function?
A consistent finding across multiple studies is that chronic use of sulfonylureas, including glibenclamide, is associated with increased beta-cell apoptosis, decreased insulin content, and diminished insulin secretion. This supports the new study’s conclusion that sulfonylureas accelerate the decline of beta-cell function and may contribute to disease progression in type 2 diabetes 1 3 5.
- Chronic sulfonylurea exposure leads to beta-cell apoptosis, confirmed in both human islets and cell lines 1 5.
- Prolonged treatment reduces insulin content and impairs the acute insulinotropic response of beta cells 3.
- These cellular effects correspond with clinical observations of secondary failure to sulfonylurea therapy over time 9 13.
- Some evidence suggests these effects may be partially reversible if drug exposure is limited and cell death does not occur 6.
How do sulfonylureas compare to other therapies for preserving beta-cell function?
Randomized controlled trials indicate that alternative diabetes therapies—including GLP-1 analogs and early insulin use—better preserve beta-cell function, improve insulin resistance, and may have anti-inflammatory benefits compared to sulfonylureas 2 12. This suggests that sulfonylureas not only fail to arrest disease progression but may accelerate it relative to other options.
- Exenatide (a GLP-1 analog) improves beta-cell function and reduces body weight and inflammation, whereas glibenclamide does not 2.
- Early insulin therapy slows the decline of beta-cell function more effectively than glibenclamide, as measured by preserved C-peptide response 12.
- Metformin and newer drugs are associated with fewer hypoglycemic episodes and less weight gain than sulfonylureas, despite similar glycemic efficacy 9 10.
- Adjunct therapies (e.g., antioxidants) may enhance glycemic control when combined with sulfonylureas 11.
What mechanisms underlie sulfonylurea-induced beta-cell impairment?
Several studies have elucidated the underlying cellular mechanisms by which sulfonylureas impair beta-cell health. These drugs close K(ATP) channels, leading to increased intracellular calcium and ER stress, ultimately promoting apoptosis and loss of cellular function 1 3 4 5 7. The new study advances this understanding by highlighting the loss of beta-cell identity as a critical, potentially reversible process.
- Sulfonylureas decrease K(ATP) channel activity and increase cytosolic calcium, which can trigger apoptosis 4 5.
- Chronic treatment induces ER stress, which is implicated in both apoptosis and the loss of beta-cell identity 7.
- GLP-1 analogs can counteract some of these harmful effects by restoring ER calcium and reducing stress-induced apoptosis 7.
- The new study’s focus on cellular identity adds a dimension to these mechanisms, suggesting alternative therapeutic targets.
Are the adverse effects of sulfonylureas on beta cells reversible?
Animal models suggest that beta-cell dysfunction from chronic sulfonylurea exposure can be rapidly reversed after discontinuation, provided that beta-cell death has not occurred 6. The new study’s finding that loss of cellular identity is potentially reversible offers hope for future interventions.
- In mice, beta-cell secretory failure due to sulfonylureas can be reversed within hours to weeks after stopping treatment 6.
- No evidence of apoptosis was observed in these animal models, supporting the idea that dysfunction rather than cell loss can predominate 6.
- The distinction between cell death and loss of cellular identity is clinically significant, as the latter may be amenable to therapeutic rescue [new study].
- Restoration of beta-cell function after drug withdrawal may explain why some patients regain glycemic control after a “resting period” off sulfonylureas 6.
Future Research Questions
While the new study clarifies several mechanisms by which sulfonylureas may worsen beta-cell dysfunction, it also raises further questions about the reversibility of these effects, the translation of in vitro findings to clinical settings, and potential therapeutic strategies to protect or restore beta-cell identity. Additional research is needed to address these gaps and to inform future clinical practice.
| Research Question | Relevance |
|---|---|
| How reversible is the loss of beta-cell identity induced by sulfonylureas? | Determining the potential for beta-cell “re-differentiation” would inform whether interventions could restore insulin secretion capacity in patients previously treated with sulfonylureas [6, new study]. |
| Do sulfonylurea-induced beta-cell identity changes translate to clinical decline in humans? | Translating in vitro and animal findings to clinical outcomes is crucial for understanding the real-world impact and guiding patient management 1 3 12. |
| Can GLP-1 analogs or other agents prevent or reverse sulfonylurea-induced beta-cell dysfunction? | Some studies suggest GLP-1 analogs can protect beta cells from sulfonylurea-induced apoptosis and ER stress, but it is unknown whether they can restore cell identity and function in clinical settings 2 7. |
| What patient factors predict sulfonylurea secondary failure and beta-cell decline? | Identifying genetic, metabolic, or treatment-related predictors could enable more personalized diabetes care and early intervention to preserve beta-cell function 9 10 13. |
| How do sulfonylureas compare to newer diabetes therapies in long-term beta-cell preservation? | Comparative studies are needed to confirm whether alternatives to sulfonylureas offer superior long-term protection of beta-cell mass and function, as suggested by current data 2 9 10 12. |
This article provides an evidence-based synthesis of recent findings on sulfonylurea therapy and beta-cell health, highlighting the need for ongoing research and careful consideration of diabetes treatment strategies.