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The biguanide compound metformin prevents desensitization of human pancreatic islets induced by high glucose
R Lupi1, S Del Guerra, C Tellini
1Department of Endocrinology and Metabolism, Ospedale Cisanello, University of Pisa, Italy.
Abstract:
Pancreatic islet desensitization by high glucose concentrations is a temporary and reversible state of beta-cell refractoriness to glucose (and possibly other secretagogues), due to repeated or prolonged pre-exposure to increased glucose concentrations. We evaluated whether the oral antidiabetic agent metformin affects this phenomenon in isolated, human pancreatic islets, and whether the possible effects of the biguanide are influenced by the presence of a sulphonylurea, glyburide. Islets prepared from five human pancreases were incubated for 24 h in M199 culture medium containing either 5.5 or 22.2 mmol/l glucose, with or without a therapeutic concentration (2.4 microg/ml) of metformin. Then, the islets were challenged with either 3.3 mmol/l glucose, 16.7 mmol/l glucose, or 3.3 mmol/l glucose + 10 mmol/l arginine, and insulin release was measured. After incubation in the absence of metformin, the human islets exposed to 22.2 mmol/l glucose showed no significant increase in insulin release when challenged with 16.7 mmol/l glucose (confirming that hyperglycemia desensitizes pancreatic beta-cells). In the presence of metformin, the islets fully maintained the ability to significantly increase their insulin release in response to glucose, even when previously exposed to 22.2 mmol/l glucose. No major effect on arginine-induced insulin release was observed, whatever the culture conditions. The protective action of metformin was observed also when glyburide was present in the incubation medium, whereas the sulphonylurea alone did not affect insulin release from the islets previously exposed to high glucose concentrations. These in vitro results suggest that metformin can prevent the desensitization of human pancreatic islets induced by prolonged exposure to increased glucose concentrations.
Insights
Metformin prevents high glucose-induced desensitization in human pancreatic islets. This oral antidiabetic agent preserves beta-cell function, even when combined with glyburide, suggesting a protective role in managing hyperglycemia.
Area of Science:
- Endocrinology
- Pharmacology
- Cell Biology
Background:
- High glucose concentrations can temporarily desensitize pancreatic beta-cells, impairing insulin secretion.
- This desensitization is a reversible state of beta-cell refractoriness to glucose stimulation.
- Understanding factors that protect against glucose-induced desensitization is crucial for diabetes management.
Purpose of the Study:
- To investigate the effect of metformin on glucose-induced desensitization in isolated human pancreatic islets.
- To determine if glyburide influences metformin's effect on islet function.
- To assess metformin's impact on insulin release in response to glucose and arginine challenges.
Main Methods:
- Human pancreatic islets were cultured for 24 hours with varying glucose concentrations (5.5 or 22.2 mmol/l) and metformin (2.4 microg/ml).
- Islets were subsequently challenged with different glucose levels (3.3 or 16.7 mmol/l) or arginine (10 mmol/l) to measure insulin release.
- Experiments were conducted with and without metformin, and in the presence of glyburide (a sulphonylurea).
Main Results:
- Human islets pre-exposed to high glucose (22.2 mmol/l) without metformin showed impaired insulin release upon glucose challenge.
- Metformin treatment preserved the ability of islets to significantly increase insulin release in response to glucose, even after high glucose pre-exposure.
- Metformin's protective effect was evident even when glyburide was present; glyburide alone did not prevent high glucose-induced desensitization.
Conclusions:
- Metformin effectively prevents the desensitization of human pancreatic islets caused by prolonged exposure to high glucose concentrations.
- Metformin maintains glucose-stimulated insulin secretion capacity in beta-cells under hyperglycemic conditions.
- These findings highlight metformin's potential therapeutic role in preserving pancreatic beta-cell function in diabetes.
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