Loss of β-cell identity in human islets treated with glibenclamide

Aims

Loss of β-cell identity can contribute to the reduction of functional β-cell mass in type 2 diabetes. Sulfonylureas show shorter durability of antihyperglycaemic action and higher rates of secondary failure compared to other antihyperglycaemic agents, suggesting that they could accelerate the decline of β-cell functional mass in type 2 diabetes. We aimed to investigate the impact of chronic exposure to sulfonylureas on β-cell identity.

Materials and Methods

Islets from human multi-organ donors were cultured for 4–7 days at 5.6 mM glucose with or without glibenclamide. β-cell function (glucose stimulated insulin secretion, GSIS), apoptosis (TUNEL) and gene (RT-qPCR) and protein expression (immunofluorescence, genetic β-cell tracing and Western Blot) were determined.

Results

Human islets exposed to glibenclamide showed increased insulin secretion at low glucose, reduced GSIS, increased apoptosis, endoplasmic reticulum (ER) stress, and loss of β-cell identity indicated by reduced gene and protein expression of key β-cell identity markers and insulin. There were no changes in the expression of disallowed or progenitor-related genes. Genetic β-cell tracing showed a similar percentage of insulin-expressing cells in control and sulfonylurea-treated islets. Addition of the chemical chaperone 4-phenylbutyrate (PBA) to the culture medium prevented glibenclamide-induced ER stress and the downregulation of key β-cell transcription factors, indicating that ER stress mediates, at least partially, the negative effects of glibenclamide on β-cell identity.

Conclusions

Chronic exposure of human islets to glibenclamide induced the loss of β-cell identity, which was mediated by ER stress, impaired β-cell function, and increased β-cell apoptosis. These negative effects of glibenclamide may contribute to the secondary failure of sulfonylureas and accelerate the decline of functional β-cell mass in patients with type 2 diabetes.