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

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.

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.

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.

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.