# Loss of Beta‐Cell Identity and Function as a Mechanism of Secondary Failure of Sulfonylurea Therapy in Diabetes

## TL;DR

This study explores why sulfonylurea drugs lose effectiveness in treating type 2 diabetes over time, finding that beta-cell identity loss and alpha-cell increase may be responsible.

## Contribution

The study identifies beta-cell identity loss and alpha-cell neogenesis as novel mechanisms for secondary sulfonylurea therapy failure in diabetes.

## Key findings

- Glibenclamide-treated mice showed initial glucose improvement but later returned to baseline levels.
- Beta-cell mass and identity markers decreased, while alpha-cell numbers increased in treated mice.
- Elevated Ngn3 and alpha-cell markers suggest dedifferentiation and neogenesis in treated mice.

## Abstract

Sulfonylureas, commonly used to treat type 2 diabetes (T2D), often lose effectiveness over time when used as monotherapy; however, the underlying mechanisms remain unclear. To investigate the mechanisms of sulfonylurea failure, glibenclamide‐releasing pellets were implanted in KK mice, a polygenic model that spontaneously develops T2D. KK mice receiving placebo pellets (KK‐Placebo) developed hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance. Notably, KK mice implanted with glibenclamide (KK‐Glib) showed improved blood glucose levels during the first 7 days, returning to KK‐Placebo levels thereafter. KK‐Glib mice exhibited reduced plasma insulin levels and insulin secretion in response to a glucose challenge compared with the markedly elevated levels in KK‐Placebo mice. KK‐Glib mice showed islet hypertrophy, reduced β‐cell mass and number, and increased α‐cell number, resulting in elevated α:β cell ratio compared with KK‐Placebo. Although mRNA expression of β‐cell identity markers remained unchanged, their protein levels were reduced in KK‐Glib, suggesting β‐cell identity loss, which may underlie the observed impaired insulin secretion. Remarkably, KK‐Glib mice showed elevated mRNA levels of Ngn3 (dedifferentiation) and α‐cell identity markers along with glucagon content, suggesting α‐cell neogenesis. These findings suggest that secondary failure of sulfonylurea therapy may, in part, result from loss of β‐cell identity‐function and increased α‐cell number‐identity.