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

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 <i>Ngn3</i> (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.