Targeting PFKFB3 Metabolic Gatekeeping of β-Cell Dysfunctional States Enables Durable Glucose Tolerance in Type 2 Diabetes

Abstract

Progressive {beta}-cell dysfunction underlies type 2 diabetes (T2D), yet existing therapies fail to correct the dysfunctional cellular states that accumulate during disease progression. We show that pharmacological inhibition of PFKFB3 markedly reduced the population of PFKFB3 dysfunctional {beta}-cells while preserving functional islet mass, consistent with selective depletion or phenotypic reprogramming of compromised {beta}-cells. In transgenic diabetic mice expressing human IAPP, PFKFB3 inhibitor AZ67 improved glucose-stimulated insulin secretion and glucose tolerance through a mechanism consistent with direct restoration of {beta}-cell function and distinct from incretin-based therapy. Critically, glycemic improvement persisted after treatment withdrawal, consistent with durable remodeling of islet functional states rather than transient pharmacological suppression. In human islet microtissues under glucotoxic and cytokine stress, AZ67 and its analogue AZ26 improved insulin secretion and proinsulin processing in a stress- and compound-dependent manner while reducing PFKFB3 dysfunctional endocrine populations. Transcriptomic profiling identified suppression of inflammatory programs and activation of cholesterol homeostasis and adaptive metabolic pathways. These findings establish PFKFB3 inhibition as a potential disease-modifying therapeutic strategy for T2D.