<scp>ChREBP</scp> drives β‐cell proliferation under metabolic stress but not in pregnancy‐induced β‐cell expansion

AIMS/INTRODUCTION: Carbohydrate responsive element-binding protein (ChREBP) is a glucose-activated transcription factor implicated in metabolic regulation and β-cell proliferation. Although in vitro studies have suggested that ChREBP promotes glucose-stimulated β-cell proliferation, its in vivo role under physiological and pathophysiological conditions remains unclear. MATERIALS AND METHODS: We generated β-cell-specific ChREBP knockout (βChrebp cKO) mice and examined β-cell proliferation and glucose metabolism under three conditions known to induce β-cell expansion: pharmacologically induced insulin resistance using the insulin receptor antagonist S961, high-fat diet (HFD) feeding, and pregnancy. β-cell proliferation was assessed by 5-Bromo-2'-deoxyuridine incorporation; islet gene expression was evaluated by quantitative PCR and RNA sequencing. RESULTS: βChrebp cKO mice displayed significantly impaired β-cell proliferation under both S961 treatment and HFD feeding, accompanied by decreased expression of the ChREBP target gene Rgs16. These mice also exhibited a mild defect in early-phase insulin secretion at 1 year of age and developed age-associated glucose intolerance. In contrast, pregnancy-induced β-cell proliferation and the expression of mitogenic genes (e.g., Tph2, Ccnb1, Ccnb2) were preserved in βChrebp cKO mice, and Rgs16 expression was unaffected. These findings suggest that ChREBP is critical for β-cell adaptation under hyperglycemia and insulin-resistant states, but not during normoglycemic pregnancy. CONCLUSIONS: ChREBP plays a context-dependent role in regulating β-cell proliferation, particularly under metabolic stress. The ChREBP-RGS16 axis may mediate adaptive β-cell proliferation in diabetes-related conditions, and this axis represents a potential therapeutic target to preserve or restore β-cell mass in type 2 diabetes.