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Idiopathic reactive hypoglycemia (IRH) is characterized by recurrent episodes of symptomatic hypoglycemia occurring within 4 hours after meals. The underlying mechanisms remain obscure.This study aimed to investigate the response of the glucoregulatory and gastrointestinal hormones to an oral glucose load (OGTT) in individuals with documented IRH.This was a cross-sectional study composed of outpatients referred to "Federico II" University of Naples.We enrolled subjects with IRH documented by a mixed meal under ordinary life conditions and healthy subjects as controls.We measured plasma glucose, insulin, glucagon-like peptide 1 (GLP-1), GIP, and glucagon response to a 75-g OGTT in cases and controls.Ten IRH and eight control subjects were enrolled. During the OGTT, mean plasma glucose tended to be lower in IRH than in control subjects, reaching a statistically significant difference at 240 minutes (T240) (43 ± 1.6 vs 72 ± 0.3 mg/dL; P = .001). Accordingly, the insulin response was higher in IRH than in control subjects (P.019) with a statistically significant difference (46%) at T90 (P = .045) and was associated with significantly lower glucagon levels in the late phase of the OGTT: at T120 (P = .031) and T180 (P = .048) in IRH than in control subjects. A greater GLP-1 response was found among IRH compared with control subjects (P = .005); GLP-1 peak was 2-fold higher in IRH individuals (9.77 ± 2.52 pmol/L) than in the control group (4.19 ± 0.53 pmol/L; P = .041). In the IRH group, GLP-1 peak inversely correlated with the nadir of plasma glucose (r = -0.66; P = .039). A multivariate analysis confirmed that GLP-1 peak independently predicted the plasma glucose nadir (β = -0.593; P = .026).GLP-1 may play a significant role in the pathogenesis of idiopathic IRH.