Early loss and progressive deterioration of glucagon responses to hypoglycemia in children with type 1 diabetes.
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INTRODUCTION: Impaired glucagon counterregulation is a major contributor to hypoglycemia risk in type 1 diabetes (T1D). While well described in adults, the timing, trajectory, and determinants of glucagon dysfunction in children remain poorly defined. Our objective was to characterize the evolution of glucagon secretion during insulin-induced hypoglycemia in children with newly diagnosed T1D and to identify biomarkers of counterregulatory failure. RESEARCH DESIGN AND METHODS: GLUcagon REsponse to hypoglycemia in children and adolescents with new-onset type 1 DIAbetes (GLUREDIA) - Work Package (WP) 1 is a prospective, multicenter longitudinal study including 22 children and adolescents (aged 2-17 years) with newly diagnosed T1D and eight healthy first-degree relatives. Participants underwent standardized insulin-induced hypoglycemia tests (IIHTs). In patients with T1D, IIHTs were performed at diagnosis and at 6, 12, and 18 months. Plasma glucagon and counterregulatory hormones were measured at baseline and during hypoglycemia. Continuous glucose monitoring (CGM) metrics and circulating biomarkers were analyzed using longitudinal mixed models and regression analyses. RESULTS: In healthy participants, IIHT elicited a robust physiological increase in glucagon during hypoglycemia (p<0.001). In contrast, children with T1D showed no significant glucagon response despite deeper hypoglycemia. Longitudinally, glucagon responsiveness was absent at diagnosis, transiently improved at 6 months (p=0.04), absent at 12 months, and paradoxically suppressed at 18 months (p=0.02). Basal glucagon levels remained stable over time. Glucagon responses correlated positively with CGM time-in-range (70-180 mg/dL) and negatively with glycemic variability and hypoglycemia frequency. A CGM-based logistic model integrating these metrics predicted impaired glucagon responses with good discrimination (area under the curve 0.79). Circulating glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, tumor necrosis factor-α, and interferon-γ correlated positively with glucagon secretion, whereas partial remission status did not. CONCLUSIONS: Glucagon counterregulation is profoundly impaired early in pediatric T1D and deteriorates dynamically within the first 18 months after diagnosis. Glycemic instability and recurrent hypoglycemia are key determinants of α-cell dysfunction. CGM-derived metrics may serve as non-invasive surrogates of impaired counterregulation and support early risk stratification for hypoglycemia in children with T1D. TRIAL REGISTRATION NUMBER: NCT06770621.