Abstract
Type 1 diabetes (T1D) destroys insulin-producing pancreatic β-cells, causing chronic hyperglycemia. Patients are also vulnerable to life-threatening hypoglycemia, driven largely by defective α-cell glucagon secretion, yet the mechanisms underlying this counterregulatory failure remain poorly understood. Using human pseudoislets from non-diabetic donors and complementary mouse models, we show that α-cells isolated from all other islet cell types fail to mount counterregulatory glucagon responses to low glucose, fully recapitulating the diabetic phenotype. Strikingly, the presence of even a few β-cells per islet is sufficient to restore α-cell counterregulatory function. These findings demonstrate that hypoglycemia-induced glucagon secretion is not an intrinsic α-cell property but depends critically on β-cell input. Defective counterregulation in diabetes therefore reflects disrupted α-β cell communication rather than intrinsic α-cell failure. By identifying β-cell loss as the primary driver of impaired glucagon secretion, this work reframes counterregulatory dysfunction as an islet network defect and highlights restoration of intra-islet β-cell signaling as a therapeutic strategy for improving glycemic stability in diabetes.