The impact of GLP-1 and incretin-based therapies on counterregulatory responses to hypoglycemia in diabetes mellitus: mechanisms and clinical implications.

Hypoglycemia unawareness is characterized by a reduction in autonomic and neuroglycopenic signals of hypoglycemia; therefore, it is hardly perceivable. Glucagon-like peptide-1 (GLP-1) plays a critical role in glucose metabolism. Experimental model of recurrent hypoglycemia in type 1 diabetes mellitus suggests that increased intestinal GLP-1 expression is associated with impaired counterregulatory responses. However, whether incretin-based drugs or elevated intestinal GLP-1 produce similar impairments, in patients with type 1 and 2 diabetes mellitus and preexisting hypoglycemia-associated autonomic failure, remain incompletely understood. Clinical applications of incretin-based therapies might require caution, especially in sensitive patients, because of GLP-1-mediated disruption of hypoglycemic counterregulation. The impaired counterregulatory response to hypoglycemia could be because of GLP-1's actions, such as glucagon suppression, reduced sympathoadrenal signaling, modulatory effects on brain signaling during hypoglycemia, delayed gastric emptying, and among others. These factors might collectively contribute to abrogation of counterregulatory mechanisms to hypoglycemia, particularly when GLP-1 is overactive. This impairment should be carefully considered when managing patients with diabetes, especially hypoglycemic-sensitive individuals utilizing incretin-based medications chronically or when these medications are combined with insulin or sulfonylureas. This review brings together the complex role of GLP-1 in disrupting hypoglycemia counterregulation, the related mechanistic insights, and new therapeutic accountabilities pertaining to incretin-based medications.