Promiscuous receptor activation mediates glucagonostatic effects of GLP-1(9-36) and GLP-1(7-36)

Plasma glucose is controlled by the hormones glucagon and insulin. In type 2 diabetes, where insulin secretion is too low and glucagon secretion too high, elevated plasma glucose levels occur. Therefore, optimal therapeutic interventions aim to both enhance insulin secretion and inhibit glucagon release. The incretin hormone glucagon-like peptide 1 (GLP-1) possesses this capacity but the underlying mechanisms by which it suppresses glucagon release are unclear as glucagon-secreting α-cells express the receptor for GLP-1 at very low levels. Nevertheless, GLP-1 inhibit glucagon secretion by a direct (intrinsic) action in α-cells. Here, we examined the underlying mechanisms. We found that GLP-1 inhibits glucagon secretion at concentrations as low as 1-10 pM in isolated mouse and human islets. The degradation product GLP-1(9-36) inhibited glucagon secretion with similar potency. Whereas the effect of GLP-1 was sensitive to the PKA inhibitor 8-Br-Rp-cAMPS, GLP-1(9-36) exerted its effect by a PKA-independent mechanism that was sensitive to pretreatment with pertussis toxin (implicating an inhibitory GTP-binding protein). The glucagonostatic effect of GLP-1 was retained in islets from Glp1r knockout mice. Receptor signaling studies suggest that GLP-1(9-36) may activate glucagon receptors (GCGRs) and GCGR antagonism prevented the inhibitory effects of GLP-1(9-36). In vivo, GLP-1(9-36) reduced counter-regulatory glucagon secretion and enhanced the plasma glucose-lowering effect of exogenous insulin in mice fasted for 5-18h. We propose that GLP-1(7-36) and GLP-1(9-36) regulate glucagon secretion via interaction with both GLP-1R and GCGR.