GLP-1(9-36) mediates the glucagonostatic effect of GLP-1 by promiscuous activation of the glucagon receptor

Abstract

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.

Proglucagon-Derived Peptides as Therapeutics

“…Additionally, a recent study suggests that GLP-1(9-36)-amide may indirectly influence glycaemia through antagonism of GCGR on alpha-cells to influence the glucagonostatic effects of GLP-1 (91). However, the implications of any GLP-1(9-36) effects on glycaemia are thought to be relatively inconsequential in comparison to GLP-1(7-36)-amide (92).…”

Revisiting the Complexity of GLP-1 Action from Sites of Synthesis to Receptor Activation

“…Another explanation for the actions of GLP-1 on -cells could be through GLP-1 degradation products. Several reports suggest that GLP-1(7-36) and GLP-1(9-36) are glucagonostatic in wild-type and Glp1r -/islets (67). Effects of GLP-1(7-36) but not GLP-1(9-36) were abolished by pre-treatment with a DPP-4 inhibitor, suggesting that GLP-1(7-36) is pro-peptide for GLP-1 in this setting (67).…”

Evidence for the existence and potential roles of intra-islet glucagon-like peptide-1

“…12,[92][93][94] Similarly, the GCGR can bind and interact with both GLP-1 and glucagon, although GLP-1's precise signaling pathway via this receptor is not well-characterized. 95 While glucagon's actions at the GLP-1R in vivo have noteworthy effects on glycemic control, the effect of GLP-1 at the GCGR may be less significant in vivo due to its lower affinity at this receptor compared to the GLP-1R. 57 This aspect of GLP-1R pharmacology has significant implications regarding the biological function of proglucagon-derived peptides, as all of these peptide-ligands are present within the localized islet environment.…”

“…Unlike the glucagonostatic effects of GLP-1(7–36), GLP-1(9–36) does not require PKA signaling to inhibit glucagon release. 95 The dipeptide fragment released from the N-terminal of GLP-1(7–36) breakdown can potentiate glucagon secretion. This effect is dose-dependent, although the receptor and mechanism of action have not yet been identified.…”