Promiscuous receptor activation mediates glucagonostatic effects of GLP-1(9-36) and GLP-1(7-36)
Guida, C.; Miranda, C.; Wernstedt Asterholm, I.; Basco, D.; Benrick, A.; Chanclon, B.; Chibalina, M.; Harris, M.; Kellard, J.; McCulloch, L.; Real, J.; Rorsman, N.; Svendsen, B.; Yeung, H. Y.; Holst, J. J.; Reimann, F.; Shigeto, M.; Clark, A.; Thorens, B.; Rorsman, P.; Ladds, G.; Ramracheya, R.
Show abstract
The incretin hormone glucagon-like peptide 1(7-36) (GLP-1(7-36)) stimulates insulin and inhibits glucagon secretion. The mechanisms by which GLP-1 suppresses glucagon release are unclear as glucagon-secreting -cells express GLP-1 receptors (GLP-1Rs) at very low levels. Here, we examine the underlying mechanisms. We find that both GLP-1(7-36) and its degradation product GLP-1(9-36) inhibit glucagon secretion at physiological (pM) concentrations. Whereas the effect of GLP-1(7-36) is sensitive to PKA inhibition, GLP-1(9-36) exerts its effect by a PKA-independent mechanism sensitive to pretreatment with pertussis. The glucagonostatic effects of both GLP-1(7-36) and (9-36) are retained in islets from Glp1r knockout mice but only GLP-1(9-36) remains glucagonostatic in the presence of the DPP-4 (the peptidase catalyzing the formation of GLP-1(9-36)) inhibitor sitagliptin. Glucagon receptor (GCGR) antagonism specifically prevents the inhibitory effects of GLP-1(9-36) whilst not affecting that of GLP-1(7-36). We conclude that GLP-1(7-36) and GLP-1(9-36) regulate glucagon secretion via interaction with GLP-1R and GCGR, respectively. HighlightsO_LIGLP-1(7-36) and GLP-1(9-36) inhibit glucagon secretion from alpha-cells C_LIO_LIGLP-1(7-36) and (9-36) retain glucagonostatic effect in Glp1r-/- islets C_LIO_LIGLP-1(7-36) and (9-36) activate distinct signal transduction mechanisms C_LIO_LIGLP-1(7-36) acts via GLP-1R and GLP-1(9-36) via GCGR C_LI
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