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.

doi:10.1101/785667

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bioRxiv · 10.1101/785667

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

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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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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.. 2019-09-30. Promiscuous receptor activation mediates glucagonostatic effects of GLP-1(9-36) and GLP-1(7-36). https://doi.org/10.1101/785667

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