Mechanisms of Action of GLP-1 in the Pancreas

A schematic drawing outlining the main signaling pathways activated in response to ligand engagement with the GLP-1R and their major downstream effects on acute insulin secretion, insulin synthesis, preservation of β cell function and mass and regulation of proliferation. Pathways are glucose dependent hence the inclusion of glucose metabolism. GLP-1/Ex-4 bind to GLP-1R causing an increase in cAMP (); this leads to activation of both PKA () and EPAC (). Localized low concentrations of cAMP lead to preferential activation of PKA. Higher cell-wide increases of cAMP by the AC stimulator forskolin (FSK) or the phosphodiesterase (PDE) inhibitor IBMX favor the EPAC pathway. cAMP is compartmentalized by PDEs most notably the PDE3B isoform as shown (). PKA anchoring proteins (AKAPs) influence the specificity of cAMP response by anchoring the PKA to specific intracellular sites (). Shown here also is the Ca2+/calmodulin binding protein IQGAP1 which co-immunoprecipitates with PKA and AKAP79 (). cAMP levels are increased as a consequence of ATP activation of AC consequent upon glucose metabolism. Binding of cAMP to the regulatory units of PKA results in release of the catalytic units from PKA and its activation. Sustained oscillatory increases in cAMP by GLP-1R activation lead to translocation of PKA to the nucleus (; ) where it regulates PDX-1 () and CREB activation and subsequently insulin transcription (; ; ). Downstream targets of PKA and Epac in acute insulin secretion, include the KATP and Kv channels, the insulin secretory vesicles and the IP3 Ca2+ channels on the endoplasmic reticulum (ER). P38 MAPK, although activated by GLP-1R agonists (; ) is not included as the exact mechanism of activation has not been described. Activation of the MEK/ERK pathway is coordinated through both the Epac moieties and the Ca2+/calmodulin kinases (; ). The effect of PKA on CREB mediated induction of the IRS2 gene is shown, this is a prolonged effect of GLP-1R activation (). Acutely PI3 kinase is also stimulated by transactivation of the EGF receptor by cSrc-activated betacellulin (BTC; ). Downstream of PI3 kinase are PKB and PKCζ both of which are implicated in β cell proliferation and PKB in prevention of β cell death (; ). FoxO1 is regulated by phosphorylation by PKB which results in its exclusion from the nucleus thus permitting the nuclear translocation of PDX-1 (). Finally enhanced ATP production due to increased mobilization of Ca2+ which in turn upregulate mitochondrial dehydrogenases leads to upregulation of mTOR activity and its downstream effector S6K1 (). mTOR is implicated in increased β cell mitosis and may also be activated by PKB. GLP-1R activation also leads to stabilization of the insulin transcript by stimulating nucleocytoplasmic translocation of polypyrimidine tract binding protein (PTB) which binds to the U-rich polypyrimidine tract of insulin and insulin secretory vesicle mRNA transcripts thereby stabilizing them (). Mechanisms that have not been clearly demonstrated are shown by broken arrows.

Publication

Mechanisms of Action of GLP-1 in the Pancreas. () Máire E. Doyle, et al. Pharmacol Ther. ;113(3):546-593. Figure: F2. All organisms Drosophila melanogaster Homo sapiens

Disease mentions