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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 (Drucker et al., 1987); this leads to activation of both PKA (Wang et al., 2001) and EPAC (Holz, 2004). 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 (Harndahl et al., 2004). PKA anchoring proteins (AKAPs) influence the specificity of cAMP response by anchoring the PKA to specific intracellular sites (Lester et al., 1997). Shown here also is the Ca2+/calmodulin binding protein IQGAP1 which co-immunoprecipitates with PKA and AKAP79 (Nauert et al., 2003). 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 (Dyachok et al., 2006; Gao et al., 2002) where it regulates PDX-1 (Wang et al., 2001) and CREB activation and subsequently insulin transcription (Chepurny et al., 2002; Hay et al., 2005; Kemp and Habener, 2001). 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 (Kemp and Habener, 2001; Montrose-Rafizadeh et al., 1999) 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 (Arnette et al., 2003; Gomez et al., 2002). The effect of PKA on CREB mediated induction of the IRS2 gene is shown, this is a prolonged effect of GLP-1R activation (Jhala et al., 2003). Acutely PI3 kinase is also stimulated by transactivation of the EGF receptor by cSrc-activated betacellulin (BTC; Buteau et al., 2003). 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 (Buteau et al., 2001; Wang and Brubaker, 2002). FoxO1 is regulated by phosphorylation by PKB which results in its exclusion from the nucleus thus permitting the nuclear translocation of PDX-1 (Buteau et al., 2006). 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 (Kwon et al., 2004a). 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 (Knoch et al., 2006). Mechanisms that have not been clearly demonstrated are shown by broken arrows.
Simplified schema of the human (A) and rat I (B) insulin promoters. The elements known to be regulated downstream of GLP-1R activation are shown in blue. There are four CRE sites in the insulin gene two upstream (CRE1 and CRE2) and two downstream (CRE3 and CRE4) of the transcription start site. With the exception of the first one (CRE1) all were shown to be induced when constructs containing fragments representing the individual sites were transfected into INS-1 cells (Hay et al., 2005). It is probable that the close proximity of the CRE1 site to the A3 element to which PDX-1 binds actively prohibits complex formation at this CRE site. All of the NFAT sites studied in the rat I insulin promoter are responsive to the combination of glucose and GLP-1, although NFAT2 was relatively insensitive to GLP-1 alone (Lawrence et al., 2002)
Schema outlining the signaling mechanisms reported to be involved in GLP-1R-induced differentiation/neogenesis of pancreatic precursor cells, proliferation and in the prevention of apoptosis. Dashed lines indicate mechanisms that are either not fully delineated or in the case of the cAMP activation of the MEK pathway are complex and are shown completely in Fig 2. The mechanism shown for involvement of BMP and TGFβ signaling pathways in differentiation is after Gittes and co-workers (Yew et al., 2005; Yew et al., 2004). PKB is shown as inhibiting FoxO1 (by phosphorylation). When FoxO1 is in its active and unphosphorylated state it inhibits the transcription of PDX-1 and its translocation to the nucleus (Kitamura et al., 2002).
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