Mechanisms of mitogenic and anti-apoptotic signaling by glucose-dependent insulinotropic polypeptide in beta(INS-1)-cells

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) acts as a glucose-dependent growth factor for -cells. Here we show that GIP and glucose also act synergistically as anti-apoptotic factors for -cells, using the welldifferentiated -cell line, INS-1. Mitogenic and anti-apoptotic signaling of GIP were dependent upon pleiotropic activation of protein kinase A (PKA)/cAMP regulatory element binder (CREB), mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-kinase)/PKB signaling modules. The signaling modules activated by GIP were dependent on glucose metabolism and calcium influx and were tightly linked by multiple activating and inhibiting cross-talk. These interactions included: (i) a central role of tyrosine phosphorylation for stimulation of PKA/CREB, MAPK and PI3-kinase/PKB, (ii) inhibition of PKA/CREB by the MAPK pathway at the level of MAPK kinase-1 or downstream, (iii) activation of MAPK signaling by PI3-kinase and PKA at the level of extracellular-signal regulated kinase 1/2 or upstream, and (iv) activation of PKB by MAPK and PKA signaling at the level of PKB or upstream. Furthermore, we demonstrated inhibition of CREB signaling by Ca 2+ / calmodulin kinase I/IV. These results indicated that GIP acts as a mitogenic and anti-apoptotic factor for -cells by pleiotropic activation of tightly linked signaling pathways in -cells.

Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells

“…These findings differ slightly from another study [40], in which basal but not GIP-stimulated proliferation was inhibited by genistein. In marked contrast to this and our present study, it has also recently been reported that the proliferative effects of GLP-1 are mediated through transactivation of the epidermal growth factor receptor tyrosine kinase in the INS-1(832/13) subclone of INS-1 cells [33].…”

“…These findings could be of clinical significance, as GLP-1 is currently in clinical trials for the treatment of hyperglycaemia in patients with Type 2 diabetes. tosis in INS-1 cells, in association with activation of PKBα, PKBβ and MAPK [37,40,43]. However, unlike the responses to GLP-1, wortmannin does not prevent GIP-induced beta-cell growth or survival [40].…”

“…tosis in INS-1 cells, in association with activation of PKBα, PKBβ and MAPK [37,40,43]. However, unlike the responses to GLP-1, wortmannin does not prevent GIP-induced beta-cell growth or survival [40]. Similarly, GLP-1 treatment prevents chemically-induced apoptosis in association with enhanced total PKB levels in baby hamster kidney fibroblasts transfected with the GLP-1 receptor [19].…”

“…Furthermore, studies on beta cell proliferative response to IGF-1 have indicated that there is a balance between these pathways in INS-1 cells, such that overexpression of PKBα can lead to down-regulation of MAPK [29]. Similar studies on the beta cell response to another growth factor, glucose-dependent insulinotropic peptide (GIP), have also indicated that these pathways are linked in INS-1 cells [37,40]. The present findings suggest that MAPK and protein kinase C-ζ could act downstream of PKB in INS-1 cells, as PKB seems to be both necessary and sufficient to modulate the actions of GLP-1 on beta-cell growth and survival.…”

Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

“…GIP and GLP-1 exert these effects through binding to specific beta cell receptors, activating adenylate cyclase and other signal recognition pathways, leading to insulin exocytosis [3]. GIP and GLP-1 have also been reported to stimulate beta cell neogenesis, differentiation and proliferation whilst affording protection from cytokine attack and apoptosis [4][5][6]. These various attributes, plus reports of GLP-1-stimulated decreases of gastric emptying, glucagon secretion and appetite [7], have focused much attention on the potential of incretin hormones for the treatment of type 2 diabetes [8,9].…”