GH Signalling in Pancreatic β-Cells

Abstract

Abstract. GH and its related peptide PRL are known to stimulate proliferation and insulin biosynthesis in pancreatic fl-cells, and assumed to be involved in their functional maturation. We investigated signal transduction of GH and PRL in insulin-secreting cells using the differentiated rat insulinoma cell line, INS-1. In these cells, both hormones stimulated proliferation and DNA synthesis, increased viability, cellular metabolism and insulin content. GH induced cytosolic Ca2+ ([Ca2+];) rises, which appear to be due to Ca2+-influx through voltage-gated Ca2+-channels. GH also promoted tyrosine phosphorylation of several proteins in INS-1 cells, one of which was identified as JAK2 tyrosine kinase. Moreover, GH caused changes in DNA binding of nuclear proteins to some interferon-'y-activated sites. Verapamil inhibited neither DNA synthesis nor JAK2 phosphorylation stimulated by GH, whereas a tyrosine kinase inhibitor, lavendustin A, blocked the mitogenic effect. Involvement of cAMP is also suggested because Rp-cAMPS, a competitive inhibitor of protein kinase A, abolished both [Ca2+]; rises and DNA synthesis stimulated by GH. The effects of GH and PRL on [Ca2+];, JAK2 phosphorylation and DNA binding of the STATs were virtually identical in INS-1 cells. Since both hormones failed to activate MAP kinase in these cells, it is strongly suggested that activation of the JAK-STAT pathway is the major signalling event for the mitogenic effects of GH and PRL in /3-cells. It remains to be clarified whether the [Ca2+]; rise mediates other effects of these hormones.

Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate beta cell apoptosis signalling via dependence receptors

“…A novel isoform of the anti-apoptotic hormone gastric inhibitory polypeptide is also produced in islets [8,9]. Growth hormone, prolactin or placental lactogens can promote beta cell survival [10,11]. Similarly, overexpression of classical growth factors such as hepatocyte growth factor and fibroblast growth factor has been shown to exert positive effects on islets [12,13], as has parathyroid hormone-related protein [14].…”

Fetal pancreatic islets express functional leptin receptors and leptin stimulates proliferation of fetal islet cells

“…25 Activation of this pathway is an important mechanism of signalling for proliferation of b-cells and is utilized by ligands like growth hormone and prolactin. 26,27 OB-Rb also mediates expression of the immediate-early gene c-fos which is often used as a criterion for functional leptin signaling. 16,28,30 c-fos is required for cell-cycle progression and is targeted by activated STAT-3, which results in induction of the protein.…”

IGF-I and GH post-receptor signaling mechanisms for pancreatic beta-cell replication

“…GH binds to the GH receptor causing dimerization, and then recruitment, tyrosine phosphorylation and activation of the tyrosine kinase, JAK2. JAK2 then phosphorylates STAT5 within a transient GH receptor/JAK2/ STAT5 signaling complex from which phosphorylated STAT5 is released for migration to the nucleus where it affects gene transcription contributing to mitogenesis (Carter-Su & Smit 1998, Sekine et al 1998.…”

“…It has been previously suggested that GH mediates increases in -cell proliferation via local IGF-I production (Swenne et al 1987). However, this is now considered unlikely, as GH predominantly induces -cell proliferation via a JAK2/STAT5 signal transduction pathway (Argetsinger & Carter-Su 1996, Sekine et al 1998, Cousin et al 1999. Interestingly, as with IGF-I, GH-induced -cell proliferation is also glucose dependent (Cousin et al 1999).…”

“…Interestingly, as with IGF-I, GH-induced -cell proliferation is also glucose dependent (Cousin et al 1999). Glucose has no independent effect on JAK2/STAT5 activation, and it is as yet unclear how glucose provides a means to permit GH action, although it has been suggested that Ca 2+ is a possible mediator (Sekine et al 1998, Cousin et al 1999. PI3 K activity, likely provided by glucose-induced activation, also appears to be required for GH to promote a -cell proliferative response (Cousin et al 1999).…”