Regulation of pancreatic β-cell mass and proliferation by SOCS-3

Abstract

Growth hormone and prolactin are important growth factors for pancreatic -cells. The effects exerted by these hormones on proliferation and on insulin synthesis and secretion in -cells are largely mediated through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Suppressors of cytokine signaling (SOCS) proteins are specific inhibitors of the JAK/STAT pathway acting through a negative-feedback loop. To investigate in vivo effects of SOCS-3 in growth hormone (GH)/prolactin signaling in -cells we generated transgenic mice with -cell-specific overexpression of SOCS-3. The relative -cell proliferation and volume in the mice were measured by morphometry. -Cell volume of transgenic female mice was reduced by over 30% compared with -cell volume in wild-type female mice. Stimulation of transgenic islets in vitro with GH showed a reduced tyrosine phosphorylation of STAT-5 when compared with wild-type islets. Transduction of primary islet cultures with adenoviruses expressing various SOCS proteins followed by stimulation with GH or glucagon-like peptide-1 (GLP-1) revealed that SOCS-3 inhibited GH-but not GLP-1-mediated islet cell proliferation, indicating that the decreased -cell volume observed in female transgenic mice could be caused by an inhibition of GH-induced -cell proliferation by SOCS-3. In spite of the reduced -cell volume the transgenic female mice exhibited enhanced glucose tolerance compared with wild-type littermates following an oral glucose-tolerance test. Together these data suggest that SOCS-3 modulates cytokine signaling in pancreatic -cells and therefore potentially could be a candidate target for development of new treatment strategies for diabetes.

Suppressor of cytokine signalling-3 expression inhibits cytokine-mediated destruction of primary mouse and rat pancreatic islets and delays allograft rejection

“…Expression of Socs3 in islets from wild-type and Socs3 transgenic mice has been described previously [24]. The pattern of expression is heterogeneous among beta cells in islets from SOCS3 transgenic mice, both at the mRNA and protein levels.…”

“…Generation of the transgenic RIP-Socs3 mice on the C57Bl/6J background has been described elsewhere [24]. BALB/c mice were purchased from B&K, Sollentuna, Sweden.…”

“…trypsin and 10 mmol/l EDTA in 1× Hanks' (Invitrogen). They were then seeded in 9 cm 2 culture flasks (NUNC, Roskilde, Denmark) and allowed to form monolayers as described [24]. The virus titre used was found by transduction of islet cells with a green fluorescent protein (GFP)-encoding adenovirus and using a concentration giving >95% GFP-positive cells.…”

Constitutive expression of suppressor of cytokine signalling-3 in skeletal muscle leads to reduced mobility and overweight in mice

“…However, it is still not clear whether increased SOCS-3 levels in vivo are a cause or rather a consequence of insulin resistance. In addition, SOCS-3 appears to affect signalling pathways differently depending on the tissue in which its production is increased [10,12].…”

“…However, using transgenic mice constitutively producing SOCS-3 in adipose tissue, it has been shown that SOCS-3 decreases insulin signalling in adipose tissue, but this is insufficient to induce organismal hormone resistance [11]. Finally, a study of transgenic mice producing high levels of SOCS-3 in pancreatic beta cells suggests a role of SOCS-3 in controlling growth hormone and cytokine pathways in vivo [12,13]. While collectively these data suggest that SOCS-3 profoundly affects cell physiology, the signalling pathways modulated by SOCS-3 appear to vary from one tissue to another.…”