Regulation of pancreatic beta-cell mass and proliferation by SOCS-3
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Regulation of pancreatic beta-cell mass and proliferation by SOCS-3. / Lindberg, K; Rønn, S G; Tornehave, D; Richter, H; Hansen, J A; Rømer, J; Jackerott, M; Billestrup, Nils.
I: Journal of Molecular Endocrinology, Bind 35, Nr. 2, 10.2005, s. 231-43.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Regulation of pancreatic beta-cell mass and proliferation by SOCS-3
AU - Lindberg, K
AU - Rønn, S G
AU - Tornehave, D
AU - Richter, H
AU - Hansen, J A
AU - Rømer, J
AU - Jackerott, M
AU - Billestrup, Nils
PY - 2005/10
Y1 - 2005/10
N2 - Growth hormone and prolactin are important growth factors for pancreatic beta-cells. The effects exerted by these hormones on proliferation and on insulin synthesis and secretion in beta-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 beta-cells we generated transgenic mice with beta-cell-specific overexpression of SOCS-3. The relative beta-cell proliferation and volume in the mice were measured by morphometry. Beta-cell volume of transgenic female mice was reduced by over 30% compared with beta-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 beta-cell volume observed in female transgenic mice could be caused by an inhibition of GH-induced beta-cell proliferation by SOCS-3. In spite of the reduced beta-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 beta-cells and therefore potentially could be a candidate target for development of new treatment strategies for diabetes.
AB - Growth hormone and prolactin are important growth factors for pancreatic beta-cells. The effects exerted by these hormones on proliferation and on insulin synthesis and secretion in beta-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 beta-cells we generated transgenic mice with beta-cell-specific overexpression of SOCS-3. The relative beta-cell proliferation and volume in the mice were measured by morphometry. Beta-cell volume of transgenic female mice was reduced by over 30% compared with beta-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 beta-cell volume observed in female transgenic mice could be caused by an inhibition of GH-induced beta-cell proliferation by SOCS-3. In spite of the reduced beta-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 beta-cells and therefore potentially could be a candidate target for development of new treatment strategies for diabetes.
KW - Animals
KW - Blood Glucose
KW - Body Weight
KW - Cell Proliferation
KW - Female
KW - Glucagon-Like Peptide 1
KW - Glucose Tolerance Test
KW - Growth Hormone
KW - In Situ Hybridization
KW - Insulin
KW - Insulin-Secreting Cells
KW - Janus Kinase 1
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Inbred DBA
KW - Mice, Transgenic
KW - Protein-Tyrosine Kinases
KW - Random Allocation
KW - Rats
KW - STAT5 Transcription Factor
KW - Signal Transduction
KW - Suppressor of Cytokine Signaling Proteins
KW - Transgenes
U2 - 10.1677/jme.1.01840
DO - 10.1677/jme.1.01840
M3 - Journal article
C2 - 16216905
VL - 35
SP - 231
EP - 243
JO - Journal of Molecular Endocrinology
JF - Journal of Molecular Endocrinology
SN - 0952-5041
IS - 2
ER -
ID: 132899726