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¹ Department of Signal Transduction,
² Department of Pharmacology, Novo Nordisk A/S, Bagsværd, Denmark
³ Steno Diabetes Center, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark
⁴ Institute of Medical Biochemistry and Genetics, Panum Institute, University of Copenhagen, Denmark

(Requests for offprints should be addressed to N Billestrup at Steno Diabetes Center, Gentofte, Denmark; Email: nbil{at}steno.dk)

(Present address of J Rømer is: Finsen Laboratory, Rigshospitalet, Denmark)

^* (K Lindberg and S G Ronn contributed equally to this paper)

Growth hormone and prolactin are important growth factors for pancreatic ß-cells. The effects exerted by these hormones on proliferation and on insulin synthesis and secretion in ß-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 ß-cells we generated transgenic mice with ß-cell-specific overexpression of SOCS-3. The relative ß-cell proliferation and volume in the mice were measured by morphometry. ß-Cell volume of transgenic female mice was reduced by over 30% compared with ß-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 ß-cell volume observed in female transgenic mice could be caused by an inhibition of GH-induced ß-cell proliferation by SOCS-3. In spite of the reduced ß-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 ß-cells and therefore potentially could be a candidate target for development of new treatment strategies for diabetes.

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