1. The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion
- Author
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C. Filloux, André Herchuelz, P. Lebrun, Fatima Bosch, P. Gontard, MF Berthault, Emmanuelle Cognard, Jesús Ruberte, Christophe Magnan, E Van Obberghen, Mariana Luppo, Nathalie Pachera, Anna Pujol, R. Bellon-Paul, Lebrun, P, Cognard, E, Gontard, P, Bellon-Paul, R, Filloux, C, Berthault, MF, Magnan, C, Ruberte, J, Luppo, M, Pujol, A, Pachera, N, Herchuelz, A, Bosch, F, and Van Obberghen, E
- Subjects
medicine.medical_specialty ,insulin secretion ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Blotting, Western ,Suppressor of Cytokine Signaling Proteins ,Biology ,transgenic mice ,Endoplasmic Reticulum ,Suppressor of cytokine signalling ,Islets of Langerhans ,Mice ,Internal medicine ,Insulin Secretion ,Calcium flux ,Internal Medicine ,medicine ,Animals ,Insulin ,SOCS3 ,SOCS2 ,Proinsulin ,Reverse Transcriptase Polymerase Chain Reaction ,Suppressor of cytokine signaling 1 ,Body Weight ,SOCS ,Rats ,Mice, Inbred C57BL ,Phenotype ,Endocrinology ,glucose intolerance ,pancreatic beta cell ,Electrophoresis, Polyacrylamide Gel ,proinsulin maturation ,Beta cell - Abstract
Aims/hypothesis: Suppressor of cytokine signalling (SOCS) proteins are powerful inhibitors of pathways involved in survival and function of pancreatic beta cells. Whereas SOCS1 and SOCS3 have been involved in immune and inflammatory processes, respectively, in beta cells, nothing is known about SOCS2 implication in the pancreas. Methods: Transgenic (tg) mice were generated that constitutively produced SOCS2 in beta cells (βSOCS2) to define whether this protein is implicated in beta cell functioning and/or survival. Results: Constitutive production of SOCS2 in beta cells leads to hyperglycaemia and glucose intolerance. This phenotype is not a consequence of decreased beta cell mass or inhibition of insulin synthesis. However, insulin secretion to various secretagogues is profoundly altered in intact animals and isolated islets. Interestingly, constitutive SOCS2 production dampens the rise in cytosolic free calcium concentration induced by glucose, while glucose metabolism is unchanged. Moreover, tg islets have a depletion in endoplasmic reticulum Ca2+ stores, suggesting that SOCS2 interferes with calcium fluxes. Finally, in βSOCS2 mice proinsulin maturation is impaired, leading to an altered structure of insulin secretory granules and augmented levels of proinsulin. The latter is likely to be due to decreased production of prohormone convertase 1 (PC1/3), which plays a key role in proinsulin cleavage. Conclusions/ Interpretations: SOCS2 was shown to be a potent regulator of proinsulin processing and insulin secretion in beta cells. While its constitutive production is insufficient to induce overt diabetes in this mouse model, it causes glucose intolerance. Thus, increased SOCS2 production could be an important event predisposing to beta cell failure. Refereed/Peer-reviewed
- Published
- 2010