The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion.
OBJECTIVE
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 (betaSOCS2) 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 Ca(2+) stores, suggesting that SOCS2 interferes with calcium fluxes. Finally, in betaSOCS2 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
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.
Lebrun
P
P
INSERM U907, Avenue de Valombrose, Nice, France. plebrun@unice.fr
Cognard
E
E
Gontard
P
P
Bellon-Paul
R
R
Filloux
C
C
Berthault
M F
MF
Magnan
C
C
Ruberte
J
J
Luppo
M
M
Pujol
A
A
Pachera
N
N
Herchuelz
A
A
Bosch
F
F
Van Obberghen
E
E
D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*
D007328:Insulin; C491409:Socs2 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins