The Potential Role of SOCS-3 in the Interleukin-1β-Induced Desensitization of Insulin Signaling in Pancreatic Beta-Cells

Abstract

Defects in insulin secretion, resulting from loss of function or destruction of pancreatic ␤-cells, trigger diabetes. Interleukin (IL)-1␤ is a proinflammatory cytokine that is involved in type 1 and type 2 diabetes development and impairs ␤-cell survival and function. Because effective insulin signaling is required for the optimal ␤-cell function, we assessed the effect of IL-1␤ on the insulin pathway in a rat pancreatic ␤-cell line. We show that IL-1␤ decreases insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS) proteins as well as phosphatidylinositol 3-kinase (PI3K) activation, and that this action is not due to the IL-1␤-dependent nitric oxide (NO) production in RINm5F cells. We next analyzed if suppressor of cytokine signaling (SOCS)-3, which can be induced by multiple cytokines and which we identified as an insulin action inhibitor, was implicated in the IL-1␤ inhibitory effect on insulin signaling in these cells. We show that IL-1␤ increases SOCS-3 expression and induces SOCS-3/IR complex formation in RINm5F cells. Moreover, we find that ectopically expressed SOCS-3 associates with the IR and reduces insulin-dependent IR autophosphorylation and IRS/PI3K pathway in a way comparable to IL-1␤ treatment in RINm5F cells. We propose that IL-1␤ decreases insulin action in ␤-cells through the induction of SOCS-3 expression, and that this effect potentially alters insulin-induced ␤-cell survival. Diabetes 53 (Suppl. 3)

Long-term treatment with interleukin-1β induces insulin resistance in murine and human adipocytes

“…Indeed, long-term treatment with IL1B during the differentiation programme (3T3-F442A cells for 8 days) or after completion of adipogenesis (3T3-L1 cells and human adipocytes for 6 days) induced cellular insulin resistance. IL1B acted at the early steps of insulin signalling by affecting the tyrosine phosphorylation of IRβ and its major substrate IRS-1 in all cell lines, in keeping with a recent study performed on a rat pancreatic cell line [38]. Moreover, insulin failed to activate Akt/PKB and ERK1/2, which is consistent with its negative effect on insulininduced glucose transport and lipogenesis.…”

Differentially Expressed MicroRNA-483 Confers Distinct Functions in Pancreatic β- and α-Cells

“…SOCS3 belongs to the SOCS family of inhibitory proteins, which can interfere with insulin signaling in muscle, liver, and adipose tissue by inhibition of tyrosine phosphorylation of IRS2 (56). In pancreatic ␤-cells, SOCS3 is induced by various cytokines and complexes with insulin receptor, leading to reduced insulin receptor autophosphorylation and impaired signaling through the IRS2/PI3K pathway (52). In addition, in the transgenic mice with ␤-cell-specific overexpression of SOCS3, SOCS3 inhibits pre-insulin transcription and ␤-cell proliferation through the JAK/STAT signaling pathway (48,49).…”

The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

“…Among the different SOCS, SOCS3 has been the most intensively studied in pancreatic islets. Recent data from our laboratory demonstrate that in pancreatic beta cells SOCS3, induced by cytokines, interacts with the insulin receptor, inhibiting the recruitment of IRS proteins and hence downstream signals [14]. Several studies from Billestrup et al reported that SOCS3 constitutively produced in beta cells reduces cytokine [15,16] and GH [9,17] signals in these cells.…”