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Diabetes and Suppressors of Cytokine Signaling Proteins

¹ Steno Diabetes Center, Gentofte, Denmark
² Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden

Address correspondence and reprint requests to Nils Billestrup, Steno Diabetes Center, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark. E-mail: nbil@steno.dk

Abbreviations: CIS, cytokine-inducible SH2-containing protein; IL, interleukin; IFN, interferon; IRS, insulin receptor substrate; JAK, Janus kinase; MAP, mitogen-activated protein; NF-B, nuclear factor-B; SOCS, suppressors of cytokine signaling; STAT, signal transducers and activators of transcription; TAK-1 kinase, transforming growth factor-ß–activated kinase; TNF, tumor necrosis factor

The first 300 words of the full text of this article appear below.

The pathogenesis of type 1 diabetes is not clearly understood, but it is generally accepted that type 1 diabetes is an immune-mediated disease caused by inflammation in the islets of Langerhans. Infiltrating macrophages release proinflammatory cytokines such as interleukin (IL)-1ß and tumor necrosis factor (TNF)-, which are toxic to the ß-cell. Activated T-cells also produce proinflammatory cytokines such as TNF- and interferon (IFN)- and express the apoptosis-inducing protein FasL. Moreover, CD8⁺ T-cells induce cell death via the perforin-granzyme pathway. The net effect of these different factors results in specific destruction of the insulin-producing ß-cells (1). Type 2 diabetes occurs when ß-cell secretory capacity fails to compensate for insulin resistance. In type 2 diabetes, cytokines are known to be involved in insulin and leptin resistance (2,3), and cytokines have also been suggested to contribute to ß-cell failure of type 2 diabetes (4).

In this review we focus on a group of proteins, the suppressors of cytokine signaling (SOCS), which affect cytokine signaling and appear to play an important role in the pathological processes leading to both type 1 and type 2 diabetes.

	SOCS PROTEINS

 
The SOCS proteins were identified in 1997 and were characterized as a family of proteins capable of inhibiting Janus kinase (JAK)–signal transducers and activators of transcription (STAT) (JAK-STAT) signaling in various tissues (5–7). Eight members of the SOCS family have been identified, SOCS-1–7 and cytokine-inducible SH2-containing protein (CIS) (8). They all contain a conserved COOH-terminal region of 40 amino acids termed the SOCS box (Fig. 1) (5). They have a central SH2 domain, while the NH₂-terminal region is of variable length with no recognizable motif (8). A kinase inhibitory region (KIR) consisting of 12 amino acids is . . . [Full Text of this Article]

	SOCS PROTEINS AND INFLAMMATION

 

	SOCS AND INSULIN RESISTANCE

 

	SOCS AND LEPTIN RESISTANCE

 

	CONCLUSION AND PERSPECTIVES

 

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