SOCS and diabetes—ups and downs of a turbulent relationship

Abstract

Diabetes mellitus is one of the most emerging diseases threatening the present world. Thus, intensive investigations are carried out to better understand the mechanisms occurring in type 1 (T1D) and 2 (T2D) diabetes, and to elaborate more potent methods to fight the disease. In this aspect, the suppressors of cytokine signalling (SOCS) are one of the most studied factors of recent years. SOCS proteins have been discovered as cytokine pathway inhibitors; however, presently, their influence seems wider. Most of the known SOCS proteins are involved in the modulation of the development of insulin resistance, β-cell failure and eventually T1D and T2D. They are also involved in complications related with diabetes, such as retinopathy, nephropathy and cardiomyopathy. In T1D, SOCS proteins regulate β-cell mass, mediate resistance to damaging factors and improve pancreatic islet graft survival. Regarding insulin resistance and T2D, SOCS proteins take part in mediating signals produced by diabetogenic substances and regulate insulin receptor functioning, affecting insulin sensitivity. However, not all of the present data are consistent, and thus, further studies are required. Finally, for several pharmacologically active substances of importance regarding the treatment of diabetes, SOCS-modulating properties have already been described. Here, we review the findings of SOCS-diabetes relations of the last decade.

Suppressor of Cytokine Signaling 1–Derived Peptide Inhibits Janus Kinase/Signal Transducers and Activators of Transcription Pathway and Improves Inflammation and Atherosclerosis in Diabetic Mice

“…Several studies have reported intriguing properties of SOCS proteins in relation to the pathogenesis of diabetes mellitus. 21,22,24 In fact, SOCS1 knockout mice exhibit a low blood glucose level and increased insulin signaling, 21,35 thus suggesting SOCS as a link between elevated levels of cytokines and insulin resistance. However, SOCS1 induction protects β-cells in vitro, 36 with target expression of SOCS1 preventing diabetes mellitus in the nonobese diabetic mouse.…”

“…8,[17][18][19] JAK/STAT is also a critical inflammatory mechanism by which hyperglycemia contribute to the pathogenesis of diabetes mellitus and its complications. [20][21][22] In fact, classical STATresponsive inflammatory genes comprise a wide array of genes including cytokines, chemokines, enzymes, vasoactive proteins, and proto-oncogenes, 7,9,10 many of them also upregulated by diabetic conditions.…”

Resveratrol prevents hepatic steatosis and endoplasmic reticulum stress and regulates the expression of genes involved in lipid metabolism, insulin resistance, and inflammation in rats

“…Increased by cytokine signaling, SOCS-3 is considered to be a key link between inflammation and insulin resistance. It has been demonstrated that SOCS-3 is able to inhibit the insulin signal pathway; SOCS-3 overexpression in the liver leads to insulin resistance and hepatic steatosis [36]. Inhibition of SOCS-3 in the livers of db/db mice by antisense treatment improved insulin sensitivity and led to the dramatic amelioration of hepatic steatosis and hypertriglyceridemia [37].…”

Protective effects of SOCS3 overexpression in high glucose-induced lung epithelial cell injury through the JAK2/STAT3 pathway

“…The JAK/STAT pathway is negatively regulated via various mechanisms, including the suppressor of cytokine signaling (SOCS) proteins, which have been identified as negative feedback regulators of cytokine signaling, and have been reported to be involved in the regulation of inflammatory responses (13–17). The mammalian cytokine-inducible SH2-containing protein (CIS)/SOCS family consists of 8 members, including CIS and SOCS1-7 (18).…”

“…In addition, SOCS-modulating properties have been attributed to pharmacological agents that are currently used for the treatment of diabetes (17). The present study aimed to investigate the function of SOCS3 in lung cells and to explore the implication of the JAK2/STAT3 signaling pathway in the molecular mechanisms underlying the effects of SOCS3 in hyperglycemia-induced lung injury.…”