Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of Langerhans

Abstract

NIDDM is characterized by progressive insulin resistance and the failure of insulin-producing pancreatic β cells to compensate for this resistance. Hyperinsulinemia, inflammation, and prolonged activation of the insulin receptor (INSR) have been shown to induce insulin resistance by decreasing INSR substrate (IRS) protein levels. Here we describe a role for SOCS7 in regulating insulin signaling. Socs7-deficient mice exhibited lower glucose levels and prolonged hypoglycemia during an insulin tolerance test and increased glucose clearance in a glucose tolerance test. Six-month-old Socs7-deficient mice exhibited increased growth of pancreatic islets with mildly increased fasting insulin levels and hypoglycemia. These defects correlated with increased IRS protein levels and enhanced insulin action in cells lacking SOCS7. Additionally, SOCS7 associated with the INSR and IRS1 -molecules that are essential for normal regulation of insulin action. These data suggest that SOCS7 is a potent regulator of glucose homeostasis and insulin signaling.

The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype‐specific mechanisms†

“…19 However, reported evidence in HCV infection is controversial: while some works attested that HCV 1b induces an increase of SOCS-1/SOCS-3 expression both in vivo and in vitro, 12,[42][43][44] others documented a decreased SOCS-1 level. 45 In our model, SOCS-1 and SOCS-3 levels are unchanged irrespectively of the genotype, while the level of SOCS-7, recently shown to be involved in IRS-1 degradation, 20 is increased in genotype 3a only. We have no explanation for the observed discrepancy with the published results concerning 1b.…”

“…Thus, as many studies have proposed a molecular mechanism of insulin resistance due to increased proteasomal degradation of IRS-1 through SOCS-1 and 3, 12,19,28-30 we measured the expression levels of these 2 members of the SOCS family in our in vitro model, together with that of SOCS-7, recently reported to modulate insulin signaling. 20 SOCS-1 and SOCS-3 mRNA levels were unchanged following transfection with both core proteins (data not shown). However, SOCS-7 mRNA levels were significantly higher in cells expressing the core protein 3a (but not in those transfected with core protein 1b) (Fig.…”

“…One pathway is operated by several suppressor of cytokine signal (SOCS) proteins, 18,19 among which SOCS-1, SOCS-3, and SOCS7 have been reported to target IRS-1 for ubiquitin-mediated degradation. 19,20 A second pathway, involving mammalian target of rapamycin (mTOR), has likewise been shown to negatively regulate insulin signal through Ser/Thr phosphorylation, subcellular redistribution, and proteasomal degradation of IRS-1. [21][22][23] Here, we present evidence that the core proteins of genotypes 3a and 1b interfere with the insulin signaling through genotype-specific mechanisms.…”

SOCS6 is a selective suppressor of receptor tyrosine kinase signaling

“…Another study suggests that SOCS6 interacts with IRS4 in response to insulin [42] and SOCS7, a close homolog of SOCS6, also associates with both INSR and IRS1 [43]. It has also been shown that overexpression of SOCS6 leads to inhibition of tyrosine phosphorylation of IRS1 indicating that SOCS6 not only regulates substrate turnover, but it also competes with the substrate for association to the INSR [40].…”

Depletion of suppressor of cytokine signaling-1a causes hepatic steatosis and insulin resistance in zebrafish

“…The observation of gigantism in SOCS2-deficient mice provides clear evidence that SOCS2 is a negative regulator of GH signaling (29). Moreover, there is a growing body of evidence suggesting a role for SOCS proteins in insulin signaling (4,17,24,42).…”