Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of Langerhans
Alexander S. Banks, … , Domenico Accili, Paul B. Rothman
Alexander S. Banks, … , Domenico Accili, Paul B. Rothman
Published September 1, 2005
Citation Information: J Clin Invest. 2005;115(9):2462-2471. https://doi.org/10.1172/JCI23853.
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Research Article Metabolism

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.

Authors

Alexander S. Banks, Jianze Li, Lisa McKeag, Marta L. Hribal, Masaki Kashiwada, Domenico Accili, Paul B. Rothman

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Figure 1

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Socs7 expression patterns, induction, and protein associations. (A) Soc...
Socs7 expression patterns, induction, and protein associations. (A) Socs7 mRNA expression was determined by Q PCR in 129S6 and C57BL mice fed a standard 10% fat diet ad libitum. Values are normalized relative to Hprt mRNA and plotted on a log scale. In addition to whole mouse tissues, collagenase-purified islets were also examined. Results are representative of 3 to 7 mice; error bars indicate ± SEM. *P < 0.05 between genotypes (1-tailed Student’s t test). 129S6 and C57BL/6 are indicated by light gray and dark gray bars, respectively. (B) A murine 129S6 multiple-tissue Northern blot was generated and probed with Socs7 full-length cDNA. Two bands were observed, the full-length transcript and a smaller, testis-specific (t.s.) isoform. The blot was stripped and reprobed with a Gapdh cDNA fragment as a loading control. Sk., skeletal. (C) Induction of Socs7 mRNA by insulin. Q-PCR for Socs7 in tissues isolated 1 hour after a physiological dose (0.75 U/kg) of insulin. Values are given as fold induction over level of Socs7 mRNA expression in untreated mice. Results from 4 treated (dark gray bars) and 4 untreated mice (light gray bars) are included. *P < 0.05 between stimulated and unstimulated mice of the same genotype (1-tailed Student’s t test). (D) Association of SOCS7 with insulin-signaling molecules. A full-length Socs7 cDNA was tagged with Xpress epitope and transfected into HEK293 cells with INSR or IRS1 as indicated. Immunoprecipitates of INSR or IRS1 and whole-cell lysates were blotted with an antibody recognizing SOCS7. Blots were stripped and reprobed with either antibodies against INSR or IRS1. WB, Western blot.