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 2

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Targeted disruption of the Socs7 gene by homologous recombination. (A) S...
Targeted disruption of the Socs7 gene by homologous recombination. (A) Schematic representation of mouse Socs7 gene (top), targeting construct (middle), and targeted allele (bottom). Relevant restriction sites are indicated: Bg, BglII; H, HindIII; N, NotI; S, SalI; X, XbaI. The black boxes indicate exons. NeoR refers to the positive selection marker. The genomic fragment used as a probe for Southern blot analysis and the expected fragments after BglII digestion are indicated. (B) Southern blot analysis of BglII-digested genomic DNA from ES cell clones. The blot was hybridized with the indicated 3′ external probe. Lanes 1 and 2 show the wild-type allele from MEF and ES cells. Lanes 3–8 are from ES cells with correctly targeted alleles. (C) PCR analysis of genomic DNA from the tails of wild-type, heterozygous (Het), and knockout littermates. (D) Northern blot analysis of liver, skeletal muscle, and testis from wild-type, heterozygous, and knockout mice, showing the absence of Socs7 full-length transcript expression. (E) Growth retardation and hydrocephalus in Socs7 –/ – C57BL/6 mice. At 20 days of age, affected knockout mice exhibited a 40% decrease in weight when compared with heterozygote littermates on the C57BL/6 background (upper panel). Severe hydrocephalus is also present in a 4-week-old Socs7 –/ – mouse (lower panels). Hydrocephalus was not apparent in the mixed-background mice used in this study (image not shown).