Increased insulin sensitivity and hypoinsulinemia in APS knockout mice
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Updated: Aug 30, 2026
Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice
Published on: November 16, 2011
Asako Minami1, Masanori Iseki, Kazuhiro Kishi
1Division of Molecular Genetics, Institute for Enzyme Research, University of Tokushima, Tokushima, Japan.
Abstract:
A tyrosine kinase adaptor protein containing pleckstrin homology and SH2 domains (APS) is rapidly and strongly tyrosine phosphorylated by insulin receptor kinase upon insulin stimulation. The function of APS in insulin signaling has heretofore remained unknown. APS-deficient (APS(-/-)) mice were used to investigate its function in vivo. The blood glucose-lowering effect of insulin, as assessed by the intraperitoneal insulin tolerance test, was increased in APS(-/-) mice. Plasma insulin levels during fasting and in the intraperitoneal glucose tolerance test were lower in APS(-/-) mice. APS(-/-) mice showed an increase in the whole-body glucose infusion rate as assessed by the hyperinsulinemic-euglycemic clamp test. These findings indicated that APS(-/-) mice exhibited increased sensitivity to insulin. However, overexpression of wild-type or dominant-negative APS in 3T3L1 adipocytes did not affect insulin receptor numbers, phosphorylations of insulin receptor, insulin receptor substrate-1, or Akt and mitogen-activated protein kinase. The glucose uptake and GLUT4 translocation were not affected by insulin stimulation in these cells. Nevertheless, the insulin-stimulated glucose transport in isolated adipocytes of APS(-/-) mice was increased over that of APS(+/+) mice. APS(-/-) mice also showed increased serum levels of leptin and adiponectin, which might explain the increased insulin sensitivity of adipocytes.
Insights
Mice lacking APS protein show enhanced insulin sensitivity and improved glucose regulation. This suggests APS plays a role in modulating insulin action in vivo.
Area of Science:
- Molecular Endocrinology
- Metabolic Signaling
Background:
- The adaptor protein APS (Abl-interactor protein with SH2 domain) is tyrosine phosphorylated by the insulin receptor upon insulin stimulation.
- The precise function of APS in insulin signaling pathways remains largely uncharacterized.
Purpose of the Study:
- To investigate the in vivo function of APS in insulin signaling and glucose homeostasis.
- To determine the physiological consequences of APS deficiency on insulin sensitivity.
Main Methods:
- Utilized APS-deficient (APS(-/-)) mice for in vivo studies.
- Performed intraperitoneal insulin tolerance tests and glucose tolerance tests.
- Conducted hyperinsulinemic-euglycemic clamp studies to assess whole-body glucose infusion rates.
- Analyzed insulin signaling components and glucose uptake in 3T3L1 adipocytes and isolated adipocytes.
Main Results:
- APS(-/-) mice exhibited increased insulin sensitivity, evidenced by enhanced blood glucose lowering and increased glucose infusion rates.
- Fasting plasma insulin levels and insulin levels during glucose tolerance tests were reduced in APS(-/-) mice.
- While in vitro studies in 3T3L1 adipocytes showed no direct effect of APS on insulin signaling components or glucose uptake, isolated adipocytes from APS(-/-) mice displayed increased insulin-stimulated glucose transport.
- APS(-/-) mice had elevated serum leptin and adiponectin levels, potentially contributing to enhanced insulin sensitivity.
Conclusions:
- APS deficiency leads to increased systemic insulin sensitivity and improved glucose homeostasis in mice.
- The findings suggest APS plays a critical role in regulating insulin action, possibly through mechanisms independent of direct effects on major insulin signaling molecules in adipocytes.
- Elevated adipokines in APS(-/-) mice may contribute to the observed metabolic phenotype.
