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Updated: Jun 19, 2025
Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice
Published on: November 16, 2011
GAS6 and AXL Promote Insulin Resistance by Rewiring Insulin Signaling and Increasing Insulin Receptor Trafficking to
Céline Schott1,2, Amélie Germain1,2, Julie Lacombe1
1Molecular Physiology Research Unit, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada.
Abstract:
Growth arrest-specific 6 (GAS6) is a secreted protein that acts as a ligand for TAM receptors (TYRO3, AXL, and MERTK). In humans, GAS6 circulating levels and genetic variations in GAS6 are associated with hyperglycemia and increased risk of type 2 diabetes. However, the mechanisms by which GAS6 influences glucose metabolism are not understood. Here, we show that Gas6 deficiency in mice increases insulin sensitivity and protects from diet-induced insulin resistance. Conversely, increasing GAS6 circulating levels is sufficient to reduce insulin sensitivity in vivo. GAS6 inhibits the activation of the insulin receptor (IR) and reduces insulin response in muscle cells in vitro and in vivo. Mechanistically, AXL and IR form a complex, while GAS6 reprograms signaling pathways downstream of IR. This results in increased IR endocytosis following insulin treatment. This study contributes to a better understanding of the cellular and molecular mechanisms by which GAS6 and AXL influence insulin sensitivity.
Insights
Growth arrest-specific 6 (GAS6) protein impairs insulin sensitivity and glucose metabolism. Reducing GAS6 levels improves insulin sensitivity, offering potential therapeutic targets for type 2 diabetes.
Area of Science:
- Molecular Biology
- Endocrinology
- Metabolic Research
Background:
- Growth arrest-specific 6 (GAS6) is a ligand for TAM receptors.
- Elevated GAS6 levels and genetic variations are linked to hyperglycemia and type 2 diabetes risk.
- The precise mechanisms of GAS6 in glucose metabolism remain unclear.
Purpose of the Study:
- To investigate the role of GAS6 in insulin sensitivity and glucose metabolism.
- To elucidate the molecular mechanisms by which GAS6 affects insulin signaling.
Main Methods:
- Utilized Gas6-deficient mice and manipulated GAS6 levels in vivo.
- Examined insulin receptor (IR) activation and downstream signaling in muscle cells in vitro and in vivo.
- Investigated the interaction between AXL and IR.
Main Results:
- Gas6 deficiency enhanced insulin sensitivity and protected against diet-induced insulin resistance in mice.
- Increased GAS6 levels reduced insulin sensitivity.
- GAS6 was found to inhibit insulin receptor activation and insulin response.
- GAS6, via AXL, reprograms IR signaling, leading to increased IR endocytosis.
Conclusions:
- GAS6 plays a critical role in negatively regulating insulin sensitivity.
- The GAS6-AXL-IR axis represents a novel pathway influencing glucose metabolism.
- Targeting GAS6 may offer a therapeutic strategy for improving insulin sensitivity and managing type 2 diabetes.
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