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Insulin receptor-deficient cells as a new tool for dissecting complex interplay in insulin and insulin-like growth
B Lamothe1, A Baudry, C T Christoffersen
1Institut Cochin de Génétique Moléculaire, INSERM U257, Paris, France.
Abstract:
Cell systems derived from knockout mice for the insulin receptor (IR) or the IGF-1 receptor (IGF-1R) represent unique tools for dissecting complex interplay in the actions of insulin and insulin-like growth factors through their cognate versus non-cognate receptor. In this study, we used a fibroblast cell line derived from IR-deficient mice to investigate metabolic and mitogenic effects of IGF-1 and insulin. IGF-1 was able to stimulate glucose uptake, glucose incorporation into glycogen and thymidine incorporation in such cells. Phosphatidylinositol 3-kinase and mitogen-activated protein kinase, two enzymes of major metabolic-mitogenic signaling pathways, were activated upon stimulating these cells with IGF-1. All these effects were also achieved when IR-deficient cells were stimulated with insulin. Thus, IGF-1R can represent an alternative receptor through which insulin might exert some of its effects.
Insights
Insulin can activate insulin-like growth factor 1 receptor (IGF-1R) signaling in cells lacking the insulin receptor (IR). This suggests IGF-1R acts as an alternative pathway for insulin
Area of Science:
- Cell biology
- Endocrinology
- Molecular signaling
Background:
- Insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) mediate distinct yet overlapping cellular functions.
- Understanding the cross-talk between these receptors is crucial for deciphering insulin and IGF-1 actions.
Purpose of the Study:
- To investigate the metabolic and mitogenic effects of IGF-1 and insulin in a fibroblast cell line deficient in the insulin receptor (IR).
- To determine if the IGF-1 receptor (IGF-1R) can mediate insulin's actions in the absence of functional IR.
Main Methods:
- Utilized a fibroblast cell line derived from IR-deficient mice.
- Stimulated cells with IGF-1 and insulin.
- Assessed glucose uptake, glucose incorporation into glycogen, and thymidine incorporation.
- Measured activation of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways.
Main Results:
- IGF-1 stimulated glucose uptake, glycogen synthesis, and thymidine incorporation in IR-deficient cells.
- IGF-1 activated PI3K and MAPK signaling pathways in these cells.
- Insulin elicited identical metabolic and mitogenic effects as IGF-1 in the IR-deficient fibroblasts.
- These findings indicate functional activation of the IGF-1R by insulin.
Conclusions:
- The insulin-like growth factor 1 receptor (IGF-1R) can mediate metabolic and mitogenic effects typically associated with the insulin receptor (IR).
- Insulin can utilize the IGF-1R as an alternative signaling pathway in cells lacking functional IR.
- This highlights a significant degree of receptor cross-talk and functional redundancy in insulin/IGF-1 signaling.