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Mechanisms of insulin-induced insulin-receptor downregulation. Decrease of receptor biosynthesis and mRNA levels
Y Okabayashi1, B A Maddux, A R McDonald
1Cell Biology Laboratory, Mount Zion Hospital, San Francisco, California 94120.
Diabetes
|February 1, 1989
Summary
Insulin reduces its own receptors in pancreatic cells by speeding up receptor breakdown and slowing down new receptor production. This dual action, affecting both degradation and biosynthesis, lowers insulin receptor levels.
Area of Science:
- Endocrinology
- Cell Biology
- Molecular Biology
Background:
- Insulin's role in glucose metabolism is critical.
- Understanding insulin receptor regulation is key to metabolic research.
- AR42J cells are a responsive model for studying insulin effects.
Purpose of the Study:
- To investigate how insulin influences the downregulation of its own receptor.
- To elucidate the mechanisms behind insulin-induced receptor loss in pancreatic acinar cells.
Main Methods:
- Utilized AR42J cultured pancreatic acinar cells.
- Employed Scatchard analysis to quantify insulin receptors.
- Performed receptor half-life studies and biosynthetic labeling.
- Analyzed insulin receptor mRNA levels using slot blots and Northern transfers.
Main Results:
- Insulin-induced downregulation was time and dose-dependent.
- A 20-hour incubation with 1 microM insulin caused an 80% loss of insulin receptors.
- Insulin accelerated insulin receptor subunit degradation by 30-60%.
- Insulin inhibited insulin receptor precursor biosynthesis by over 30%.
- Insulin reduced insulin receptor mRNA levels by approximately 50%.
Conclusions:
- Insulin diminishes its receptor concentration through accelerated degradation.
- Insulin inhibits insulin receptor biosynthesis at the mRNA level.
- These combined mechanisms regulate insulin receptor levels in target cells.