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Genetic engineering in mice: impact on insulin signalling and action
B Lamothe1, A Baudry, P Desbois
1Institut Cochin de Génétique Moléculaire, INSERM U257, 24, rue du Faubourg Saint-Jacques, 75014 Paris, France.
The Biochemical Journal
|October 8, 1998
Summary
Altering genes involved in insulin signaling, like insulin receptor (IR) and glucose transporters, in mice models revealed crucial roles in diabetes development and insulin action. These studies highlight the complex interplay of genetic factors in metabolic regulation.
Area of Science:
- Metabolic and molecular biology
- Genetics and genomics
- Endocrinology
Background:
- Insulin signaling is critical for glucose homeostasis and metabolic regulation.
- Genetic manipulation of key insulin pathway components provides insights into diabetes pathogenesis.
- Understanding gene redundancy and specificity is essential for deciphering complex biological systems.
Purpose of the Study:
- To investigate the in vivo roles of genes involved in insulin signaling and action using transgenic and knockout mouse models.
- To explore the functional redundancy and specificity between insulin receptor (IR) and insulin-like growth factor I receptor (IGF-IR).
- To validate the 'diabetogenes' concept in non-insulin-dependent diabetes mellitus (NIDDM) by combining mutations.
Main Methods:
- Generation and analysis of transgenic and knockout mice with altered expression of genes encoding insulin, IR, insulin receptor substrates (IRS-1, IRS-2), glucose transporters (GLUT4, GLUT2), and glucokinase.
- Phenotypic characterization of these mouse models, including metabolic assessments and survival rates.
- Studies using cell lines derived from deficient mice to assess receptor and substrate redundancy.
Main Results:
- Altered gene expression led to phenotypes ranging from mild defects to severe diabetes with ketoacidosis and early death.
- Overexpression of regulatory proteins improved insulin action.
- Combining mutations validated the 'diabetogenes' concept for NIDDM.
- IR and IGF-IR signaling pathways are not fully redundant, though IR can substitute for IGF-IR under certain conditions.
- IRS-1 and IRS-2 exhibit distinct roles and are not completely interchangeable.
Conclusions:
- Genetic alterations in insulin signaling components profoundly impact metabolic regulation and can lead to diabetes.
- The insulin and IGF signaling systems possess both overlapping and distinct functions, with context-dependent redundancy.
- IRS-1 and IRS-2 play non-redundant roles in insulin signal transduction, underscoring their specific contributions.