[Insulin signaling: mechanisms altered in insulin resistance].
Insulin has a major anabolic function leading to storage of lipidic and glucidic substrates. All its effects result from insulin binding to a specific membrane receptor which is expressed at a high level on the 3 insulin target tissues: liver, adipose tissue and muscles. The insulin receptor exhibits a tyrosine-kinase activity which leads, first, to receptor autophosphorylation and then to tyrosine phosphorylation of substrates proteins, IRS proteins in priority. This leads to the formation of macromolecular complexes close to the receptor. The two main transduction pathways are the phosphatidylinositol 3 kinase pathway activating protein kinase B which is involved in priority in metabolic effects, and the MAP kinase pathway involved in nuclear effects, proliferation and differentiation. However, in most cases, a specific effect of insulin requires the participation of the two pathways in a complex interplay which could explain the pleiotropy and the specificity of the insulin signal. The negative control of the insulin signal can result from hormone degradation or receptor dephosphorylation. However, the major negative control results from phosphorylation of serine/threonine residues on the receptor and/or IRS proteins. This phosphorylation is activated in response to different signals involved in insulin resistance, hyperinsulinism, TNFalpha or increased free fatty acids from adipose tissue, which are transformed inside the cell in acyl-CoA. A deleterious role for molecules issued from the adipose tissue is postulated in the resistance to insulin of the liver and muscles present in type 2 diabetes, obesity and metabolic syndrome.
Capeau
Jacqueline
J
Inserm U.402, Hôpital Tenon, Faculté de médecine Saint-Antoine, Université Pierre-et-Marie-Curie, 27, rue Chaligny, 75571 Paris Cedex 12, Paris, France. capeau@st-antoine.inserm.fr
D017667:Adipocytes / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000502:physiology; D015398:Signal Transduction
D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose