Abstract
In healthy subjects, the balance between glucose production and its usage is precisely controlled. When circulating glucose reaches a critical threshold, pancreatic β-cells secrete insulin, which has two major actions: lowering circulating glucose concentrations by facilitating its uptake mainly in skeletal muscles and the liver, and inhibiting glucose production. Triglycerides are the main source of fatty acids to meet the energy needs of oxidative tissues and any excess is stored in adipocytes. Thus, adipose tissue acts as a trap for excess fatty acids released from plasma triglycerides. When the buffering action of adipose tissue to store fatty acids is impaired, they accumulate in other tissues where they are metabolized in several lipid species, including sphingolipid derivatives such as ceramides. Numerous studies have shown that ceramides are among the most active lipid second messengers to inhibit insulin signalling. This review describes the major role played by ceramides in the development of insulin resistance in peripheral tissues.
Highlights
Triglycerides are the main source of fatty acids to meet the energy needs of oxidative tissues and any excess is stored in adipocytes
Adipose tissue acts as a trap for excess fatty acids released from plasma triglycerides
When the buffering action of adipose tissue to store fatty acids is impaired, they accumulate in other tissues where they are metabolized in several lipid species, including sphingolipid derivatives such as ceramides
Summary
Comme le muscle squelettique représente 40 % de la masse corporelle humaine, et qu’il est quantitativement le tissu le plus important pour la capture du glucose en réponse à l’insuline, il est considéré comme la principale cible cellulaire dans le développement de la résistance à l’insuline. La plupart des études portant sur les mécanismes de résistance à l’insuline induite par lipotoxicité ont donc été réalisées principalement dans les tissus musculaires. En 1963, Randle et ses collaborateurs ont postulé qu’une compétition entre le glucose et les acides gras, pour leur oxydation et leur absorption, était responsable de l’apparition d’une résistance à l’insuline dans le muscle et le tissu adipeux [7]. Des études réalisées in vivo chez des rongeurs et chez l’homme ont confirmé la relation entre lipides et résistance à l’insuline, mais elles ont également montré que, contrairement à l’hypothèse initiale de Randle, la résistance à l’insuline induite par les lipides n’était pas secondaire à une inhibition de la glycolyse [5]. Il semble également qu’une accumulation lipidique hépatique, que l’on appelle stéatose hépatique non alcoolique (NAFLD pour nonalcoholic fatty liver disease), soit associée à une résistance à l’insuline hépatique [9]
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