Abstract
Insulin-resistance is a characteristic feature of type 2 diabetes (T2D) and plays a major role in the pathogenesis of this disease. Skeletal muscles are quantitatively the biggest glucose users in response to insulin and are considered as main targets in development of insulin-resistance. It is now clear that circulating fatty acids (FA), which are highly increased in T2D, play a major role in the development of muscle insulin-resistance. In healthy individuals, excess FA are stored as lipid droplets in adipocytes. In situations like obesity and T2D, FA from lipolysis and food are in excess and eventually accumulate in peripheral tissues. High plasma concentrations of FA are generally associated with increased risk of developing diabetes. Indeed, ectopic fat accumulation is associated with insulin-resistance; this is called lipotoxicity. However, FA themselves are not involved in insulin-resistance, but rather some of their metabolic derivatives, such as ceramides. Ceramides, which are synthetized de novo from saturated FA like palmitate, have been demonstrated to play a critical role in the deterioration of insulin sensitivity in muscle cells. This review describes the latest progress involving ceramides as major players in the development of muscle insulin-resistance through the targeting of selective actors of the insulin signaling pathway.
Highlights
A worldwide obesity and diabetes epidemic has been spreading in humans all over the world in the last four decades
A study conducted in mice fed a high-fat diet and treated with myriocin demonstrated that inhibition of ceramide synthesis was sufficient to partially restore insulin-stimulated Akt phosphorylation in gastrocnemius muscles [26]
Hage Hassan et al demonstrated that PKR was activated in vitro in muscle cell lines treated with palmitate or directly with ceramides, in vivo in muscles obtained from high-fat diet fed mice and from genetically obese mice, and in human diabetic patient muscle cells [79]
Summary
A worldwide obesity and diabetes epidemic has been spreading in humans all over the world in the last four decades. After several years of unbalanced diabetes, complications altering the quality of life of patients appear and can lead to premature death. There are two main types of diabetes: (i) type 1 diabetes (T1D), resulting from a total insulin deficiency (insulinopenia) subsequent of destruction of insulin-producing cells, which accounts for 10% of diabetes cases; and (ii) type 2 diabetes (T2D), the most common diabetes (90% of diabetes cases), characterized by two major cell dysfunctions: insulin resistance of peripheral organs such as liver, adipose tissue, and skeletal muscles, and partial insulinopenia from the β-cells. When the insulin secretory function is insufficient to counterbalance increasing insulin resistance, hyperglycemia appears This insulin secretion dysfunction is linked to genetic/epigenetic and environmental factors [4]. We will provide an overview of our present understanding of known machineries and mechanisms by which ceramides affect negatively glucose homeostasis in skeletal muscles
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