thermozymocidin and Diabetes-Mellitus--Type-2

Obesity is a major health concern that increases the risk for insulin resistance, type 2 diabetes (T2D), and cardiovascular disease. Thus, an enormous research effort has been invested into understanding how obesity-associated dyslipidemia and obesity-induced alterations in lipid metabolism increase the risk for these diseases. Accordingly, it has been proposed that the accumulation of lipid metabolites in organs such as the liver, skeletal muscle, and heart is critical to these obesity-induced pathologies. Ceramide is one such lipid metabolite that accumulates in tissues in response to obesity, and both pharmacological and genetic strategies that reduce tissue ceramide levels yield salutary actions on overall metabolic health. We will review herein why ceramide accumulates in tissues during obesity and how an increase in intracellular ceramide impacts cellular signaling and function as well as potential mechanisms by which reducing intracellular ceramide levels improves insulin resistance, T2D, atherosclerosis, and heart failure. Because a reduction in skeletal muscle ceramide levels is frequently associated with improvements in insulin sensitivity in humans, the beneficial findings reported for reducing ceramides in preclinical studies may have clinical application in humans. Therefore, modulating ceramide metabolism may be a novel, exciting target for preventing and/or treating obesity-related diseases.

Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Ceramides; Diabetes Mellitus, Type 2; Dyslipidemias; Fatty Acids, Monounsaturated; Heart Failure; Humans; Insulin Resistance; Lipid Metabolism; Liver; Mitochondria; Molecular Targeted Therapy; Muscle, Skeletal; Myocardium; Obesity

Nowadays wrong nutritional habits and lack of physical activity give a rich soil for the development of insulin resistance and obesity. Many researches indicate lipids, especially the one from the sphingolipids class, as the group of molecules heavily implicated in the progress of insulin resistance in skeletal muscle. Recently, scientists have focused their scrutiny on myriocin, a potent chemical compound that inhibits ceramide (i.e., central hub of sphingolipids signaling pathway) de novo synthesis. In the present research we evaluated the effects of myriocin application on type 2 diabetes mellitus in three different types of skeletal muscles: (1) slow-oxidative (red gastrocnemius), (2) oxidative-glycolytic (soleus), and (3) glycolytic (white gastrocnemius). For these reasons the animals were randomly divided into four groups: "control" (C), "myriocin" (M), "high fat diet" (HFD), "high fat diet" (HFD), and "high fat diet + myriocin" (HFD + M). Our in vivo study demonstrated that ceramide synthesis inhibition reduces intramuscular ceramide, its precursor sphinganine, and its derivatives sphingosine and sphingosine-1-phosphate concentrations. Moreover, FFA and TG contents were also decreased after myriocin treatment. Thus, myriocin presents potential therapeutic perspectives with respect to the treatment of insulin resistance and its serious consequences in obese patients.

Topics: Animals; Ceramides; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Fatty Acids, Monounsaturated; Glycolysis; Insulin Resistance; Lysophospholipids; Male; Muscle, Skeletal; Oxygen; Rats; Rats, Wistar; Signal Transduction; Sphingolipids; Sphingosine

Topics: Adipose Tissue; Ceramides; Diabetes Mellitus, Type 2; Fatty Acids, Monounsaturated; Humans; Insulin Resistance; Obesity; Palmitoyl Coenzyme A; Sphingomyelin Phosphodiesterase