Journal
CURRENT MEDICINAL CHEMISTRY
Volume 11, Issue 7, Pages 901-908Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/0929867043455620
Keywords
muscle; glucose transport; glycogen; insulin signal transduction; diabetes; amino acids; free fatty acids
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Nutrient excess is associated with reduced insulin sensitivity (insulin resistance) and plays a central role in the pathogenesis of type 2 diabetes. Recently, free fatty acids as well as amino acids were shown to induce insulin resistance by decreasing glucose transport/phosphorylation with subsequent impairment of glycogen synthesis in human skeletal muscle. These results do not support the traditional concept of direct substrate competition with glucose for mitochondrial oxidation but indicate that the cellular mechanisms of such lipotoxicity and proteotoxicity might primarily affect the insulin signaling cascade. The signaling pathways involved in nutrient dependent modulation of insulin action include protein kinase C isoforms and IkappaB kinase. Therefore, pharmacological modulation of these enzymes might represent a promising target for future treatment of insulin resistance. Finally, hyperglycemia which occurs late in the insulin resistance syndrome further augments insulin resistance by mechanisms summarized as glucose toxicity. Chronic hyperglycemia might lead to inhibition of lipid oxidation and thereby to accumulation of intracellular lipid metabolites. Therefore, glucotoxicity might be in part indirectly caused by lipotoxicity (glucolipotoxicity). In conclusion, different nutrients affect common metabolic pathways and thereby induce insulin resistance in humans.
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