Tissue specificity on insulin action and resistance: past to recent mechanisms.
Insulin resistance is the most important pathophysiological feature in many pre-diabetic states. Type 2 diabetes mellitus is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion by pancreatic β-cells. The creation of monogenic or polygenic genetically manipulated mice models in a tissue-specific manner was of great help to elucidate the tissue specificity of insulin action and its contribution to the overall insulin resistance. However, a complete understanding of the molecular bases of insulin action and resistance requires the identification of intracellular pathways that regulate insulin-stimulated proliferation, differentiation and metabolism. Accordingly, cell lines derived from insulin target tissues such as brown adipose tissue, liver and beta islets lacking insulin resistance or sensitive candidate genes such as IRS-1, IRS-2, IRS-3, IR and PTP1B have been developed. Indeed, these cell lines have also been very useful to understand the tissue specificity of insulin action and inaction. Obesity is a risk factor for several components of the metabolic syndromes such as type 2 diabetes, dyslipidaemia and systolic hypertension, because white and brown adipose tissues as endocrine organs express and secrete a variety of adipocytokines that can act at both local and systemic levels, modulating the insulin sensitivity. Recent studies revealed that the subjects with the highest transcription rates of genes encoding TNF-α and IL-6 were prone to develop obesity, insulin resistance and type 2 diabetes. Accordingly, we specifically focus in this review on the impact of those adipocytokines on the modulation of insulin action in skeletal muscle.
Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Madrid, Spain. benito@farm.ucm.es
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D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D008954:Models, Biological; D009928:Organ Specificity; D010179:Pancreas / Q000378:metabolism*; D015398:Signal Transduction
D005947:Glucose