Non-insulin dependent diabetes mellitus (type 2 diabetes) is the most common metabolic disease among older North Americans. Epidemiological studies suggest that chronic alcohol consumption is a risk factor for type 2 diabetes. Chronic ethanol consumption is associated with insulin resistance and impaired glucose tolerance; however, the mechanisms by which ethanol disrupts glucose homeostasis are not well understood. In the past granting period, we have investigated the molecular and cellular mechanisms by which acute and chronic ethanol disrupt glucose transport by adipose and muscle, two major sites of insulin-stimulated glucose disposal. Insulin-stimulated glucose transport is dependent on phosphatidylinositol-3 kinase (PI-3 kinase). However, we have found that long-term ethanol feeding decreases both insulin- and endothelin-1-stimulated glucose uptake by PI-3 kinase independent mechanisms in rat adipocytes. We have also discovered that TNF( is required for chronic ethanol-induced suppression of glucose transport in adipocytes. TNF( is a potent inducer of insulin resistance. Since chronic ethanol exposure is associated with increased expression of TNF( we hypothesized that TNF( may play a role in ethanol-induced insulin resistance. Consistent with this hypothesis, adipocytes from transgenic mice lacking the TNF( receptor I do not develop insulin resistance after ethanol feeding. We have also found that co-culture with ethanol sensitizes 3T3-L1 adipocytes in culture to TNF(-induced insulin resistance. The objective of the current application is to further explore the mechanisms by which ethanol disrupts the regulation of glucose transport, focusing on the novel targets for ethanol action we have identified including PI 3-kinase independent signaling mechanisms and the role of TNF( in chronic ethanol-induced insulin resistance. We will 1) investigate the effects of chronic ethanol feeding on in vivo glucose production and utilization using tracer methodologies, 2) identify the insulin-stimulated PI 3-kinase independent signaling pathways that disrupt hormone-stimulated glucose transport in adipocytes after chronic ethanol exposure, 3) investigate the mechanisms by which chronic ethanol prevents the final fusion of the GLUT4 vesicle with the plasma membrane and 4) determine the role of increased inflammatory cytokine expression in the development of chronic ethanol-induced insulin resistance in adipocytes. Investigation of the mechanisms by which chronic ethanol disrupts glucose transport provide information useful for development of strategies to either prevent or reverse the long-term effects of ethanol on glucose homeostasis. ? ?
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