Diabetes is taking on epidemic proportions, not only in western society. Via the blood, glucose is transported to the organs in the human body. When a meal is consumed, blood glucose levels rise.... Show moreDiabetes is taking on epidemic proportions, not only in western society. Via the blood, glucose is transported to the organs in the human body. When a meal is consumed, blood glucose levels rise. Insulin is secreted from the pancreas in response to the increased blood glucose levels and lowers blood glucose by increasing glucose uptake in insulin-sensitive tissues. Under conditions of insulin resistance, insulin does not have its full effect resulting in increased blood glucose levels, which left untreated will result in diabetes. Also at the signal transduction level insulin resistance is evident. An important signaling intermediate is protein kinase B (PKB/Akt). Its activity is decreased under conditions of insulin resistance. However PKB/Akt phosphorylates many targets and not all phosphorylation targets have been linked to a specific function. Therefore the aim of the research conducted in the thesis was to examine the role of PKB/Akt phosphorylation target PRAS40 in insulin action. PRAS40 is expressed in insulin sensitive tissues and is phosphorylated in response to insulin. PRAS40 interacts with another component of the insulin signaling cascade: mammalian target of rapamycin. Under conditions of insulin resistance, PRAS40 phosphorylation is decreased and higher expression of PRAS40 has a protective role in insulin resistance. Show less
We have identified ATF2 as a component of the cellular and in vivo insulin signaling systems. Insulin induced ATF2-phosphorylation in A14 fibroblasts, 3T3L1-adipocytes and several mouse tissues in... Show moreWe have identified ATF2 as a component of the cellular and in vivo insulin signaling systems. Insulin induced ATF2-phosphorylation in A14 fibroblasts, 3T3L1-adipocytes and several mouse tissues in vivo. In cell lines, the insulin-induced ATF2-phosphorylation was dependent on cooperation between two Ras-dependent MAPK-pathways: ERK and p38/JNK. Analysis of several described ATF2-target genes identified insulin-induced expression of Egr1, ATF3, c-jun and SREBP1c as being ATF2-dependent in cell lines. These genes encode transcription factors whose targets have been postulated to be involved in several aspects of normal insulin action, like control of hepatic fat and glucose metabolism and proliferation and differentiation of beta-cells. Quantitative PCR analysis showed increased mRNA expression of these genes in mouse livers correlating with hepatic ATF2-phosphorylation induced by insulin, but also in response to HFD-induced insulin resistance. In addition, the known ATF2 target genes, the inflammatory cytokines IL1-beta and TNF-alpha were also significantly induced by the HFD in liver. Although the elucidation of the exact role of ATF2 activation under these conditions needs further experimentation, the data presented in this thesis suggest a potential dual function for ATF2 as a mediator of insulin action on the one hand and a putative regulator of the development or maintenance of insulin resistance and/or diabetes-associated complications on the other. Show less
