Mechanisms of insulin signal transduction in macrophages in the development of diabetic neovasculatization of the retina

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Type 2 diabetes mellitus represents the most common endocrine disease affecting more than 6% of western populations with steadily increasing prevalence. The disease is caused by a genetically determined and environmentally modified insulin resistance. Insulin receptors are not only expressed in the classical insulin target tissues such as skeletal muscle, liver and adipose tissue, but they are also found to a similar extent on granulocytes and macrophages. Nevertheless, the role of insulin signal transduction in these cell types remains largely unclear. To determine the role of insulin signal transduction here, we have conditionally inactivated the insulin receptor gene in mice by crossing mice carrying a loxP-flanked insulin receptor allele with those expressing the Cre recombinase under control of the lysozyme M promoter. Resulting myeloid lineage-specific insulin receptor knockout mice exhibit a largely reduced induction of target genes of the transcription factor hypoxiainducible factor (HIF)-1 α both in response to IPS and hypoxia stimulation. The goal of the present research proposal is to investigate the role of insulin signal transduction in macrophages in the regulation of angiogenetic factors like VEGF, and to determine in vivo the role of insulin signal transduction in myeloid cells with respect to the development of retinal neovascularization during the course of diabetes.