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Insulin resistance has been associated with the progression of chronic kidney disease in both diabetes and obesity. This study characterizes insulin signaling in renal tubules and glomeruli in insulin resistant and diabetic states. Insulin-induced phosphorylation of insulin receptor substrate-1 (IRS1), Akt, endothelial nitric oxide (eNOS), and glycogen synthase kinase 3α (GSK3α) were selectively inhibited in the glomeruli but not in the renal tubules of both streptozotocin (STZ)-diabetic and Zucker fatty, insulin resistant rats compared to non-diabetic and Zucker lean rats. Protein levels, but not the mRNA expression, of IRS1 were decreased only in the glomeruli of STZ-diabetic rats and increased its association with ubiquitination. Protein kinase C (PKC) β isoform inhibitor, ruboxistaurin (RBX), treatment enhanced insulin actions and elevated IRS1 expression. In glomerular endothelial cells, high glucose inhibited phosphorylation of Akt, eNOS and GSK3α, decreased IRS1 protein expression and increased association with ubiquitination. Overexpression of IRS1 or the addition of RBX reversed the inhibitory effects of high glucose. Selective inhibition of the IRS1/PI3K/Akt pathway and insulin activation of eNOS and GSK3α in the glomeruli in diabetes and insulin resistance is partly due to increased IRS1 degradation and PKCβ activation. The loss of insulin's effect on endothelial eNOS and GSK3α activation may contribute to the glomeropathy observed in diabetes and obesity.