Objectives: Podocytes are specialized cells essential for preserving the integrity and function of the glomerular filtration barrier and plays an important role in the development of diabetic nephropathy. Insulin-like growth factors (IGFs) are also associated with the development of diabetic nephropathy. However, it is not yet known about the effect of high glucose on IGF secretion in podocytes. Furthermore, the relationship between cAMP and high glucose on the secretion of IGFs in podocytes was not elucidated. This study was aimed to explore the mechanisms by which high glucose regulates secretion of IGF-I in rat podocytes. Methods: The concentration of IGF-I and cAMP was evaluated. Results: Glucose increased IGF-I secretion in a dose-dependent manner (greater than 15 mM; P < 0.05), 1.74 folds by 35 mM. The increase of IGF-I secretion is not mediated by osmotic effects, since mannitol and L-glucose did not affect IGF-I secretion. 8-Br-cAMP, forskolin, and IBMX mimicked high glucose-induced secretion of IGF-I. High glucose-induced stimulation of IGF-I secretion was blocked by pertussis toxin (G protein inhibitor), SQ 22536 (adenylate cyclase inhibitor), Rp-cAMP (cAMP antagonist), and myristoylated protein kinase A (PKA) inhibitor amide 14-22 (protein kinase A inhibitor). ...