Glucose-Dependent Insulinotropic Polypeptide Reduces Fat-Specific Expression and Activity of 11b-Hydroxysteroid Dehydrogenase Type 1 and Inhibits Release of Free Fatty Acids

Glucose-dependent insulinotropic polypeptide (GIP) has been suggested to have direct effects on nonislet tissues. GIP also reportedly increased glucose uptake and inhibition of lipolysis in adipocytes after inhibition of the intracellular cortisone-cortisol shuttle 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1). We here analyzed whether GIP modifies lipid metabolism and further elucidated the relation between GIP, 11b-HSD1, and fatty acid metabolism. GIP reduced activity of 11b-HSD1 promoter con-structs and the expression and activity of 11b-HSD1 in differen-tiated 3T3-L1 adipocytes in a time- and dose-dependent fashion. This was paralleled by a reduction of free fatty acid (FFA) release and a reduced expression of key enzymes regulating lipolysis in adipose tissue. Preinhibition of 11b-HSD1 completely abolished GIP-induced effects on FFA release. To investigate the acute ef-fects of GIP in humans, a randomized clinical trial was performed