Secreted ligands of the insulin family promote cell growth and maintain sugar homeostasis. Insulin release is tightly regulated in response to dietary conditions, but how insulin-producing cells (IPCs) coordinate their responses to distinct nutrient signals is unclear. Here we show that regulation of insulin secretion in Drosophila larvae has been segregated into distinct branches - whereas amino acids promote the secretion of Drosophila insulin-like peptide 2 (Dilp2), circulating sugars promote the selective release of Dilp3. Dilp3 is uniquely required for the sugar-mediated activation of TOR signalling and suppression of autophagy in the larval fat body. Sugar levels are not sensed directly by the IPCs, but rather by the adipokinetic hormone (AKH)-producing cells of the corpora cardiaca, and we demonstrate that AKH signalling is required in the IPCs for sugar-dependent Dilp3 release. Thus, IPCs integrate multiple cues to regulate the secretion of distinct insulin subtypes under varying nutrient conditions.
Bibliographical noteFunding Information:
We thank Drs Ronald Kühnlein, Pierre Leopold, Jae Park and Jan Veenstra for generous gifts of flies and antibodies. We also thank the Vienna Drosophila RNAi Center, the Bloomington Drosophila Stock Center and the Developmental Studies Hybridoma bank at the University of Iowa for providing fly stocks and antibodies. This work was supported by NIH grant R01 GM62509 to T.P.N.