Insulin plays an important role in metabolic regulation as well as in growth, fecundity and stress resistance. In order to understand more about the regulation of insulin-like peptide (DILP) production and release we investigate the impact of neuropeptide (DTK) signaling and classical neurotransmitter (GABA) signaling onto the insulin producing cells of the Drosophila brain.

DTK was shown to regulate insulin production through DTK receptors found on the insulin producing cells of the brain. DTK has an impact on carbohydrate and lipid levels as well as effect stress resistance (Paper I). Manipulations of DTK signaling differentially affect Dilp transcript levels. We also showed that GABA regulates the production and release of insulin-like peptides via GABA_BRs (Paper II). Both these two signaling pathways have an inhibitory action on insulin production and release.

The Malpighian (renal) tubules were discovered as a novel site of insulin-like peptide expression and DTK signaling was shown to converge on the insulin pathway also here (Paper III). Stress seems to induce hormonal release of DTK that acts on the renal tubules to regulate DILP 5 signaling. Manipulations of superoxide dismutase (SOD2) in principal cells also affect survival at stress, suggesting that DILP 5 acts locally on tubules, possibly in oxidative stress regulation.

Finally, we demonstrated that a cholecystokinin-like (CCK) peptide, DSK, is present in the IPCs and affects meal size regulation and food preference (Paper IV). DSK, like CCK, therefore acts to induce satiety. DSK and Dilp transcripts levels were also found to affect each other, suggesting coordination and possibly a feedback mechanism between the two signaling pathways.

In summary, we have studied control of Insulin signaling in Drosophila and have found that the different DILP isoforms have may separate functions and that they are separately regulated by both neuropeptides and classical neurotransmitters.