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To investigate the in vivo dynamics of IPC activity, we quantified the effects of nutritional and internal state changes on IPCs using electrophysiological recordings. We found that the nutritional state strongly modulates IPC activity. IPC activity decreased with increasing periods of starvation. Refeeding flies with glucose or fructose, two nutritive sugars, significantly increased IPC activity, whereas non-nutritive sugars had no effect. In contrast to feeding, glucose perfusion did not affect IPC activity. This was reminiscent of the mammalian incretin effect, where glucose ingestion drives higher insulin release than intravenous application. Contrary to IPCs, Diuretic hormone 44-expressing neurons in the pars intercerebralis (DH44\n                    <jats:sup>PI<\/jats:sup>\n                    Ns) responded to glucose perfusion. Functional connectivity experiments demonstrated that these DH44\n                    <jats:sup>PI<\/jats:sup>\n                    Ns do not affect IPC activity, while other DH44Ns inhibit them. Hence, populations of autonomously and systemically sugar-sensing neurons work in parallel to maintain metabolic homeostasis. Accordingly, activating IPCs had a small, satiety-like effect on food-searching behavior and reduced starvation-induced hyperactivity, whereas activating DH44Ns strongly increased hyperactivity. Taken together, we demonstrate that IPCs and DH44Ns are an integral part of a modulatory network that orchestrates glucose homeostasis and adaptive behavior in response to shifts in the metabolic state.\n                  <\/jats:p>","DOI":"10.7554\/elife.98514","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T14:36:07Z","timestamp":1719930967000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.98514","source":"Crossref","is-referenced-by-count":9,"title":["Nutritional state-dependent modulation of insulin-producing cells in Drosophila"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8312-7191","authenticated-orcid":true,"given":"Rituja S","family":"Bisen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00fbnyb24","id-type":"ROR","asserted-by":"publisher"}],"name":"Neurobiology and Genetics, Theodor-Boveri-Institute, Biocenter, Julius-Maximilians-University of 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