Nutritional state-dependent modulation of Insulin-Producing Cells in Drosophila

Insulin plays a key role in regulating metabolic homeostasis across vertebrate and invertebrate species. Drosophila Insulin-Producing Cells (IPCs) are functional analogues to mammalian pancreatic beta cells and release insulin directly into circulation. IPC activity is modulated by nutrient availability, circadian time, and the behavioral state of animals. To investigate the in vivo dynamics of IPC activity in the context of metabolic homeostasis, we quantified effects of nutritional and internal state changes on IPCs using electrophysiological recordings. We found that the nutritional state strongly modulates IPC activity. IPCs were less active in starved flies than in fed flies. Refeeding starved flies with glucose significantly increased IPC activity, suggesting that IPCs are regulated by hemolymph sugar levels. In contrast to glucose feeding, glucose perfusion had no effect on IPC activity. This was reminiscent of the mammalian incretin effect, in which ingestion of glucose drives higher insulin release than intravenous glucose application. Contrary to IPCs, Diuretic hormone 44-expressing neurons in the pars intercerebralis (DH44 ^PI Ns), which are anatomically similar to IPCs, significantly increased their activity during glucose perfusion. Functional connectivity experiments based on optogenetic activation demonstrated that glucose-sensing DH44 ^PI Ns do not affect IPC activity, while other DH44Ns inhibit IPCs. This suggests that populations of autonomously and systemically glucose-sensing neurons are working in parallel to maintain metabolic homeostasis. Ultimately, metabolic state changes affect animal behavior. For example, hungry flies increase their locomotor activity in search of food to maintain metabolic homeostasis. In support of this idea, activating IPCs had a small, satiety-like effect in starved flies, resulting in reduced walking activity, whereas activating DH44Ns strongly increased walking activity. Taken together, we show that IPCs and DH44Ns are an integral part of a sophisticated modulatory network that orchestrates glucose homeostasis and adaptive behavior in response to shifts in the metabolic state.