Nutritional state-dependent modulation of Insulin-Producing Cells inDrosophila

Insulin plays a key role in metabolic homeostasis across vertebrate and invertebrate species.DrosophilaInsulin-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. To investigate thein vivodynamics 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 became less active with increasing periods of starvation. Refeeding starved flies with glucose or fructose, two nutritive sugars, significantly increased IPC activity, whereas non-nutritive sugar and protein had no effect. In contrast to feeding, glucose perfusion did not affect 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^PINs), which are anatomically similar to IPCs, responded to glucose perfusion. Functional connectivity experiments demonstrated that glucose-sensing DH44^PINs do not affect IPC activity, while other DH44Ns inhibit IPCs. This suggests that populations of autonomously and systemically sugar-sensing neurons work in parallel to maintain metabolic homeostasis. Ultimately, metabolic state changes affect behavior. For example, hungry flies increase their locomotor activity in search of food. In support of this idea, activating IPCs had a small, satiety-like effect on 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.