Figure 11. Schematic diagram of putative mechanism of orexin-induced increase in food and water intake, wakefulness and arousal.

Diabetes mellitus, with the resulting decrease in intracellular glucose, leads to increased expression of OX₁R in pancreatic islet cells such as glucagon (GLU) and pancreatic polypeptide (PP). All of these, in combination with circulating and neural-derived orexins stimulate GLU and PP release. GLU induces gluconeogenesis and glycogenolysis resulting in energy utilization, wakefulness and arousal. Moreover, GLU and PP from the circulation and via paracrine effect may stimulate insulin (INS) release resulting in increased intracellular glucose, and energy utilization. DM = diabetes mellitus; OX₁R = orexin-1 receptor; INS = insulin; GLU = glucagon; PP = pancreatic polypeptide. (+) = stimulate; (−) = inhibit.