Hormonal peptides like ghrelin, orexin A (OXA) or nesfatin-1 not only regulate appetite, which is their basic biological function, but also contribute to mechanisms responsible for maintaining integrity of the gastric mucosa. Previous studies including those from our laboratory have revealed that their gastroprotective effect results from cooperation with other factors responsible for protection of the gastric mucosa, including prostaglandin (PG) synthesis pathway, nitric oxide (NO) and the sensory afferent fibres releasing the vasoactive neurotransmitters. The aim of the present study was to determine whether ghrelin, orexin-A (OX-A) or nesfatin-1 with their protective effect on the gastric mucosa, also can modify the healing of chronic gastric ulcers. Furthermore, an attempt was made to explain participation of these peptides in healing processes of chronic gastric ulcers with comorbid conditions for the human beings resulted from diabetes mellitus. In our study, a model of gastric ulcers caused by concentrated acetic acid to induce the chronic gastric ulcers was used, while the clinical condition corresponding to diabetes was induced by single injection of streptozotocin (STZ). We found that ghrelin, OX-A and nesfatin-1 accelerate dynamics of the acetic acid ulcers healing, confirmed by a reduction in the ulcer area and this effect was accompanied by an increase in gastric blood flow at the ulcer margin. Destruction of sensory afferent fibres with capsaicin or blocking of vanilloid receptors with capsazepine resulted in a significant reduction of ghrelin, OX-A and nesfatin-1-induced acceleration of ulcer healing. Similar results were obtained when an NO-synthase blocker, L-NNA was used in a combination with these peptides. Moreover, it was found that OX-A and nesfatin-1 failed to accelerate the healing process under diabetic condition because both these hormones induced reduction in the ulcer area and the increase in blood flow in normal, non-diabetic rats were completely lost in the group of animals with diabetes. Treatment with OX-A and nesfatin-1 increased superoxide dismutase (SOD) mRNA expression even in acetic acid ulcers concurrent with diabetes. However, the treatment with OX-A and nesfatin-1 failed to alter the increase in gastric mucosal mRNA expression for ghrelin and hypoxia-inducible factor 1-alpha (HIF-1α), this latter effect that had been strongly pronounced in diabetic animals. We conclude that the hormonal peptides involved in the regulation of satiety and hunger such as ghrelin, OX-A and nesfatin-1 contribute to the process of chronic gastric ulcers healing cooperating with NO and sensory afferent nerve endings releasing vasoactive neuropeptide CGRP. Furthermore, OX-A and nesfatin-1, the two relatively unrecognized peptides, play an essential role in healing process of chronic gastric ulcers activating the gastric blood flow at ulcer margin and the mucosal regeneration and both ulcer healing and accompanying hyperemia at ulcer margin are greatly impaired during diabetes. Possibly, loss of the healing effect of these peptides during diabetes results from an interaction with radical generation processes as reflected by an increase of mRNA expression for SOD as well as the failure of their attenuating activity on proinflammatory factors such as HIF-1α.