## 1 Introduction  
Diabetic patients often suffer from gastrointestinal (GI) symptoms such as nausea, vomiting, diarrhea, constipation, dyspepsia, or abdominal pain. These complications are associated with structural and functional alterations of the enteric nervous system (ENS), which is known as diabetic enteropathy [1]. The ENS is structured as two major ganglionated plexuses. The myenteric plexus is located between the circular and the longitudinal muscle layers of the gut wall and regulates intestinal motility [2]. The submuc plexus is situated in the submucosal tissue layer close to the muscularus mucosa and the intrinsic vasculature; in small animals, it is found in one layer, while in larger animals and humans, it is in two layers. The submuc neurons influence mucosal secretion, electrolyte absorption across the mucosa, blood flow, and intestinal motility [3, 4, 5, 6]. The ENS is particularly sensitive to hyperglycemia. The persistence of a high level of blood glucose disturbs the intracellular glucose metabolism and leads to the generation of reactive oxygen species damaging the ENS [7, 8, 9]. Diabetes-related alterations in the enteric neuronal microenvironment contribute to pathological pathways [10]. These alterations include structural neuronal changes, altered secretion of neurotransmitters, or loss of enteric neurons, which in turn modify GI motility and secretory functions and lead to the abovementioned GI symptoms in diabetic patients [11; 12]. Serotonin (5-hydroxytryptamine, 5-HT) in the central nervous system is mainly associated with mood, depression, sleep, and appetite, but the gut can store a vast amount of 5-HT. Although enteric 5-HT received more attention recently, most of these studies focused on the 5-HT produced by mucosal enterochromaffin cells [13; 14], which accounts for about 90% of the body's total 5-HT. However, enteric 5-HT is also synthetized by the ENS. 5-HT-immunoreactive (IR) neurons, although in small proportions, are present along the GI tract in rodents [15] and humans [16; 17]. The physiological roles of these neurons in GI motility are controversial [18; 19]. On the one hand, this discrepancy arises from the large number of different 5-HT receptors, such as 5-HT1, 5-HT2, 5-HT3, 5-HT4, and 5-HT7, and their subtypes [20]. On the other hand, 5-HT-IR neurons have extensive projections. The immunohistochemical study of [PERSON] et al. [16] determined the presence of 5-HT-IR neurons and 5-HT-IR nerve fibers in the myenteric ganglia, motor endplates, lamina muscularis mucosae, and blood vessels of a mice esophagus. In a murine colon, [PERSON] et al. [21] observed the divergence of myenteric 5-HT-IR neurons throughout the myenteric and submuc plexus, the pacemaker, intramuscular and submuc interstitial cells of Cajal, and submuc arterioles. Moreover, 5-HT-IR neurons appear to synapse with one another, and most neuronal nitric oxide synthase (nNOS)-IR neurons and glial cells are found in the murine colon. This diverse range of targets suggests that these neurons function not only as interneurons or sensory neurons but also as motor neurons innervating interstitial cells of Cajal and blood vessels. Furthermore, this study offers the possibility that myenteric 5-HT-IR neurons coordinate motility with blood flow and secretion in the colon [22]. Despite unanswered questions, such as whether the endogenous 5-HT originates from mucosa or enteric neurons or whether it is essential in GI motility, there is evidence about its important role in gut pathophysiology. 5-HT signaling has been altered in patients with diverticular disease [23], irritable bowel syndrome [24], Hirschsprung's-associated enterocolitis [25], and autism spectrum disorders [26; 27]. Furthermore, the manipulation of 5-HT3; 5-HT4 receptors; and tryptophan hydroxylase, the rate limiting the enzyme of the 5-HT synthesis, is a therapeutic target in the treatment of GI motility disorders [20].