The role of mosapride and levosulpiride in gut function and glycemic control in diabetic rats

Diabetes mellitus, a global health problem, is the most common endocrine disorder worldwide [1]. It causes chronic hyperglycemia, which impairs carbohydrate, fat, and protein metabolism. Chronic hyperglycemia causes several micro- and macrovascular problems [2].

Diabetic neuropathy is a condition that is linked to the length and severity of hyperglycemia [3]. Several hypotheses have been proposed regarding the pathophysiology of diabetic autonomic neuropathy, including polyol pathway activation, diacylglycerol protein kinase C cascade activation, oxidative stress, and non-enzymatic glycation. This causes neuronal abnormality with neural cell ischemia and hypoxia [4].

Gastroparesis is a well-known consequence of long-standing diabetes that presents with gastric dysmotility in the absence of gastric outlet obstruction [5]. It causes blood sugar level fluctuation and poor health states [6]. Hyperglycemia causes fundal tone and antral motility inhibition, increased pyloric contractions, and reduced intestinal transit [7]. Furthermore, loss of interstitial cells of Cajal, which are the pacemaker cells that regulate the gastric motor activity, occurs [8]. Inhibitory nitric oxide neuron impairment and oxidative stress have also been implicated [9].

Management of diabetic gastroparesis involves optimum dietary and glycemic control and the use of prokinetic and antiemetic agents [6]. Prokinetics include dopaminergic antagonists, motilin receptor agonists, serotonin 5HT4 receptor agonists, and ghrelin receptor agonists [10].

Metformin is the current first-line pharmacological therapy for type 2 diabetes mellitus (T2DM) [11]. Metformin causes the secretion of glucagon-like peptide 1 (GLP-1) from the gut tissue of both normal and type 2 diabetic patients [12].

Mosapride is a 5HT4 agonist that activates serotonergic receptors, thereby causing increased smooth muscle contraction through cholinergic pathways [13]. In healthy and diabetic individuals, mosapride is used to treat gastroparesis, gastritis, and dyspepsia [14], [15]. According to Cataldo et al., (2019) [16], serotonin is stored in pancreatic islet cells and co-secreted with insulin. Mosapride activates serotonergic 5HT4 receptors in pancreatic islet β cells, with a simultaneous increase in insulin secretion and reduction in blood glucose levels in rats [17]. Additionally, it boosts the production of GLP-1 from human gut epithelial cells [18].

Levosulpiride is a dopamine D2 receptor antagonist with a prokinetic effect that can be used to treat functional dyspepsia as dopaminergic pathways affect gastrointestinal motility. It also functions as a serotonergic 5HT4 agonist that may help improve its therapeutic effectiveness [19]. Levosulpiride is an atypical antipsychotic that can be used in chemotherapy-induced nausea and emesis, functional dyspepsia, diabetic gastroparesis, and irritable bowel syndrome [20]. This study aimed to compare the effects of serotonin 5HT4 agonist, mosapride, and dopamine D2 antagonist, levosulpiride, either alone or in combination with metformin on improving gastric emptying meanwhile regulating glycemic levels in T2DM in rats.

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