Use of novel MRI technology to study pathophysiology diabetic gastroparesis

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PROJECT ABSTRACT Delayed gastric emptying is a common and serious complication among patients with long standing and poorly controlled diabetes. Current prokinetic therapies are limited and elicit serious side effects. An improved understanding of the pathophysiology of diabetic gastroparesis is critical to the development of new approaches in the treatment of this difficult disorder. Gastric emptying is a complex process that is tightly coordinated. Fundic accommodation, peristaltic and tonic antral contractions, and antral-pyloric coordination all play important roles in regulating gastric emptying. Because of technical limitations, we still do not know to what extent gastric emptying is produced by each of these gastric motor components. To address these deficiencies, we developed a robust strategy to image and characterize gastric motility and emptying in rats and humans based on contrast-enhanced magnetic resonance imaging (MRI) and computer-assisted image processing. This novel technology not only shows gastric anatomy, but also captures and quantifies stomach emptying, intestinal filling, antral contractions and pylorus opening with fully automated image processing. Based on our pilot investigations and studies derived from computational modeling and simulations of gastric flow, we hypothesize that proper coordination of gastric motor function is required for optimal emptying. Fundic motor events, antral contractions, and opening of the pylorus are closely coordinated. Abnormalities in these events can result in delayed gastric emptying. To test this hypothesis, we plan to perform gastric MRI studies in healthy and diabetic rats and humans. We have 3 Specific Aims: Aim 1: Develop and perform gastric MRI to examine gastric motor events under postprandial conditions in rats and healthy subjects. This will define normal gastric MRI profiles and elucidate how each component of the gastric motor events contribute to emptying in health. Aim 2: Apply MRI technology to study gastroparesis in STZ-induced diabetes in rats and investigate how vagal stimulation might improve antral duodenal coordination and enhance gastric emptying. Aim 3: Employ MRI technology to study gastric motility and emptying in diabetic patients with gastroparesis. We will examine how abnormalities of different components of gastric motor function contribute to delayed gastric emptying. In separate studies, we will investigate the mechanisms by which prucalopride improves gastric motility and emptying. Gastric MRI profiles will be compared between prucalopride responders and non- responders to elucidate which components of the gastric motor function are modified by prucalopride resulting in improved emptying. These gastric MRI studies may provide novel information to identify new strategies to improve gastric emptying in diabetic gastroparesis.