DESCRIPTION (provided by applicant): Diabetes is an increasingly common disorder, recently estimated to affect 9.3% of the US population and 25.9% of individuals over 65 years of age (National Diabetes Statistics Report, June 2014). Because the VHA is a continuing system of care, all short- and long-term complications of diabetes are encountered in an expanding veteran group (Miller, 2004). Moreover, diabetes care in the VHA system is complex, since patients frequently have co-morbidities such as advancing age and post-traumatic stress disorder. Deleterious effects of diabetes on gastric function are highly prevalent and associated with considerable morbidity. However, the management of diabetic gastric complications remains unsatisfactory, despite an excellent record of adherence to accepted treatment guidelines, in part because mechanisms of gastric emptying abnormalities are so poorly understood. As a result, diagnosis of the underlying pathophysiology in individual cases is difficult, and since current treatment approaches are largely empirical rather than rationally designed, effective therapeutic options are often lacking. The study of the pathogenesis and treatment of gastric abnormalities in diabetes is complicated because: 1) symptoms may arise from either fast or slow gastric emptying; 2) gastric emptying is determined by the integrated response of independently regulated anatomic and functional regions of the stomach, so similar defects may result in either fast or slow gastric emptying depending on the region and/or cell type that is involved; and 3) different patterns of gastric motility regulate gastric emptying of solids and liquids during the digestive and inter-digestive periods; 4) finally, it is not entirely clear how best to use diabeti animal models in investigating diabetic gastroparesis. While many animal models of diabetes are available, it is unknown which of them most closely represents the features of human disease. Gastric emptying is regulated by distinct activities in gastric fundus, corpus/antrum and pylorus. Fast gastric emptying most often results from loss of inhibitory neurotransmission in the fundus, which is composed of tonic muscle and serves to store and accommodate ingested food by relaxing under the influence of inhibitory nerves. Slow gastric emptying often results from defective propulsive activity in the corpus/pylorus or defective relaxation of the pylorus. Defects in smooth muscle, interstitial cells of Cajal (ICC) and neuromuscular neurotransmission have all been described in the stomach of diabetic animals, with loss of ICC and impaired nitrergic and cholinergic neurotransmission being the most consistent findings. However, we find that purinergic neurotransmission is also lost, suggesting that both vesicular and non-vesicular neurotransmission are impaired. The purpose of this proposal is to investigate the pathogenesis of diabetes-associated changes in gastric emptying. In Aim 1, we w...