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 will investigate the spectrum of neurotransmission deficits in different stomach regions of diabetic mice with predefined fast and slow gastric emptying. These studies will be performed in different animal models of diabetes to determine the degree to which these models share a common pathophysiology. These studies will define the pathogenesis of fast and slow gastric emptying, and generate reliable, reproducible data in disordered diabetic stomach.
In Aim 2, we will systematically examine the hypothesis that dysfunction of the intracellular cargo motor, myosin 5a (myo5a), is an important cause of neurotransmitter deficit in diabetic stomach. This hypothesis is based on our studies showing myo5a dysfunction results in impaired release of multiple neurotransmitters.
Aim 3 will test the hypothesis that hyperglycemia leads to elevated myo5a O-GlcNAcylation, suppressing its activity and inhibiting neurotransmission, as well as enabling its premature degradation. Elucidation of the pathway involved in suppression of enteric neurotransmission may identify novel targets of therapy for diabetic stomach.
Appropriate medical care of diabetes represents an enormous problem in the VHA, particularly as the already large number of diabetic veterans continues to grow. The prevalence of diabetes in the VHA system rose from 16.7% in fiscal year 1998 to 19.6% in fiscal year 2000 (Miller 2004). Moreover, care of diabetic veterans poses a special problem because of associated morbidities such as age and post-traumatic stress disorder. Since VHA is a continuing system of care, we are confronted with long-term complications of diabetes. Gastrointestinal complications are common, cause significant morbidity and seriously confound the management of diabetes. Despite an excellent record of adherence to medical guidelines, the management of gastric complications of diabetes remains unsatisfactory, in part because the mechanism of gastric emptying abnormalities is poorly understood. A proper understanding of the pathogenesis of gastric complications of diabetes may not only ameliorate morbidity associated with gastroparesis but help improve its management.