Tissue-derived Factors and Macrophage Polarization in Diabetic Gastroenteropathy
The long list of complications associated with diabetes mellitus includes gastroenteropathies such as gastroparesis, a syndrome defined by delayed emptying of gastric contents with no mechanical obstruction. Few treatments are available for diabetic gastroparesis, which can be a disabling disorder due to not only the symptoms of nausea, vomiting, early satiety, bloating and pain but also the adverse impact of altered gastric emptying on glycemic control. Recently it has become clear that several cell types that regulate gastrointestinal motility are affected in the pathophysiology of diabetic gastroparesis including neurons and smooth muscle but the most robust link is between delayed gastric emptying and changes in macrophage polarization, which associates with loss of pacemaker cells (interstitial cells of Cajal, ICC) in the gastric muscularis propria. Our overall hypothesis is that development of diabetic gastroparesis depends on molecules generated in response to diabetes by cells in the gastrointestinal muscle layers and that these molecules alter the balance of tissue macrophage polarization between injurious and cytoprotective phenotypes. We will test this central hypothesis in one specific aim, which is supported by strong preliminary data, by determining the molecules generated in gastric tissues exposed to diabetes that alter the balance between injurious and protective phenotypes of macrophages in gastric tunica muscularis. We have found that: 1. 62 genes including leptin were associated with development of delayed gastric emptying in diabetic mice. 2. Leptin protein was highly expressed in a subset of cells in the gastric muscularis propria of diabetic mice with delayed gastric emptying. 3. Expression profiling identified predominantly cytoprotective markers in sorted gastric muscularis propria macrophages from diabetic mice with loss of function mutations in the leptin receptor (Leprdb/db). We will use a combination of deep sequencing analysis, FACS separation of cell types, in vitro models of diabetic injury, and in vivo mouse models to study diabetes and macrophages to investigate the central hypothesis. As a result we expect to find that local synthesis of leptin in combination with other factors predisposes gastric tunica muscularis to macrophagemediated injury. Completion of the project will identify new directions for testing novel options to treat both gastroparesis and other complications of diabetes.