Neurohumoral Regulation in Diabetic Enteropathy

糖尿病性肠病是一种鲜为人知的疾病，它会导致显著的发病率，损害血糖控制，并且不能用迷走神经功能障碍和高血糖来充分解释。我们的初步数据部分基于PPG的同事进行的体外研究，表明除了迷走神经功能障碍外，包括肠促胰岛素（特别是GLP-1）、肠道紊乱（特别是氮能神经传递）和交感神经功能障碍在内的综合神经激素轴对糖尿病性肠病的病理生理至关重要，并为该疾病提供了新的治疗途径。我们的具体目的是验证以下假设：- (1)GLP-1诱导的胃近端松弛是由肠内氮能神经元介导的，不涉及外源性（即迷走神经或交感神经）；(2)中期给予外源性硝酸盐可恢复胃排空和调节功能紊乱

Diabetic enteropathy is a poorly understood disorder which causes significant morbidity, impairs glycemic control and is not adequately explained by vagal dysfunction and hyperglycemia. Our preliminary data, partly based on in vitro studies conducted by colleagues in this PPG, suggest that in addition to vagal dysfunction, an integrated neurohormonal axis comprising incretins (particularly GLP-1), disordered enteric, particularly nitrergic neurotransmission, and sympathetic dysfunction are critical to the pathophysiology of diabetic enteropathy, and provide novel therapeutic avenues for this disorder. Our SPECIFIC AIMS are to test the HYPOTHESES that:- (1) GLP-1 induced proximal gastric relaxation is mediated by enteric nitrergic neurons and does not involve extrinsic (i.e. vagus or sympathetic) nerves; (2) Medium-term administration of exogenous nitrates will restore disturbances of gastric emptying and accommodation in diabetic dyspepsia, irrespective of the presence of vagal neuropathy; and (3) alpha2 adrenoreceptor mediated sympathetic inhibition retards gastrointestinal transit in diabetics with constipation. Hypothesis 1 will be confirmed by demonstrating that the nitric oxide synthase inhibitor L-NMMA, but not the alpha2-antagonist yohimbine inhibits GLP-1 induced gastric accommodation in healthy subjects; validated canine models of extrinsic vagal and sympathetic denervation will confirm that the effects on GLP-1 on gastric accommodation are not mediated by extrinsic nerves. Hypothesis 2 will be tested by measuring the effect of acute (1 day) and medium-term (6-week) treatment with isosorbide mononitrate on gastric emptying in diabetics with dyspepsia with or without abdominal vagal neuropathy. For hypothesis 3, we will characterize dose-effects of yohimbine on colonic transit, followed by a medium-term (6-week p.o.) trial of yohimbine on colonic transit in diabetics with constipation. In addition to state-of-the-art assessments of gastrointestinal transit, 99mTc SPECT imaging of gastric accommodation and intra-luminal colonic motor activity, we also propose, based on encouraging preliminary data, to develop and validate a novel 3-D MR imaging sequence to visualize gastric accommodation, avoiding radiation exposure. We anticipate that these hypotheses-driven studies that directly apply insights from in vitro and in vivo studies to diabetic patients will improve our understanding of disordered mechanisms and provide novel therapies for diabetic enteropathy in humans.