Neurohumoral Regulation in Diabetic Enteropathy

糖尿病性肠病是一种了解不多的疾病，它导致显著的发病率，损害血糖控制，并且不能用迷走神经功能障碍和高血糖症充分解释。我们的初步数据部分基于本PPG中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的综合神经激素轴对糖尿病肠病的病理生理学至关重要，并为该疾病提供了新的治疗途径。我们的具体目的是检验以下假设：（1）GLP-1诱导的近端胃舒张是由肠氮能神经元介导的，不涉及外源性（即迷走神经或交感神经）神经;（2）外源性硝酸盐的中期给药将恢复胃排空和调节障碍， 糖尿病性消化不良，与迷走神经病变的存在无关;和（3）α 2肾上腺素受体介导的交感神经抑制延缓糖尿病便秘患者的胃肠转运。假设1将通过证明一氧化氮合酶抑制剂L-NMMA而非α 2-拮抗剂育亨宾抑制健康受试者中GLP-1诱导的胃调节来证实;经验证的外源性迷走神经和交感神经去神经支配犬模型将证实GLP-1对胃调节的影响不由外源性神经介导。假设2将通过测量急性（1天）和 单硝酸异山梨酯对伴有或不伴有腹部迷走神经病变的消化不良糖尿病患者胃排空的中期（6周）治疗。对于假设3，我们将描述育亨宾对结肠运输的剂量效应，然后进行中期（6周p.o.）育亨宾对糖尿病便秘患者结肠传输功能的影响除了最先进的胃肠传输评估，胃调节和腔内结肠运动活动的99 mTc SPECT成像，我们还建议，基于令人鼓舞的初步数据，开发和验证一种新的3-D MR成像序列，以可视化 胃调节，避免辐射暴露。我们预计，这些假设驱动的研究直接将体外和体内研究的见解应用于糖尿病患者，将提高我们对紊乱机制的理解，并为人类糖尿病肠病提供新的治疗方法。

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.