Neurohumoral Regulation in Diabetic Enteropathy

糖尿病肠病是一种知之甚少的疾病，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同事进行的体外研究，表明除了迷走神经功能障碍外，由胰岛素(特别是GLP-1)组成的整合的神经激素轴、肠道功能障碍，特别是氮能神经传递和交感神经功能障碍在糖尿病肠道病变的病理生理学中至关重要，并为这种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诱导的近端胃松弛是由肠内氮能神经元介导的，而不涉及外源性(即迷走神经或交感神经)；(2)中期给予外源性硝酸盐将恢复胃排空和调节障碍。 糖尿病消化不良，与迷走神经病变的存在无关；以及(3)α2肾上腺素受体介导的交感神经抑制阻碍了糖尿病便秘患者的胃肠传输。假设1将被证实，证明一氧化氮合酶抑制剂L-NMMA，而不是α2拮抗剂育亨宾抑制GLP-1诱导的健康受试者的胃调节；经过验证的犬外源性迷走神经和交感神经失神经模型将证实，GLP-1对胃调节的影响不是由外部神经介导的。假设2将通过测量急性(1天)和 单硝酸异山梨酯中期(6周)治疗对伴有或不伴有腹部迷走神经病变的糖尿病消化不良患者胃排空的影响。对于假设3，我们将描述育亨宾对结肠运输的剂量效应，然后是中期(6周口服)。育亨宾对糖尿病便秘患者结肠传输的试验。除了最先进的胃肠转运评估、胃调节和肠腔内结肠运动的99mTcSPECT成像外，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三维磁共振成像序列以进行可视化 调节胃部，避免辐射暴露。我们预计，这些假设驱动的研究将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，并为人类糖尿病肠道病变提供新的治疗方法。

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.