Diabetic Microangiopathy and Alveolar O2 Transport

描述（由申请人提供）：肺泡毛细血管网络是体内最大的微血管床。由于肺泡毛细血管储备很大，微血管床的广泛损失是可以容忍的，而不会在休息时发生呼吸困难；因此，临床上对肺糖尿病微血管病变的认识不足。然而，肺泡-毛细血管气体交换出现可测量的异常，可以在肺部或其他器官出现症状之前检测到。即使肺泡微血管功能的轻微损失也可以通过肺弥散能力（DL）及其组成部分来量化：相对于同时测量的心输出量（Qc），膜弥散能力（Dm）和肺毛细血管血容量（Vc）。从休息到极限运动，肺泡毛细血管的增加通常会导致DL增加100%以上。DL和Qc的关系与肺泡超微结构（肺泡-毛细血管表面积和血气屏障厚度）密切相关，为微血管储备提供了准确的指标。无症状1型糖尿病糖化血红蛋白（HbAlc）升高的DL和Dm在给定Qc下显著降低，但在病程相似且HbAlc维持接近正常5-6年的糖尿病患者中几乎正常；类似的损害见于2型糖尿病，并与临床终末器官并发症的患病率相关。初步数据得出以下假设：1)DL、Dm与Qc的关系为继发肺动脉微血管病变提供了定量指标。2)微血管病变在相对较短时间的严格血糖控制后是可逆的。我们将评估新近发病或长期存在的1型和2型糖尿病患者休息和分级运动时的心肺功能；测量结果将与微血管功能（肾病、视网膜病变和神经病变）的肺外指标相关。在血糖控制得到优化时，对患者进行前瞻性随访，并在结束时重复研究。结果将进行纵向分析：a)糖尿病组内和糖尿病组之间，以及与年龄匹配的非糖尿病对照；b)与控制不良的糖尿病患者和正常对照进行横断面比较。我们的目标是建立长期队列，以确定糖尿病患者肺泡微血管功能障碍的自然进展和潜在可逆性，并为评估肺作为糖尿病药物递送途径提供前瞻性参考数据。鉴于目前对吸入胰岛素治疗发展的强烈兴趣，人们越来越需要了解糖尿病进展和治疗对肺功能的影响。

DESCRIPTION (provided by the applicant): The alveolar-capillary network is the largest microvascular bed in the body. Owing to the large alveolar-capillary reserves, extensive loss of the microvascular bed can be tolerated without developing dyspnea at rest; hence pulmonary diabetic microangiopathy is under-recognized clinically. Nevertheless, measurable abnormalities in alveolar-capillary gas exchange develop and can be detected before symptoms appear either in the lung or in other organs. Even modest loss of alveolar microvascular function can be quantified from lung diffusing capacity (DL) and its components: membrane diffusing capacity (Dm) and pulmonary capillary blood volume (Vc), relative to simultaneously measured cardiac output (Qc). From rest to maximal exercise, recruitment of more alveolar capillaries normally causes DL to increase more than 100%. The relationship between DL and Qc correlate strongly with alveolar ultrastructure (alveolar-capillary surface area and blood-gas barrier thickness) and provide accurate indicators of microvascular reserves. DL and Dm measured at a given Qc are significantly reduced in asymptomatic type-1 diabetics with elevated glycosylated hemoglobin (HbAlc), but are almost normal in diabetics of similar disease duration who maintained near-normal HbAlc for 5-6 years; similar impairment is seen in type-2 diabetes and correlates with the prevalence of clinical end-organ complications. Preliminary data lead to these hypotheses: 1) Relationships of DL and Dm to Qc provide quantitative indices for following pulmonary diabetic microangiopathy. 2) Microangiopathy is reversible after a relatively short duration of rigorous glycemic control. We will assess cardiopulmonary function at rest and during graded exercise in patients with recent onset or long-standing type-1 and type-2 diabetes; measurements will be correlated to extrapulmonary indices of microvascular function (nephropathy, retinopathy and neuropathy). Patients will be followed prospectively while glycemic control is optimized and the studies repeated at the end. Results will be analyzed a) longitudinally within and among diabetic groups and with respect to age-matched non-diabetic controls, and b) in cross-sectional comparison to poorly controlled diabetics and normal controls. Our objectives are to establish long-term cohorts to determine the natural progression and potential reversibility of alveolar microvascular dysfunction in diabetes, and to provide prospective reference data for the evaluation of the lung as a route for drug delivery in diabetes. Given the current intense interest in the development of inhaled insulin therapy, there is a growing need to understand the effects of diabetic progression and treatment on lung function.