Diabetic Microangiopathy and Alveolar O2 Transport

描述（由申请人提供）：肺泡毛细血管网是体内最大的微血管床。由于肺泡毛细血管储备大，微血管床的广泛损失可以耐受，而不会在休息时发生呼吸困难;因此，肺糖尿病微血管病变在临床上被低估。然而，肺泡-毛细血管气体交换的可测量异常发展，并且可以在肺或其他器官出现症状之前检测到。即使是肺泡微血管功能的适度损失也可以从肺弥散量（DL）及其组分：相对于同时测量的心输出量（Qc）的膜弥散量（Dm）和肺毛细血管血容量（Vc）来量化。从休息到最大运动，更多肺泡毛细血管的募集通常导致DL增加超过100%。DL和Qc之间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，并提供了准确的微血管储备指标。在给定Qc下测量的DL和Dm在具有升高的糖化血红蛋白（HbAlc）的无症状1型糖尿病患者中显著降低，但在具有类似疾病持续时间的糖尿病患者中几乎是正常的，所述糖尿病患者维持接近正常的HbAlc达5-6年;在2型糖尿病中观察到类似的损害，并且与临床终末器官并发症的患病率相关。初步的数据导致这些假设：1）DL和Dm与Qc的关系为糖尿病肺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。我们将评估近期发作或长期存在的1型和2型糖尿病患者在静息和分级运动期间的心肺功能;测量结果将与肺外微血管功能指标（肾病、视网膜病变和神经病变）相关。在优化血糖控制的同时对患者进行前瞻性随访，并在结束时重复研究。将对结果进行分析：a）在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组进行纵向分析，以及B）与控制不良的糖尿病患者和正常对照组进行横断面比较。我们的目标是建立长期队列，以确定糖尿病肺泡微血管功能障碍的自然进展和潜在的可逆性，并提供前瞻性的参考数据，以评估肺作为糖尿病药物输送途径。鉴于目前对吸入性胰岛素治疗发展的强烈兴趣，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.