Diabetic Microangiopathy and Alveolar O2 Transport

描述(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，可以忍受广泛的微血管床丢失而不会出现静息呼吸困难；因此，临床上对肺型糖尿病微血管病变的认识不足。然而，肺泡-毛细血管气体交换会出现可测量的异常，并且可以在肺部或其他器官出现症状之前被发现。肺泡微血管功能的轻微丧失也可以从肺弥散能力(DL)及其组成部分--膜弥散能力(DM)和肺毛细血管血容量(VC)--相对于同时测量的心输出量(QC)来量化。从静息到极量运动，肺泡毛细血管的充盈通常会导致DL增加100%以上。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。糖化血红蛋白(HbAlc)升高的无症状1型糖尿病患者在给定的QC下测得的Dl和Dm显著降低，但在病程相近、HbAlc维持接近正常5-6年的糖尿病患者中几乎正常；类似的损害也见于2型糖尿病，并与临床终末器官并发症的发生率相关。初步数据得出以下假设：1)Dl、Dm与Qc的关系为后续的肺糖尿病微血管病变提供了定量指标。2)在相对较短的时间内严格控制血糖后，微血管病变是可逆的。我们将评估新近发病或长期存在的1型和2型糖尿病患者在休息和分级运动中的心肺功能；测量结果将与微血管功能的肺外指数(肾病、视网膜病变和神经病变)相关。对患者进行前瞻性跟踪，同时优化血糖控制，并在结束时重复研究。结果将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)与控制不佳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，并为评估糖尿病患者肺作为药物输送途径提供前瞻性参考数据。鉴于目前对吸入型胰岛素治疗发展的浓厚兴趣，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.