Diabetic Microangiopathy and Alveolar O2 Transport

糖尿病微血管病和肺泡 O2 运输

• 批准号: 7367896
• 负责人: Connie C. W. Hsia
• 金额: $ 31.89万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7367896
• 关键词: Address; Affect; Age; Air; Alveolar; Alveolar wall; Area; Autopsy; Basement membrane; Blood Volume; Blood capillaries; Blood gas; Breathing; Carbon Monoxide; Cardiac; Cardiac Output; Cardiopulmonary; Clinical; Complications of Diabetes Mellitus; Condition; Confounding Factors (Epidemiology); Connective Tissue; Cross-Sectional Studies; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Microangiopathies; Diffuse; Diffusion; Doctor of Medicine; Drug Delivery Systems; Dyspnea; Elevation; Epithelial; Erythrocytes; Evaluation; Exercise; Functional disorder; Funding; Gases; Glycosylated Hemoglobin; Heart; Heart failure; Hyperglycemia; Impairment; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Invasive; Kidney; Kidney Diseases; Laboratories; Lead; Lung; Measurable; Measurement; Measures; Medical; Membrane; Microcirculatory Bed; Modality; Modeling; Monitor; N(delta)-acetylornithine, -isomer; N-dodecanoylglutamic acid, -isomer, sodium salt; Natural History; Nature; Neuropathy; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Organ; Organ failure; Output; Oxygen; Patients; Perfusion; Peripheral Nerves; Pharmaceutical Preparations; Physical Fitness; Physiological; Prevalence; Pulmonary Heart Disease; Rate; Relative (related person); Research Personnel; Respiratory physiology; Rest; Retina; Retinal Diseases; Route; Sea; Skeletal Muscle; Source; Structure; Surface; Symptoms; Techniques; Testing; Therapeutic; Thick; Ventricular; alpha-difluoromethyl-DOPA, -isomer; alpha-methylornithine dihydrochloride, -isomer; base; capillary; cohort; diabetic; disability; falls; glycemic control; illness length; indexing; insight; interest; non-diabetic; novel therapeutics; programs; prospective; response; treatment center; type I and type II diabetes; type I diabetic; uptake

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.

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较大，可以容忍微血管床的大量损失，而不会在休息时出现呼吸困难；因此，临床上对肺糖尿病微血管病的认识不足。然而，肺泡-毛细血管气体交换出现可测量的异常，并且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丧失也可以通过肺弥散能力（DL）及其组成部分进行量化：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）。从休息到最大程度的运动，更多的肺泡毛细血管的募集通常会导致 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，并提供微血管储备的准确指标。在糖化血红蛋白 (HbAlc) 升高的无症状 1 型糖尿病患者中，在给定 Qc 下测量的 DL 和 Dm 显着降低，但在病程相似且 HbAlc 维持接近正常 5-6 年的糖尿病患者中，DL 和 Dm 几乎正常；类似的损害也存在于 2 型糖尿病中，并且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 和 Dm 与 Qc 的关系为后续肺糖尿病微血管病提供定量指标。 2）经过相对较短的严格血糖控制时间后，微血管病变是可逆的。我们将评估近期发病或长期患有 1 型和 2 型糖尿病的患者在休息时和分级运动时的心肺功能；测量结果将与微血管功能的肺外指数（肾病、视网膜病和神经病）相关。在优化血糖控制的同时，将对患者进行前瞻性随访，并在最后重复研究。结果将a）在糖尿病组内和之间纵向分析，并与年龄匹配的非糖尿病对照进行分析，b）与控制不佳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输送途径提供前瞻性参考数据。鉴于目前对吸入胰岛素疗法开发的浓厚兴趣，越来越需要了解糖尿病进展和治疗对肺功能的影响。