Acid-base status and the development of hypertension and diabetes

描述（由申请人提供）：最近的数据表明，酸碱状态的微小变化可能在高血压和2型糖尿病的发展中起重要作用。较低的pH值可能通过促进肾盐潴留而导致血压升高，并可能通过抑制胰岛素与其受体的结合而导致胰岛素抵抗。在国家健康和营养检查调查的健康参与者中，血压、空腹血糖和血浆碳酸氢盐在正常范围内，较低的碳酸氢盐与较高的血压和更大的胰岛素抵抗相关，与体型和肾功能无关。由于碳酸氢盐是细胞外液中的主要缓冲液，较低的血浆碳酸氢盐通常反映较低的细胞外ph值。作为对酸产生的代偿反应的一部分，肾脏减少了尿中柠檬酸盐的损失——我们之前报道过护士健康研究（NHS）高血压患者24小时尿中柠檬酸盐的降低。高碱饮食（如DASH饮食）可降低血压，观察性研究报告称，较高的饮食钾（碱摄入量的标志）与较低的糖尿病风险相关。由于先前对酸碱状态、高血压和糖尿病之间关系的人体研究是横断面的，所以尚不清楚低度代谢性酸中毒是这些疾病的原因还是结果。为了确定酸碱状态与随后高血压和2型糖尿病风险之间的独立关联，我们建议对NHS I和II期的女性进行以下前瞻性研究：1)血浆碳酸氢盐与高血压发病风险相关性的巢式病例对照研究（N = 1500）， 2) 24小时尿柠檬酸盐与高血压发病风险相关性的队列研究（N = 2000）， 3)无糖尿病女性血浆碳酸氢盐与胰岛素抵抗变化相关性的队列研究（N = 750）， 4)血浆碳酸氢盐与糖尿病发病风险相关性的巢式病例对照研究（N = 1500）。这项应用是首次大规模前瞻性研究酸碱状态对高血压、胰岛素抵抗和2型糖尿病风险的影响。该应用程序的独特优势包括：1)更新，详细的暴露信息积累在很长一段时间内，2)存档等离子体，和3)大样本量提供高统计能力。公共卫生相关性：我们建议对酸碱状态对高血压和糖尿病风险的影响进行首次前瞻性研究。我们希望我们的研究能为高血压和糖尿病的发展提供新的见解，并提出新的策略，如碱疗法，来预防这些疾病。

DESCRIPTION (provided by applicant): Recent data suggest that small changes in acid-base status may play an important role in the development of hypertension and type 2 diabetes. Lower pH may result in higher blood pressure by promoting renal salt- retention and may lead to insulin resistance by inhibiting binding of insulin to its receptors. In healthy participants of the National Health and Nutrition Examination Survey who had blood pressure, fasting glucose, and plasma bicarbonate in ranges considered normal, lower bicarbonate was associated with higher blood pressure and greater insulin resistance, independent of body size and kidney function. Because bicarbonate is the primary buffer in extra-cellular fluid, lower plasma bicarbonate generally reflects lower extra-cellular pH. As part of the compensatory response to acid production, the kidney decreases the amount of citrate lost in the urine - and we previously reported lower 24-hour urinary citrate in Nurses Health Study (NHS) participants with hypertension. High alkali diets (such as the DASH diet) reduce blood pressure, and observational studies report that higher dietary potassium (a marker of alkali intake) is associated with a lower risk of diabetes. Because previous human studies examining the relations between acid-base status, hypertension, and diabetes were cross-sectional, it is unknown whether low-grade metabolic acidosis is a cause or a consequence of these diseases. To determine the independent associations between acid-base status and the subsequent risk of hypertension and type 2 diabetes, we propose the following prospective studies of women in NHS I and II: 1) a nested case-control study of the association between plasma bicarbonate and risk of incident hypertension (N = 1500), 2) a cohort study of the association between 24-hour urinary citrate and risk of incident hypertension (N = 2000), 3) a cohort study of the association between plasma bicarbonate and changes in insulin resistance in women without diabetes (N = 750), and 4) a nested case-control study of the relation between plasma bicarbonate and risk of incident diabetes (N = 1500). This application represents the first large-scale prospective effort to examine the impact of acid-base status on the risk of developing hypertension, insulin resistance, and type 2 diabetes. The unique strengths of this application include 1) updated, detailed exposure information accumulated prospectively over long periods, 2) archived plasma, and 3) large sample sizes providing high statistical power. PUBLIC HEALTH RELEVANCE: We propose to conduct the first prospective studies of the impact of acid-base status on the risk of hypertension and diabetes. We expect our study to provide novel insights into the development of hypertension and diabetes and to suggest new strategies, such as alkali therapy, to prevent these diseases. .