THE ROLE OF CIRCADIAN PERIODICITY IN HUMAN CARDIOVASCULAR DISEASE AND DIABETES

 描述（由申请人提供）：内源性褪黑激素产生较低与人类胰岛素抵抗和2型糖尿病的风险较高、高血压的风险较高和全身炎症程度较高相关。动物和体外实验，观察性研究，和不受控制的干预措施表明，外源性褪黑激素的补充，特别是控释褪黑激素，可以改善这些心血管危险因素。然而，缺乏严格控制的试验，使用夜间管理的控释褪黑激素（模拟正常褪黑激素生理）。肥胖、糖尿病前期个体（BMI ≥ 30 kg/m2; HbA 1c，5.7-6.5%）存在胰岛素抵抗增加、胰岛功能降低、血压升高和全身性炎症的风险;此外，他们的内源性褪黑激素分泌也显著减少。因此，这些人代表了一个理想的研究人群，以检查褪黑激素对这些心血管疾病的危险因素的影响。我们计划进行一项双盲、安慰剂对照的随机临床试验，我们将入组120例肥胖（BMI ≥ 30 kg/m2）和糖尿病前期（HbA 1C，5.7-6.4%）受试者。受试者将以1：1随机分配接受安慰剂或2 mg控释褪黑激素，每晚睡前口服，持续12周。我们将评估褪黑激素对共同主要终点外周胰岛素抵抗（使用高胰岛素-正葡萄糖钳夹）和胰岛-胰岛细胞功能（使用高葡萄糖钳夹）的影响。次要终点将是平均24小时动态血压，第三终点将是炎症，特别是通过趋化因子CC家族的水平来标记。从科学的角度来看，这项试验将提供有关补充褪黑激素对外周胰岛素抵抗、胰岛细胞功能和炎症影响的首个人体实验数据。从公共卫生的角度来看，这项试验的结果将为预防糖尿病、高血压和心血管疾病的策略和未来试验提供信息。

 DESCRIPTION (provided by applicant): Lower endogenous melatonin production is associated with a higher risk of insulin resistance and type 2 diabetes, a higher risk of hypertension, and a higher degree of systemic inflammation in humans. Animal and in vitro experiments, observational studies, and uncontrolled interventions suggest that exogenous melatonin supplementation, particularly controlled-release melatonin, may ameliorate these cardiovascular risk factors. However, rigorously controlled trials using nighttime administration of controlled-release melatonin (to mimic normal melatonin physiology) are lacking. Obese, pre-diabetic individuals (BMI ≥ 30 kg/m2; HbA1c, 5.7-6.5%) are at risk of having increased insulin resistance, decreased pancreatic -islet function, elevated blood pressure, and systemic inflammation; in addition, they also have markedly reduced endogenous melatonin secretion. Such individuals therefore represent an ideal study population to examine the effects of melatonin on these risk factors for cardiovascular disease. We plan to conduct a double-blind, placebo-controlled randomized clinical trial, in which we will enroll 120 subjects with obesity (BMI ≥ 30 kg/m2) and pre-diabetes (HbA1C, 5.7-6.4%). Subjects will be randomly assigned 1:1 to receive either placebo or 2 mg of controlled- release melatonin, taken orally every evening before bed for 12 weeks. We will evaluate the effect of melatonin on the co-primary endpoints of peripheral insulin resistance using a hyperinsulinemic euglycemic clamp and pancreatic -islet cell function using a hyperglycemic clamp. The secondary endpoint will be mean 24-hour ambulatory blood pressure and the tertiary endpoint will be inflammation marked especially by levels of the CC family of chemokines. From a scientific standpoint, this trial will provide the fist experimental human data regarding the effects of melatonin supplementation on peripheral insulin resistance, pancreatic -islet cell function, and inflammation. From a public health standpoint, the results of this trial will inform strategies and future trials designed to prevent he incidence of diabetes, hypertension, and cardiovascular disease.