THE ROLE OF CIRCADIAN PERIODICITY IN HUMAN CARDIOVASCULAR DISEASE AND DIABETES

 描述(由申请人提供)：在人类中，内源性褪黑素的产生与较高的胰岛素抵抗和2型糖尿病的风险、较高的高血压风险和较高的全身炎症程度相关。动物和体外实验、观察性研究和非受控干预表明，外源性褪黑素补充，特别是控释褪黑素，可能会改善这些心血管危险因素。然而，使用夜间控释褪黑素(模拟正常褪黑素生理)给药的严格对照试验尚缺乏。肥胖、糖尿病前期个体(体重指数≥30 kg/m2；糖化血红蛋白5.7-6.5%)存在胰岛素抵抗增加、胰腺-胰岛功能降低、血压升高和全身炎症的风险；此外，他们还显著减少内源性褪黑素的分泌。因此，这些个体代表了理想的研究人群，以检验褪黑素对心血管疾病这些危险因素的影响。我们计划进行一项双盲、安慰剂对照的随机临床试验，纳入肥胖(体重指数≥30 kg/m2)和糖尿病前期(HbA1C，5.7-6.4%)的受试者120人。受试者将被随机分配为1：1，接受安慰剂或2毫克控释褪黑素，每天晚上睡前口服，持续12周。我们将使用高胰岛素正血糖钳夹评估褪黑素对外周胰岛素抵抗共同初级终点的影响，并使用高血糖钳夹评估胰腺-胰岛细胞功能。第二个终点是平均24小时动态血压，第三个终点是炎症，特别是CC家族趋化因子的水平。从科学的角度来看，这项试验将首次提供有关补充褪黑素对外周胰岛素抵抗、胰腺-胰岛细胞功能和炎症的影响的人类实验数据。从公共卫生的角度来看，这项试验的结果将为旨在预防糖尿病、高血压和心血管疾病的策略和未来的试验提供参考。

 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.