INSULIN SECRETORY DEFECTS IN PIMA INDIANS AT HIGH RISK FOR NIDDM

皮马印第安人的胰岛素分泌缺陷是 NIDDM 的高风险

• 批准号: 6162081
• 负责人: R PRATLEY
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162081
• 关键词: Native Americans; blood glucose; body composition; clinical research; diabetes mellitus genetics; disease /disorder proneness /risk; family genetics; gestational diabetes mellitus; glucose clamp technique; glucose tolerance test; hormone regulation /control mechanism; human subject; hyperglycemia; insulin; longitudinal human study; magnetic resonance imaging; noninsulin dependent diabetes mellitus; placental transfer; secretion

The Pima Indians have the highest reported prevalence of NIDDM of any population in the world. Within this population, it is possible to identify subgroups of individuals at a particularly high risk for NIDDM. This project examines whether defects in insulin secretion contribute to the higher risk of NIDDM in these subgroups and whether they progress over the course of the disease. Healthy Pima men and women with normal glucose tolerance at high risk for NIDDM including individuals in the following 3 groups will be recruited: 1) persons whose mother and/or father developed diabetes at an early age (< 35 y); 2) persons whose mothers were diabetic during pregnancy; and 3) persons whose birth-weight was <2500 g. These individuals, as well as subjects with none of the above risk factors, will be admitted to the NIH Clinical Research Unit at Phoenix Indian Medical Center for the following series of studies. Body composition will be determined by DXA scanning and by measuring the amount of visceral abdominal fat using MRI. A 75-g oral glucose tolerance test will be performed. Insulin action will be measured with a hyperinsulinemic-euglycemic glucose clamp (insulin infusion: 40 mU/m2/min) and insulin secretory responses to glucose will be measured during a 5-step hyperglycemic glucose clamp immediately thereafter. This will be followed by a prolonged (42 hour) low-dose glucose infusion (4-6 mg/kg/min). A repeat euglycemic-step hyperglycemic glucose clamp will then be performed to test whether the glucose infusion alters insulin action and potentiates insulin secretion. Subjects will be followed longitudinally after discharge from the unit and oral glucose tolerance tests will be performed every three months. Individuals who transition from normal to impaired glucose tolerance or impaired to diabetic will be invited back to the Clinical Research Center for repeat testing. By comparing insulin secretion-glucose dose-response curves and the ability of glucose to potentiate insulin secretion in these groups, it may be possible to discern subtle defects in insulin secretion predisposing these individuals to NIDDM. In addition, comparison of the responses in the offspring of diabetic pregnancies with those in the offspring of mothers who subsequently became diabetic may allow us to separate defects due to genetic causes from those due to the intrauterine environment. To date, 12 subjects have completed the inititial testing phase. Preliminary data from these studies suggests that insulin secretory rates are a linear function of the level of hyperglycemia. Furthermore, there appear to be large differences between subjects in the slope of the curve relating insulin secretion to plasma glucose suggesting that this technique will be useful to distinguish subtle differences between groups of Pima Indians at high risk for NIDDM.

据报道，皮马印第安人的NIDDM患病率最高， 世界人口。 在这个群体中， 确定NIDDM特别高风险个体的亚组。 本项目研究胰岛素分泌缺陷是否有助于 这些亚组中NIDDM的高风险以及他们是否进展 在疾病的过程中。 健康的皮马男性和女性， 葡萄糖耐量处于NIDDM高风险中，包括 将招募以下3组：1）母亲和/或 父亲在早期（< 35岁）患糖尿病; 2） 母亲在怀孕期间患有糖尿病; 3） 出生体重<2500 g。 这些人，以及受试者 没有上述风险因素，将被送往NIH临床 凤凰城印度医学中心的研究单位， 的研究。 身体成分将通过DXA扫描和 用核磁共振成像测量腹部内脏脂肪的量。 75 g口服 将进行葡萄糖耐量试验。 胰岛素的作用将是 用高胰岛素-正常血糖葡萄糖钳夹（胰岛素 输注：40 mU/m2/min），对葡萄糖的胰岛素分泌反应将 在5步高血糖葡萄糖钳夹期间立即测量 然后 随后将进行长时间（42小时）低剂量给药 葡萄糖输注（4-6 mg/kg/min）。 重复血糖正常步骤 然后将进行高血糖葡萄糖钳夹以测试 葡萄糖输注改变胰岛素作用并增强胰岛素 分泌物 受试者出院后将接受纵向随访 从单位和口服葡萄糖耐量试验将进行， 三个月 从正常到受损的个体 葡萄糖耐量或受损的糖尿病将被邀请回到 临床研究中心进行重复检测。 通过比较胰岛素 分泌-葡萄糖剂量反应曲线和葡萄糖的能力， 增强这些人群的胰岛素分泌， 发现胰岛素分泌的微妙缺陷， 个人NIDDM。 此外，还比较了 糖尿病妊娠的后代与母亲的后代 可以让我们区分出 遗传因素和子宫内环境因素的区别到 截至目前，已有12名受试者完成了初始测试阶段。 这些研究的初步数据表明， 速率是高血糖水平的线性函数。 此外，委员会认为， 受试者之间的斜率似乎存在很大差异， 胰岛素分泌与血浆葡萄糖相关的曲线表明， 这项技术将有助于区分 Pima印第安人的NIDDM高危人群。