Dysregulation of Glucose Homeostasis in Aging

衰老过程中血糖稳态失调

• 批准号: 6965951
• 负责人: NIR J BARZILAI
• 金额: $ 31.77万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6965951
• 关键词: adipose tissue; aging; antibody; binding proteins; bioenergetics; body composition; body weight; caloric dietary content; calorimetry; central nervous system; cerebral ventricles; corticosterone; gene expression; hormone regulation /control mechanism; insulin; insulin sensitivity /resistance; insulinlike growth factor; laboratory rat; leptin; microarray technology; neuroregulation; nutrient intake activity; polymerase chain reaction; somatotropin

DESCRIPTION (provided by applicant): Aging is associated with an increase in the ratio of fat mass to lean body mass, changes in fat distribution, and resistance to the action of insulin. These characteristics of the metabolic syndrome of aging (MS) are associated with increased incidence of age-related diseases such as diabetes, cardio-vascular diseases, cancer, and Alzheimer's disease. In the last few years we have studied the biological and physiological dysregulation associated with changes in fat distribution and insulin action. We have proved a cause-effect relationship between visceral fat (VF) and insulin resistance, and implicated the age-dependent resistance to the fat-derived peptide leptin in these metabolic derangements of aging. In parallel to the development of 'leptin resistance', aging is also characterized by decrease in growth hormone (GH) secretion and influencing the levels of insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (BP-3), and is the subject for this competitive renewal. We hypothesize that IGF-1 and BP3 have 2 direct but opposing effects on 1) body fat distribution, and 2) on insulin action. Furthermore, we hypothesize that these effects are mediated through pathways in the central nervous system (CNS). We will study young and old rats, by chronic and acute administration of IGF-1 peripherally and in to the third ventricle (ICV). We will bock IGF-1 and insulin receptors and block some of the IGF-1/insulin signaling pathways in order to identify the down stream pathway for IGF-1 action in the CNS. Similarly, we will administer acutely and chronically BP3 peripherally and ICV, as well as a BP3 mutant that lacks the active site of BP3. From the studies with chronic administration IGF-1 (SA1) and BP3 (SA2) we will learn their opposing effects on body fat distribution, muscle mass, energy expenditure, and the biological characteristics of fat depots (by gene array technology and RT-PCR). From the acute study, we will determine the opposing effects of IGF-1 (SA3) and BP3 (SA4) on peripheral and hepatic insulin action (by clamp technology). Because GH administration has unwarranted side effects in aging subjects, a better understanding of the age-dependent changes due to decline in the GH/IGF-1/BP3 axis is likely to lead to better strategies to prevent and/or reverse this constellation of metabolic defects early during the aging process.

描述（由申请人提供）：衰老与脂肪量与去脂体重之比的增加、脂肪分布的变化以及对胰岛素作用的抵抗有关。衰老代谢综合征（MS）的这些特征与糖尿病、心血管疾病、癌症和阿尔茨海默病等年龄相关疾病的发病率增加有关。 在过去的几年中，我们研究了与脂肪分布和胰岛素作用变化相关的生物和生理失调。我们已经证明了内脏脂肪（VF）和胰岛素抵抗之间的因果关系，并表明对脂肪源肽瘦素的年龄依赖性抵抗与这些衰老代谢紊乱有关。 在出现“瘦素抵抗”的同时，衰老的另一个特点是生长激素 (GH) 分泌减少，并影响胰岛素样生长因子 1 (IGF-1) 和 IGF 结合蛋白 3 (BP-) 的水平。 3)，并且是本次竞争性更新的主题。我们假设 IGF-1 和 BP3 对 1) 身体脂肪分布和 2) 胰岛素作用有 2 个直接但相反的影响。此外，我们假设这些效应是通过中枢神经系统（CNS）中的途径介导的。我们将通过在外周和第三脑室 (ICV) 中慢性和急性施用 IGF-1 来研究年轻和年老的大鼠。我们将阻断 IGF-1 和胰岛素受体，并阻断一些 IGF-1/胰岛素信号通路，以确定 IGF-1 在 CNS 中作用的下游通路。同样，我们将急性和长期外周注射 BP3 和 ICV，以及缺乏 BP3 活性位点的 BP3 突变体。从长期服用IGF-1（SA1）和BP3（SA2）的研究中，我们将了解它们对身体脂肪分布、肌肉质量、能量消耗和脂肪库的生物学特性的相反影响（通过基因阵列技术和RT-PCR ）。通过急性研究，我们将确定 IGF-1 (SA3) 和 BP3 (SA4) 对外周和肝脏胰岛素作用的相反作用（通过钳夹技术）。 由于 GH 给药对衰老受试者有不必要的副作用，因此更好地了解由于 GH/IGF-1/BP3 轴下降而导致的年龄依赖性变化可能会导致更好的策略来预防和/或逆转这一代谢群。老化过程早期的缺陷。