Dopamine mechanisms in development of type-2 diabetes

2 型糖尿病发展中的多巴胺机制

• 批准号: 6704050
• 负责人: ANDRAS HAJNAL
• 金额: $ 28.59万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6704050
• 关键词: age difference; biological signal transduction; dopamine; dopamine transporter; histology; hyperinsulinism; in situ hybridization; laboratory rat; male; methylphenidate; microdialysis; motivation; neurotransmitter metabolism; noninsulin dependent diabetes mellitus; overeating; prediabetic state

DESCRIPTION (provided by applicant): Obesity causes or exacerbates many chronic illnesses, most notably non-insulin-dependent diabetes mellitus (NIDDM). Most obesity is caused by modest, but chronic overeating. Otsuka Long-vans Tokushima fatty (OLETF) rats, which lack the CCK-A receptor, are hyperphagic, obese, and gradually develop NIDDM. In OLETF rats, increased food intake is necessary for the development of obesity, suggesting that the NIDDM is secondary to the prediabetic hyperphagia. Thus, OLETF rats are reasonable model of the most prevalent form of NIDDM in humans. The underlying cause of the chronic hyperphagia in this strain is unknown and cannot be explained entirely by their peripheral satiation deficits. Rather, a dysfunction in central pathways critical to the control of meal size is the most likely contributor. In this project, OLETF rats are used to study the relationship between the hyperphagic behavioral phenotype and dopamine (DA) signaling within the central motivational system during the development of type-2 diabetes. We propose that altered dopaminergic functioning in the mesoaccumbens dopamine (DA) system contributes to the overeating in OLETF rats by increasing preference for the orosensory stimulatory effects of normally preferred foods. Behavioral, neurochemical and histological methods will be employed to challenge this hypothesis. The application has four specific aims: 1) to characterize the basic dopaminergic phenotype (basal and stimulated DA release and reuptake) of the OLETF rats at three ages, reflecting the development of diabetes; 2) to characterize hyperphagic behavioral phenotype by investigating nutrient preference functions in prediabetic OLETF rats based on their orosensory and postabsorbtive properties; 3) to assess the relationship between behavior and DA signaling by comparing the effects of sham-feeding of preferred sucrose or fat solutions between prediabetic OLETF and age- and body weight-matched non-mutant control (LETO) rats; 4) to address causality of the relationship by using chronic treatment of the psychostimulant methylphenidate to reverse preference for and intake of sucrose and fat, and to delay onset of diabetes in OLETF rats. These studies will help determine how plasticity in the dopaminergic system affects behavioral and metabolic factors related to hyperphagia and the development of dietary-induced NIDDM.

描述（由申请人提供）：肥胖导致或加剧许多慢性疾病，最显著的是非胰岛素依赖型糖尿病（NIDDM）。大多数肥胖是由适度但长期的暴饮暴食引起的。缺乏CCK-A受体的OLETF （Otsuka Long-vans Tokushima fatty，简称OLETF）大鼠出现贪食、肥胖，并逐渐发展为NIDDM。在OLETF大鼠中，增加的食物摄入量是肥胖发展的必要条件，这表明NIDDM是继发于糖尿病前期贪食。因此，OLETF大鼠是人类最常见的NIDDM的合理模型。该品系慢性贪食的根本原因尚不清楚，不能完全用外周饱足不足来解释。相反，控制食量的关键中枢通路的功能障碍是最有可能的原因。本项目利用OLETF大鼠研究2型糖尿病发展过程中贪食行为表型与中枢动机系统多巴胺（DA）信号的关系。我们认为，在OLETF大鼠中，伏隔中脑多巴胺（DA）系统中多巴胺能功能的改变，通过增加对通常喜欢的食物的感官刺激作用的偏好，有助于暴饮暴食。