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）：肥胖原因或加剧了许多慢性疾病，最著名的是非胰岛素依赖性糖尿病（NIDDM）。大多数肥胖是由适中但长期暴饮暴食引起的。缺乏CCK-A受体的大鼠Otsuka Long-Vans Tokushima Fatty（OLETF）是肥大，肥胖的，并且逐渐发展为NIDDM。在OLETF大鼠中，增加的食物摄入量对于肥胖的发展是必要的，这表明NIDDM是糖尿病前晶状体的继发性。因此，OLETF大鼠是人类最普遍的NIDDM形式的合理模型。在这种菌株中慢性多晶状体的根本原因是未知的，不能完全通过其外周的饱腹损失来解释。相反，最有可能的贡献者是对饮食大小控制至关重要的中心途径的功能障碍。在这个项目中，OLETF大鼠用于研究中央动机系统中型号行为表型和多巴胺（DA）信号传导在2型糖尿病的发展过程中的关系。我们提出，通过增加对通常优选食品的口感感觉刺激作用的偏爱，改变了中丙胺多巴胺（DA）系统中多巴胺能功能的作用。 将采用行为，神经化学和组织学方法来挑战这一假设。该应用具有四个特定的目的：1）表征OLETF大鼠在三个年龄的基本多巴胺能表型（基底和刺激的DA释放和再摄取），这反映了糖尿病的发展； 2）通过根据其口感和效果后的特性研究糖尿病前大鼠中的养分偏好功能来表征倍率行为表型； 3）通过比较糖尿病前OLETF与年龄和体重匹配的非突变控制（LETO）大鼠的首选蔗糖或脂肪溶液的假手术的影响来评估行为和DA信号之间的关系； 4）通过使用精神刺激性哌醋甲酯的慢性治疗来解决这种关系的因果关系，以逆向蔗糖和脂肪的逆向偏好和摄入，并延迟OLETF大鼠糖尿病的发作。这些研究将有助于确定多巴胺能系统中的可塑性如何影响与脾脏相关的行为和代谢因素以及饮食诱导的NIDDM的发展。