Targeting cellular bioenergetics for the prevention and treatment of diabetes

描述（由申请人提供）：糖尿病是美国增长最快的疾病（反映了肥胖率的增长），并且正在上升为主要由心血管相关疾病引起的死亡的主要原因。目前糖尿病患病率约为9%，糖尿病前期患病率约为30%。据估计，2007年美国糖尿病的直接和间接费用为1740亿美元。令人信服的证据表明，线粒体功能障碍与肥胖、胰岛素抵抗和2型糖尿病的病理生理有关。用于治疗糖尿病的胰岛素增敏剂如噻唑二酮类（TZDs）可诱导线粒体生物发生，这可能部分解释了它们的治疗作用。尽管它们具有治疗作用，但它们也有可能产生严重的副作用。据报道，黄酮类化合物作为TZDs可以诱导线粒体生物发生，对细胞和器官的生物能量学产生有利的影响。这类天然化合物通常被认为是安全的。然而，它们作为治疗糖尿病前期或糖尿病的药物的可能性尚未得到充分探讨。根据这项题为“针对细胞生物能量学治疗糖尿病前期和糖尿病：团队方法”的提案，我们将创建一个高度整合的多学科研究团队，专门组织系统地探索可可黄烷醇(-)-表儿茶素（和新的合成衍生物）对细胞/器官生物能量学的有利影响。我们打算收集初步数据，以消除黄烷醇主要作为抗氧化剂以及“剂量越大，效果越好”的普遍观念。相反，我们打算产生有关它们在特定剂量-反应谱中作用于特定细胞受体的影响的证据。在最初的种子期，我们将充分组建和整合一个由基础科学家（分子和器官生理学家）和转化专家组成的独特和经验丰富的团队，系统地研究表儿茶素及其新衍生物作为治疗前驱糖尿病和糖尿病的药物的前景。

DESCRIPTION (provided by applicant): Diabetes is the fastest growing disease in the USA (mirroring increases in obesity rates) and is rising as a leading cause of death mostly from cardiovascular related pathologies. The current prevalence of diabetes is ~9% with a further ~30% as pre-diabetics. Estimated 2007 direct and indirect costs of diabetes in the USA are $174 billion. Compelling evidence has emerged implicating mitochondrial dysfunction in the pathophysiology of obesity, insulin resistance and type 2 diabetes. Insulin sensitizing agents used for the treatment of diabetes such as thiazoledinediones (TZDs) induce mitochondrial biogenesis and this may partly explain their therapeutic action. In spite of their therapeutic benefit they however, have the potential for serious side-effects. Flavonoids as TZDs have been reported to induce mitochondrial biogenesis favorably impacting cellular and organ bioenergetics. This class of natural compounds is in general, recognized as safe. However, their possible use as drugs for the treatment of pre-diabetes or diabetes has been poorly explored. Under this proposal, entitled "Targeting cellular bioenergetics for the treatment of pre-diabetes and diabetes: A team approach", we will create a highly integrated, multidisciplinary research team specifically assembled to systematically explore the prospect of the cacao flavanol (-)-epicatechin (and novel synthetic derivatives) to favorably affect cellular/organ bioenergetics. We intend to gather preliminary data to dispel the common notion that flavanols act mainly as antioxidans and that "the higher the dose, the greater the effect". Rather, we intend to generate evidence pertaining to their effect on specific cell receptors acting within specific dose-response profiles. During this initial seed period, we will fully assemble and integrate a unique and highly-experienced team consisting of basic scientists (molecular and organ physiologists) and translational experts to systematically examine the promise of epicatechin and novel derivatives as agents for the treatment of pre-diabetes and diabetes.