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（反映肥胖率的增加），并且正在上升为主要由心血管相关病理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学有关。用于治疗糖尿病的胰岛素增敏剂，如噻唑烷二酮类（TZDs）诱导线粒体生物合成，这可能部分解释其治疗作用。尽管它们具有治疗益处，但它们具有严重副作用的可能性。据报道，黄酮类化合物作为TZD诱导线粒体生物发生，有利地影响细胞和器官生物能量学。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用途尚未得到充分探索。根据这项名为“靶向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，专门负责系统地探索可可黄烷醇（-）-表儿茶素（和新型合成衍生物）对细胞/器官生物能量学的有利影响的前景。我们打算收集初步的数据，以消除黄烷醇主要作为抗氧化剂和“剂量越高，效果越大”的共同概念。相反，我们打算产生有关其对特定细胞受体作用的证据，这些受体在特定的剂量-反应曲线内起作用。在最初的种子期，我们将充分组装和整合一支由基础科学家（分子和器官生理学家）和翻译专家组成的独特且经验丰富的团队，以系统地研究表儿茶素和新型衍生物作为糖尿病前期和糖尿病治疗药物的前景。

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.