Dineley Kelly T, Jahrling Jordan B, Denner Larry
Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
Neurobiol Dis. 2014 Dec;72 Pt A:92-103. doi: 10.1016/j.nbd.2014.09.001. Epub 2014 Sep 16.
Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD.
胰岛素是调节新陈代谢的关键激素。胰岛素与细胞表面胰岛素受体结合会激活许多并行和串行运作的信号中间体,以控制葡萄糖、能量和脂质,同时还调节细胞增殖和发育。这些中间体中任何一种功能的紊乱,在多种疾病中都会出现,会导致对胰岛素的敏感性降低和胰岛素抵抗,进而引发代谢功能障碍。随之而来的慢性炎症会加剧代谢稳态的受损。由于胰岛素在学习和记忆中起关键作用,并且直接调节早期阿尔茨海默病(AD)中受损的那种学习和记忆所需的激酶ERK,胰岛素抵抗已被确定为AD发病的主要危险因素。AD或胰岛素抵抗或两者兼具的动物模型表明,AD病理和胰岛素信号受损形成了一种相互关系。值得注意的是,针对改善胰岛素抵抗的人类和动物模型研究已导致将核受体和转录因子过氧化物酶体增殖物激活受体γ(PPARγ)确定为早期AD的干预工具。对胰岛素信号网络内其他节点的策略性靶向已在动物模型中揭示了与先前和正在进行的临床试验方法相契合的疾病阶段治疗窗口。因此,利用胰岛素抵抗与AD之间的联系为描绘减缓或阻断AD发病机制的治疗干预措施提供了有力机会。