3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, Guimarães, Portugal.
ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Adv Exp Med Biol. 2020;1250:159-176. doi: 10.1007/978-981-15-3262-7_11.
Diabetes mellitus type 2 (type-2 diabetes) is a metabolic disorder characterized by the increased blood glucose concentration and insulin resistance in peripheral tissues (e.g., muscles and adipose tissue). The initiation of the pathological cascade of events that lead to type-2 diabetes has been subject of debate; however, it has been commonly accepted that the oversecretion of human islet amyloid polypeptide (hIAPP, a hormone co-secreted with insulin) by the pancreatic 𝛽-cells is the main trigger of type-2 diabetes. In fact, 90% of the type-2 diabetes patients present hIAPP deposits in the extracellular space of the 𝛽-cells. These hIAPP supramolecular arrangements (both fibrillar and oligomeric) have been reported to be the origin of cytotoxicity, which leads to 𝛽-cell dysfunction through a series of different mechanisms, including the interaction of hIAPP oligomers with the cell membrane that leads to the influx of Ca and increase in the cellular oxidative stress, among others. This overview shows the importance of developing type-2 diabetes treatment strategies able to (1) remodel of the secondary structure of cytotoxic hIAPP oligomers entrapping them into off-pathway nontoxic species and (2) reestablish physiological levels of oxidative stress. Natural polyphenols are a class of antioxidant compounds that are able to perform both functions. Herein we review the published literature of the most studied polyphenols, in particular for their ability to remodel the hIAPP aggregation pathway, to rescue the in vitro pancreatic 𝛽-cell viability and function, as well as to perform under a complex biological environment, i.e., in vivo animal models and clinical trials. Overall, natural polyphenols are able to control the cytotoxic hIAPP aggregation and minimize hIAPP-mediated cellular dysfunction and can be considered as important lead compounds for the treatment of type-2 diabetes.
2 型糖尿病（type-2 diabetes）是一种代谢紊乱疾病，其特征为外周组织（如肌肉和脂肪组织）中血糖浓度升高和胰岛素抵抗。导致 2 型糖尿病的病理级联事件的起始一直存在争议；然而，人们普遍认为胰腺β细胞中人胰岛淀粉样多肽（hIAPP，与胰岛素共同分泌的激素）的过度分泌是 2 型糖尿病的主要触发因素。事实上，90%的 2 型糖尿病患者的β细胞外泌体中存在 hIAPP 沉积。这些 hIAPP 超分子结构（纤维状和寡聚体）已被报道是细胞毒性的起源，通过一系列不同的机制导致β细胞功能障碍，包括 hIAPP 寡聚体与细胞膜的相互作用导致 Ca 内流增加和细胞氧化应激增加等。本文综述了开发 2 型糖尿病治疗策略的重要性，这些策略能够（1）重塑具有细胞毒性的 hIAPP 寡聚物的二级结构，将其包裹成非毒性的异常途径物种，（2）重建生理水平的氧化应激。天然多酚是一类具有抗氧化作用的化合物，能够同时实现这两种功能。本文综述了已发表的研究最广泛的多酚类化合物的文献，特别是它们重塑 hIAPP 聚集途径的能力，以挽救体外胰腺β细胞活力和功能，以及在复杂的生物环境（即体内动物模型和临床试验）下的表现。总的来说，天然多酚能够控制具有细胞毒性的 hIAPP 聚集并最小化 hIAPP 介导的细胞功能障碍，可被视为治疗 2 型糖尿病的重要先导化合物。
