Al-Mrabeh Ahmad
Faculty of Medical Sciences, Translational and Clinical Research Institute, Magnetic Resonance Centre, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Biomedicines. 2021 Feb 23;9(2):226. doi: 10.3390/biomedicines9020226.
Cardiovascular disease (CVD) remains a major problem for people with type 2 diabetes mellitus (T2DM), and dyslipidemia is one of the main drivers for both metabolic diseases. In this review, the major pathophysiological and molecular mechanisms of β-cell dysfunction and recovery in T2DM are discussed in the context of abnormal hepatic lipid metabolism and cardiovascular health. (i) In normal health, continuous exposure of the pancreas to nutrient stimulus increases the demand on β-cells. In the long term, this will not only stress β-cells and decrease their insulin secretory capacity, but also will blunt the cellular response to insulin. (ii) At the pre-diabetes stage, β-cells compensate for insulin resistance through hypersecretion of insulin. This increases the metabolic burden on the stressed β-cells and changes hepatic lipoprotein metabolism and adipose tissue function. (iii) If this lipotoxic hyperinsulinemic environment is not removed, β-cells start to lose function, and CVD risk rises due to lower lipoprotein clearance. (iv) Once developed, T2DM can be reversed by weight loss, a process described recently as remission. However, the precise mechanism(s) by which calorie restriction causes normalization of lipoprotein metabolism and restores β-cell function are not fully established. Understanding the pathophysiological and molecular basis of β-cell failure and recovery during remission is critical to reduce β-cell burden and loss of function. The aim of this review is to highlight the link between lipoprotein export and lipid-driven β-cell dysfunction in T2DM and how this is related to cardiovascular health. A second aim is to understand the mechanisms of β-cell recovery after weight loss, and to explore new areas of research for developing more targeted future therapies to prevent T2DM and the associated CVD events.
心血管疾病（CVD）仍然是2型糖尿病（T2DM）患者面临的主要问题，而血脂异常是这两种代谢性疾病的主要驱动因素之一。在本综述中，将在肝脏脂质代谢异常和心血管健康的背景下讨论T2DM中β细胞功能障碍和恢复的主要病理生理及分子机制。（i）在正常健康状态下，胰腺持续暴露于营养刺激会增加对β细胞的需求。从长远来看，这不仅会给β细胞带来压力并降低其胰岛素分泌能力，还会削弱细胞对胰岛素的反应。（ii）在糖尿病前期阶段，β细胞通过胰岛素过度分泌来补偿胰岛素抵抗。这增加了应激β细胞的代谢负担，并改变肝脏脂蛋白代谢和脂肪组织功能。（iii）如果这种脂毒性高胰岛素血症环境不被消除，β细胞开始失去功能，由于脂蛋白清除率降低，CVD风险上升。（iv）一旦发生，T2DM可通过体重减轻得到逆转，这一过程最近被称为缓解。然而，热量限制导致脂蛋白代谢正常化并恢复β细胞功能的确切机制尚未完全明确。了解缓解期间β细胞衰竭和恢复的病理生理及分子基础对于减轻β细胞负担和功能丧失至关重要。本综述的目的是强调T2DM中脂蛋白输出与脂质驱动的β细胞功能障碍之间的联系，以及这与心血管健康的关系。第二个目的是了解体重减轻后β细胞恢复的机制，并探索新的研究领域，以开发更具针对性的未来疗法，预防T2DM及相关的CVD事件。
