Chang-Chen K J, Mullur R, Bernal-Mizrachi E
Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, USA.
Rev Endocr Metab Disord. 2008 Dec;9(4):329-43. doi: 10.1007/s11154-008-9101-5.
Type 2 diabetes mellitus is a complex disease characterized by beta-cell failure in the setting of insulin resistance. In early stages of the disease, pancreatic beta-cells adapt to insulin resistance by increasing mass and function. As nutrient excess persists, hyperglycemia and elevated free fatty acids negatively impact beta-cell function. This happens by numerous mechanisms, including the generation of reactive oxygen species, alterations in metabolic pathways, increases in intracellular calcium and the activation of endoplasmic reticulum stress. These processes adversely affect beta-cells by impairing insulin secretion, decreasing insulin gene expression and ultimately causing apoptosis. In this review, we will first discuss the regulation of beta-cell mass during normal conditions. Then, we will discuss the mechanisms of beta-cell failure, including glucotoxicity, lipotoxicity and endoplasmic reticulum stress. Further research into mechanisms will reveal the key modulators of beta-cell failure and thus identify possible novel therapeutic targets. Type 2 diabetes mellitus is a multifactorial disease that has greatly risen in prevalence in part due to the obesity and inactivity that characterize the modern Western lifestyle. Pancreatic beta-cells possess the potential to greatly expand their function and mass in both physiologic and pathologic states of nutrient excess and increased insulin demand. beta-cell response to nutrient excess occurs by several mechanisms, including hypertrophy and proliferation of existing beta-cells, increased insulin production and secretion, and formation of new beta-cells from progenitor cells [1, 2]. Failure of pancreatic beta-cells to adequately expand in settings of increased insulin demand results in hyperglycemia and diabetes. In this review, we will first discuss the factors involved in beta-cell growth and then discuss the mechanisms by which beta-cell expansion fails and leads to beta-cell failure and diabetes (Fig. 1).
2型糖尿病是一种复杂疾病，其特征为在胰岛素抵抗的情况下β细胞功能衰竭。在疾病早期，胰腺β细胞通过增加数量和功能来适应胰岛素抵抗。随着营养过剩持续存在，高血糖和游离脂肪酸升高会对β细胞功能产生负面影响。这通过多种机制发生，包括活性氧的产生、代谢途径的改变、细胞内钙的增加以及内质网应激的激活。这些过程通过损害胰岛素分泌、降低胰岛素基因表达并最终导致细胞凋亡，对β细胞产生不利影响。在本综述中，我们将首先讨论正常情况下β细胞数量的调节。然后，我们将讨论β细胞功能衰竭的机制，包括糖毒性、脂毒性和内质网应激。对这些机制的进一步研究将揭示β细胞功能衰竭的关键调节因子，从而确定可能的新型治疗靶点。2型糖尿病是一种多因素疾病，其患病率大幅上升，部分原因是现代西方生活方式的肥胖和缺乏运动特征。胰腺β细胞在营养过剩和胰岛素需求增加的生理和病理状态下，都具有极大地扩展其功能和数量的潜力。β细胞对营养过剩的反应通过多种机制发生，包括现有β细胞的肥大和增殖、胰岛素产生和分泌增加，以及祖细胞形成新的β细胞[1,2]。在胰岛素需求增加的情况下，胰腺β细胞未能充分扩展会导致高血糖和糖尿病。在本综述中，我们将首先讨论参与β细胞生长的因素，然后讨论β细胞扩展失败并导致β细胞功能衰竭和糖尿病的机制（图1）。
