Maedler K, Donath M Y
Division of Endocrinology and Diabetes, University Hospital Zürich, Switzerland.
Horm Res. 2004;62 Suppl 3:67-73. doi: 10.1159/000080503.
Type 2 diabetes mellitus manifests itself in individuals who lose the ability to produce sufficient amounts of insulin to maintain normoglycaemia in the face of insulin resistance. The ability to secrete adequate amounts of insulin depends on beta-cell function and mass. Chronic hyperglycaemia is detrimental to pancreatic beta-cells, causing impaired insulin secretion and playing an essential role in the regulation of beta-cell turnover. This paper will address the effect of chronically elevated glucose levels on beta-cell turnover and function. In previous studies we have shown that elevated glucose concentrations induce apoptosis in human beta-cells due to an interaction between constitutively expressed Fas ligand and upregulated Fas. Human beta-cells produce interleukin (IL)-1beta in response to high glucose concentrations, independently of an immune-mediated process. This was antagonized by the IL-1 receptor antagonist (IL-1Ra), a naturally occurring anti-inflammatory cytokine also found in the beta-cell. Therefore the balance of IL-1beta and IL-1Ra may play a crucial role in the pathogenesis of diabetes. Inhibition of glucotoxicity represents a promising therapeutic stratagem in diabetes therapy to preserve functional beta-cell mass.
2型糖尿病在那些面对胰岛素抵抗时失去产生足够量胰岛素以维持正常血糖能力的个体中表现出来。分泌足够量胰岛素的能力取决于β细胞功能和数量。慢性高血糖对胰腺β细胞有害，导致胰岛素分泌受损，并在β细胞更新调节中起重要作用。本文将探讨长期升高的葡萄糖水平对β细胞更新和功能的影响。在先前的研究中，我们已经表明，由于组成性表达的Fas配体与上调的Fas之间的相互作用，升高的葡萄糖浓度会诱导人β细胞凋亡。人β细胞在高葡萄糖浓度下产生白细胞介素（IL）-1β，这与免疫介导的过程无关。这被IL-1受体拮抗剂（IL-1Ra）所拮抗，IL-1Ra是一种天然存在的抗炎细胞因子，也存在于β细胞中。因此，IL-1β和IL-1Ra的平衡可能在糖尿病发病机制中起关键作用。抑制糖毒性是糖尿病治疗中一种有前景的治疗策略，以保留功能性β细胞数量。
