Karaca M, Magnan C, Kargar C
Université Paris-Diderot, 75205 Paris cedex 13, France.
Diabetes Metab. 2009 Apr;35(2):77-84. doi: 10.1016/j.diabet.2008.09.007. Epub 2009 Feb 28.
In the adult, the pancreatic beta-cell mass adapts insulin secretion to meet long-term changes in insulin demand and, in particular, in the presence of insulin resistance that is either physiological, such as pregnancy, or pathophysiological, such as obesity. The failure of beta cells to compensate for insulin resistance is a major component of impaired glucose homeostasis and overt diabetes. This defect is clearly the consequence of a decline of insulin response to glucose due to functional beta-cell deficiency. It is also the consequence of an inability of the endocrine pancreas to adapt the beta-cell mass to insulin demand (pancreas plasticity), which eventually leads to a decrease in functional beta-cell mass. This idea has resulted in considerable attention being paid to the development of new therapeutic strategies aiming to preserve and/or regenerate functional beta-cell mass. The latter is governed by a constant balance between beta-cell growth (replication from pre-existing beta cells and neogenesis from precursor cells) and beta-cell death (mainly apoptosis). Disruption of this balance may lead to rapid and marked changes in beta-cell mass. Glucagon-like peptide-1 (GLP-1), an incretin, enhances beta-cell survival (by activating beta-cell proliferation and differentiation, and inhibiting beta-cell apoptosis), thus contributing to the long-term regulation of insulin secretion by maintaining a functional beta-cell mass. The development of drugs regulating this parameter will be the major challenge of the next few years in the management of type 2 diabetes.
在成年人中，胰腺β细胞群会调节胰岛素分泌，以适应胰岛素需求的长期变化，特别是在存在生理性胰岛素抵抗（如妊娠）或病理性胰岛素抵抗（如肥胖）的情况下。β细胞无法代偿胰岛素抵抗是葡萄糖稳态受损和显性糖尿病的主要因素。这种缺陷显然是由于功能性β细胞缺乏导致胰岛素对葡萄糖反应下降的结果。这也是内分泌胰腺无法使β细胞群适应胰岛素需求（胰腺可塑性）的结果，最终导致功能性β细胞群减少。这一观点使得人们相当关注旨在保存和/或再生功能性β细胞群的新治疗策略的开发。后者受β细胞生长（来自已有β细胞的复制和前体细胞的新生）与β细胞死亡（主要是凋亡）之间持续平衡的支配。这种平衡的破坏可能导致β细胞群迅速而显著的变化。胰高血糖素样肽-1（GLP-1），一种肠促胰岛素，可增强β细胞存活（通过激活β细胞增殖和分化以及抑制β细胞凋亡），从而通过维持功能性β细胞群来促进胰岛素分泌的长期调节。调节这一参数的药物开发将是未来几年2型糖尿病管理中的主要挑战。
