Leahy Jack L
University of Vermont College of Medicine, Burlington, VT 05405, USA.
Arch Med Res. 2005 May-Jun;36(3):197-209. doi: 10.1016/j.arcmed.2005.01.003.
The pathological sequence for type 2 diabetes is complex and entails many different elements that act in concert to cause that disease. This review proposes a sequence of events and how they interact by a careful analysis of the human and animal model literature. A genetic predisposition must exist, although to date very little is known about specific genetic defects in this disease. Whether the diabetes phenotype will occur depends on many environmental factors that share an ability to stress the glucose homeostasis system, with the current explosion of obesity and sedentary lifestyle being a major cause of the worldwide diabetes epidemic. We also propose that a lowered beta-cell mass either through genetic and/or beta-cell cytotoxic factors predisposes for glucose intolerance. As the blood glucose level rises even a small amount above normal, then acquired defects in the glucose homeostasis system occur--initially to impair the beta cell's glucose responsiveness to meals by impairing the first phase insulin response--and cause the blood glucose level to rise into the range of impaired glucose tolerance (IGT). This rise in blood glucose, now perhaps in concert with the excess fatty acids that are a typical feature of obesity and insulin resistance, cause additional deterioration in beta-cell function along with further insulin resistance, and the blood glucose levels rise to full-blown diabetes. This sequence also provides insight into how to better prevent or treat type 2 diabetes, by studying the molecular basis for the early defects, and developing targeted therapies against them.
2型糖尿病的病理过程复杂，涉及许多不同因素，这些因素共同作用导致该疾病。本综述通过对人类和动物模型文献的仔细分析，提出了一系列事件及其相互作用方式。虽然目前对该疾病的特定基因缺陷知之甚少，但遗传易感性肯定存在。糖尿病表型是否会出现取决于许多能够给葡萄糖稳态系统造成压力的环境因素，当前肥胖症的激增和久坐不动的生活方式是全球糖尿病流行的主要原因。我们还提出，无论是通过遗传因素和/或β细胞细胞毒性因素导致的β细胞量减少，都易引发葡萄糖不耐受。当血糖水平即使比正常水平略有升高时，葡萄糖稳态系统就会出现后天性缺陷——最初是通过损害第一阶段胰岛素反应来削弱β细胞对进食的葡萄糖反应能力——并导致血糖水平上升到糖耐量受损（IGT）范围。血糖的这种升高，现在可能与肥胖和胰岛素抵抗的典型特征——过量脂肪酸共同作用，导致β细胞功能进一步恶化以及胰岛素抵抗加剧，血糖水平上升至全面糖尿病状态。这个过程也为通过研究早期缺陷的分子基础并开发针对这些缺陷的靶向治疗方法，更好地预防或治疗2型糖尿病提供了思路。
