Groop L C
Department of Endocrinology, Lund University, University Hospital Malmö, Sweden.
Diabetes Obes Metab. 1999 May;1 Suppl 1:S1-7. doi: 10.1046/j.1463-1326.1999.0010s1001.x.
Type 2 diabetes is a heterogeneous condition that is not attributable to a single pathophysiological mechanism. In general, both insulin resistance and impaired insulin secretion are required for the disease to become manifest. Thus, as long as the pancreatic beta cells can compensate for the degree of insulin resistance, glucose tolerance remains normal. Clustering of type 2 diabetes in certain families and ethnic populations points to a strong genetic background for the disease. However, environmental factors such as obesity and a sedentary lifestyle are usually required to unmask the genes. Impaired insulin-stimulated glucose metabolism (particularly non-oxidative) in skeletal muscle represents a key feature of type 2 diabetes and is observed early in the pre-diabetic state. It is not clear, though, whether this represents an inherited defect in muscle or whether it develops secondarily, for example, to abdominal obesity. In favour of the latter hypothesis are findings that abdominal obesity and a low metabolic rate seem to precede the development of insulin resistance in offspring of type 2 diabetic patients. According to the thrifty gene hypothesis, individuals living in an environment with an unstable food supply could increase their probability of survival if they could maximize storage of surplus energy, for instance, as abdominal fat. Exposing this energy-storing genotype to the abundance of food typical of westernized societies is detrimental, causing insulin resistance and, subsequently, type 2 diabetes. There are a number of potential thrifty genes, including those that regulate lipolysis or code for the beta3-adrenergic receptor, the hormone-sensitive lipase, and lipoprotein lipase. Type 2 diabetes develops as a consequence of a collision between thrifty genes and a hostile affluent environment. Insulin resistance is a key trigger for the disease, and optimal management of type 2 diabetes should therefore aim to ameliorate insulin resistance early.
2型糖尿病是一种异质性疾病，不能归因于单一的病理生理机制。一般来说，疾病的发生需要胰岛素抵抗和胰岛素分泌受损同时存在。因此，只要胰腺β细胞能够代偿胰岛素抵抗的程度，糖耐量就会保持正常。2型糖尿病在某些家族和种族人群中的聚集现象表明该病具有很强的遗传背景。然而，通常需要肥胖和久坐不动的生活方式等环境因素来使这些基因显现出来。骨骼肌中胰岛素刺激的葡萄糖代谢受损（尤其是非氧化代谢）是2型糖尿病的一个关键特征，在糖尿病前期状态早期就可观察到。不过，尚不清楚这是代表肌肉中的遗传性缺陷，还是继发产生的，例如继发于腹部肥胖。支持后一种假设的证据是，在2型糖尿病患者的后代中，腹部肥胖和低代谢率似乎先于胰岛素抵抗的出现。根据节俭基因假说，生活在食物供应不稳定环境中的个体，如果能够将多余能量最大化储存，比如储存为腹部脂肪，就可以增加生存概率。将这种能量储存基因型暴露于西方化社会典型的丰富食物环境中是有害的，会导致胰岛素抵抗，进而引发2型糖尿病。有许多潜在的节俭基因，包括那些调节脂肪分解或编码β3 - 肾上腺素能受体、激素敏感性脂肪酶和脂蛋白脂肪酶的基因。2型糖尿病是节俭基因与不利的富裕环境相互作用的结果。胰岛素抵抗是该疾病的关键触发因素，因此2型糖尿病的最佳管理应旨在尽早改善胰岛素抵抗。
