University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Diabet Med. 2011 Dec;28(12):1476-86. doi: 10.1111/j.1464-5491.2011.03463.x.
Sir Harold Himsworth first observed and articulated the phenomenon of insulin resistance in the late 1930s. Although a long delay followed before his observations were acknowledged and enshrined in formal diagnostic classifications of diabetes mellitus, insulin resistance-related pathology in the early 21st century poses one of the major global healthcare challenges for contemporary physicians. Whilst insulin resistance is closely related to obesity and decreased physical fitness, despite intensive investigation it has proved extremely challenging to discriminate key events in its causation from epiphenomena, many related to compensation for the primary defect. Thus, a complete account of the molecular pathogenesis of insulin resistance-related diseases remains elusive. One approach circumventing such problems is the study of patients with single gene defects causing severe insulin resistance. In such patients the primary defect is known, and thus lessons may be learned about human physiology from detailed physiological study allied to knowledge of the function of the mutated protein. This review discusses developments in understanding of monogenic severe insulin resistance since discovery of the first insulin receptor mutations in 1988 and reviews the physiological lessons learnt, including the critical role of adipose tissue in human metabolic health and the meaning and importance of 'partial' insulin resistance for major human disease.
哈罗德·希姆斯沃思爵士（Sir Harold Himsworth）于 20 世纪 30 年代末首次观察到并阐述了胰岛素抵抗现象。尽管在此之后，他的观察结果被承认并被纳入糖尿病的正式诊断分类经历了很长一段时间，但在 21 世纪早期，与胰岛素抵抗相关的病理学给当代医生带来了全球医疗保健的主要挑战之一。尽管胰岛素抵抗与肥胖和身体活动减少密切相关，但尽管进行了深入研究，仍极难区分其病因中的关键事件与继发现象，许多继发现象与对主要缺陷的代偿有关。因此，对胰岛素抵抗相关疾病的分子发病机制的全面描述仍然难以捉摸。一种解决此类问题的方法是研究因单个基因突变导致严重胰岛素抵抗的患者。在这些患者中，主要缺陷是已知的，因此，通过对突变蛋白功能的了解和详细的生理学研究，可能会了解到有关人类生理学的知识。这篇综述讨论了自 1988 年首次发现胰岛素受体突变以来，对单基因严重胰岛素抵抗的理解的发展，并回顾了从中吸取的生理学教训，包括脂肪组织在人类代谢健康中的关键作用，以及“部分”胰岛素抵抗对重大人类疾病的意义和重要性。
