Endocrine Abstracts

Implicit in the justification for the enormous increase in investment in bio-molecular research that has occurred over the past 20 years has been the promise that this would provide insights relevant to the understanding of human pathophysiology and the ultimate alleviation of suffering from human disease. To this end, model organisms are enormously attractive as they provide tractable and controllable systems in which precise and ‘clean’ data can be obtained. In contrast the study of complex human disease is fraught with difficulties related to the multifactorial nature of most human illness, and the challenges of controlling for the effects of largely immeasurable confounding factors, both genetic and environmental. While it is critical that research on complex human phenotypes and diseases continues an approach that focuses on extreme human phenotypes has established itself as a useful complementary strategy. Firstly, it is more likely that extreme human phenotypes are caused by tractable monogenic or oligogenic defects. Secondly, the consequences of such defects are not always identical to those seen in animal models. Thirdly, once a link between a major mutation particular gene and a human phenotype is established it is much more likely that subtle variation in those genes is involved in influencing susceptibility to common human diseases. Finally, discoveries in this area may lead to effective mechanism-based therapies which provide justification for the continuation of investment in basic biomedical research. In this presentation I will discuss advances that have come from the studies of two cohorts of humans with extreme phenotypes, namely obesity and insulin resistance.