How does insulin resistance arise, and how does it cause disease?: Human genetic lessons
European Journal of Endocrinology
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Semple, R. (2016). How does insulin resistance arise, and how does it cause disease?: Human genetic lessons. European Journal of Endocrinology, 174 R209-R223. https://doi.org/10.1530/EJE-15-1131
Insulin orchestrates physiological responses to ingested nutrients, however although it elicits widely ramifying metabolic and trophic responses from diverse tissues, "insulin resistance", a pandemic metabolic derangement commonly associated with obesity, is usually defined solely by blunting of insulin's hypoglycaemic effect. Recent study of monogenic forms of insulin resistance has established that biochemical subphenotypes of insulin resistance exist, clustering into those caused by primary disorders of adipose tissue, and those caused by primary defects in proximal insulin signalling. Insulin resistance is often first recognised by virtue of its associated disorders, including type 2 diabetes, dyslipidaemia, fatty liver and polycystic ovary syndrome. Although these clinically observed associations are confirmed by cross sectional and longitudinal population-based studies, causal relationships among these phenomena have been more difficult to establish. Single gene insulin resistance is important to recognise in order to optimise clinical management, and also permits testing of causal relationships among components of the insulin resistance syndrome using the principle of Mendelian randomisation. Thus, where a precisely defined genetic defect is identified that directly produces one component of the syndrome, then phenomena that are causally linked to that component should be seen. Where this is not the case, then a simple causal link is refuted. This article summarises known forms of monogenic severe insulin resistance and considers the lessons to be learned about the pathogenic mechanisms both upstream from common insulin resistance, and those downstream linking it to disorders such as dyslipidaemia, fatty liver, polycystic ovary syndrome and cancer.
insulin resistance, genetics, lipodystrophy, insulin receptor, fatty liver, PCOS, polycystic ovaries, diabetes, phosphatidylinositol-3-kinase, insulin signalling
Dr Semple is supported by a Senior Research Fellowship from the Wellcome Trust [Grant 7WT098498].
Wellcome Trust (098498/Z/12/Z)
External DOI: https://doi.org/10.1530/EJE-15-1131
This record's URL: https://www.repository.cam.ac.uk/handle/1810/253829