"Treasure Your Exceptions"-Studying Human Extreme Phenotypes to Illuminate Metabolic Health and Disease: The 2019 Banting Medal for Scientific Achievement Lecture

Stephen O'Rahilly, Stephen O'Rahilly

Abstract

The study of humans with genetic mutations which lead to a substantial disturbance of physiological processes has made a contribution to biomedical science that is disproportionate to the rarity of affected individuals. In this lecture, I discuss examples of where such studies have helped to illuminate two areas of human metabolism. First, the control of insulin sensitivity and its disruption in states of insulin resistance and second, the regulation of energy balance and its disturbances in obesity.

© 2020 by the American Diabetes Association.

Figures

Figure 1
Figure 1
Robert Turner (1938–1999). An exceptional physician-scientist.
Figure 2
Figure 2
Loss-of-function (LOF) mutations in components of the insulin signaling pathway found in patients with syndromes characterized by severe insulin resistance. PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate.
Figure 3
Figure 3
Studies of the pathophysiology of insulin resistance syndrome indicate that patients with lipodystrophy share all the key features characteristic of common metabolic syndrome. In contrast, patients with primary disorders disrupting insulin signaling have only a subset of such features and do not have all the typical features of metabolic syndrome.
Figure 4
Figure 4
The “Soggy Bathroom Carpet” model of metabolic disease.
Figure 5
Figure 5
Severe early-onset obesity resulting from congenital leptin deficiency in two first cousins, ages 8 and 2 years.
Figure 6
Figure 6
The physiological role of GDF15, a sentinel hormone signaling a range of somatic stresses to the brain. AP, area postrema; NTS, nucleus tractus solitarius; PI3K, phosphatidylinositol 3-kinase.

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Source: PubMed

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