Endocrine Abstracts

My career has been shaped by two real legends of endocrinology, Nick Hales and Steve O’Rahilly. Nick first introduced me to both the fascination of insulin action and the power of antibodies as analytical reagents, when for my PhD I set up immunoassays for cyclic nucleotides and applied these in studies of metabolic regulation. After Cesar Milstein described techniques to produce monoclonal antibodies, I used that technology in the development of immunoassays for polypeptides and then in the study of cell surface receptors. In the 1980s, with commercial support my lab established ultrasensitive, two-site immunoassays for glycoprotein hormones and, in collaboration with Nick, specific assays for proinsulin. However my focus turned back to the mechanism of insulin action as my group developed large panels of monoclonal antibodies for insulin receptors and IGF-1 receptors. In the early 1990s Nick recruited Steve O’Rahilly to the department, who immediately became an inspiring colleague. My group discovered that the structurally related receptors for insulin and IGF-1 can assemble as heteromeric hybrids and, in collaboration with Steve, we studied mechanisms underlying specificity in the actions of insulin and IGFs. An intriguing property of many anti-receptor antibodies was their ability to activate receptors and act as insulin-mimetics, an action that extends to some mutant receptors that are not responsive to insulin itself. As my own career draws to a close, my former colleagues Rob Semple and Gemma Brierley are now exploring the potential to use anti-receptor antibodies as therapeutics in insulin-resistance syndromes. For more than 50 years I have been excited to see advances in understanding insulin receptor structure and function and the mechanism of insulin action, while collaborations have always been central to my own productivity and the satisfaction. It has always been a lot of fun!