An Appreciation of Robert Turner

Robert Turner (1938–1999) was a remarkable man. Although he is perhaps best known for the groundbreaking UK Prospective Diabetes Study (UKPDS), the breadth and depth of his contributions to diabetes research are remarkable. It is a privilege for us, just a few of his many close friends and colleagues, to be able to review his contributions as a scientist and to remember him as a unique human being. His seminal discoveries spanned three broad areas of diabetes research—namely, the physiology of insulin secretion, the etiopathogenesis of type 2 diabetes, and the clinical management of diabetes. In all of these areas, his combination of intense curiosity, intelligence, indefatigability, and passion for improved patient care led to landmark discoveries that have withstood the test of time. Robert was a medical student in Cambridge and undertook his clinical training and MD research at the Middlesex Hospital in London with Dr. John Nabarro; his thesis was entitled “Plasma Glucose Control of Insulin Secretion in Man.” The interactions of insulin and glucose occupied much of his physiological interests in those early days. His early mathematical examination of insulin delivery rate (1) was rediscovered many years later, and the concepts of feedback control were brilliantly exemplified with fish insulin, which cleared glucose but did not cross-react with insulin assays, thus allowing endogenous insulin to be assayed (2). In these early days, through exposure to scientists such as Roger Ekins, a pioneer of immunoassay, Robert was discovering that lab-based techniques were the window into complex in vivo interactions. He moved to Oxford in the early 1970s and began to develop the Diabetes Research Laboratory (DRL), which, from humble beginnings, became one of the world’s leading centers for diabetes research. The DRL began to hum with activity as the charcoal separation assay developed when Robert was working with Ekins at the Middlesex was further refined and perfected (3). C-peptide assays then came online, and the complex interactions between glucose and insulin began to be delineated and modeled. Robert attracted enthusiastic young clinical researchers such as Rury Holman and David Matthews with a likeminded bent toward mathematical understanding of physiology, and their studies of feedback models of the “livercell loop” (4) and the description of insulin oscillations (5–7) proved to be seminal observations that continue to influence physiological thinking to this day. These were further formalized and delineated in the homeostasis assessment (HOMA) and continuous infusion glucose model assessment (CIGMA) models (8,9) that are now used widely. The original article describing HOMA has been cited 4,600 times (8). Importantly, these observations reflected Robert’s philosophical view that diabetes should be considered as an endocrine disorder (indeed, the most important endocrine disease) involving dysfunction of the endocrine cells producing the critical hormone insulin. That may seem obvious now, but at that time, there was a widespread (and entirely false) hierarchical division in the U.K between “clever endocrinologists” who worked on fascinating but relatively uncommon endocrine disorders requiring deep thinking and sophisticated investigation, and seemingly worthy but intellectually pedestrian “sugar doctors” who struggled to look after vast numbers of patients with a common but rather uninteresting disease. Robert once commented that he would not rest until a clinician seeing a patient with diabetes would be fueled by the same desire to understand its mechanisms as was an endocrinologist when seeing a new patient with Cushing’s syndrome. Although Robert was equally interested in improving the clinical care of patients with type 1 or type 2 diabetes, he realized quite early on that he was not an immunologist and that he would be most usefully employed working out why people developed type 2 diabetes. As was so often the case, Robert’s views went against the mainstream but turned out to be right. For decades, during which the concept of insulin resistance came to utterly dominate international thinking about the pathogenesis of type 2 diabetes, Robert and his colleagues, with a small but insightful band of international colleagues (including Erol Cerasi, Gordon Weir, and Dan Porte) continued to emphasize the critical importance of inherent defects in pancreatic -cell function as a key etiological factor in the disease (10). It is sad that he did not live to see the results of the recent genome-wide association studies, which have finally vindicated his view that the principal source of inherited variation predisposing to type 2 diabetes is likely to be in genes involved in islet function (11). Robert’s work on the etiopathogenesis of type 2 diabetes can now be seen as a coherent and prescient body of work that was ahead of its time. With Rury Holman and David Matthews, he characterized the nature of the quantitative and qualitative defects in -cell function in patients at the early stages of type 2 diabetes (4,12). Stephen O’Rahilly joined the team as a research fellow, and together they demonstrated that such -cell defects were also present in nondiabetic first-degree relatives of patients with type 2 diabetes, suggesting that such defects were inherent to the disease process (13). Robert was never content to restrict himself to physiological observation and wanted to have a From the University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, U.K.; the Section on Islet Transplantation and Cell Biology, Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts; and the Oxford Centre for Diabetes, Endocrinology, and Metabolism, Oxford, U.K. Corresponding author: David R. Matthews, [email protected]. DOI: 10.2337/db07-1644 © 2008 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details.