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Reflections on the History and Biology of Insulin and Leptin REVIEW Starvation in the Midst of Plenty: Reflections on the History and Biology of Insulin and Leptin Jeffrey S. Flier1 1Department of Medicine and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115 ORCiD numbers: 0000-0001-8606-3640 (J. S. Flier). ABSTRACT Insulin and leptin are critical metabolic hormones that play essential but distinct roles in regulating the physiologic switch between the fed and starved states. The discoveries of insulin and leptin, in 1922 and 1994, respectively, arose out of radically different scientific environments. Despite the dearth of scientific tools available in 1922, insulin’s discovery rapidly launched a life- saving therapy for what we now know to be type I diabetes, and continually enhanced insulin therapeutics are now effectively applied to both major forms of this increasingly prevalent disease. In contrast, although the discovery of leptin provided deep insights into the regulation of central nervous system energy balance circuits, as well as an effective therapy for an extremely rare form of obesity, its therapeutic impact beyond that has been surprisingly limited. Despite an enormous accumulated body of information, many important questions remain unanswered about the mechanisms of action and role in disease of both hormones. Additionally, although many decades apart, both discoveries reveal the complexities inherent to scientific collaboration and the assignment of credit, even when the efforts are spectacularly successful. (Endocrine Reviews 40: 1 – 16, 2019) he history of endocrinology often begins (b)] (). Although starvationandobesitycould T with accounts of the discovery of hormones. not, on the surface, be more different, starvation is These discoveries enable subsequent research actually a key physiologic feature of both insulin into the physiology, mechanisms of action, and and leptin deficiencies. Type I diabetes has been rolesofhormonesinpathogenesisandthera- described as “starvation in the midst of plenty.” peutics of disease. Insulin and leptin are two Why? Despite hyperphagia and high levels critical hormonal regulators of metabolism. Dis- of circulating fuels, insulin deficiency prevents covered years apart, in and ,exam- effective use of fuels by many tissues, hence ination of the similarities and differences between “starving” them of nutrition. However, despite these venerable hormones provides important their massive obesity, the physiology of leptin- ISSN Print: 0163-769X insights into the history of these molecules deficient children also entails starvation in the ISSN Online: 1945-7189 as well as the broader evolution of metabolic midst of plenty. In this case, primary leptin deficiency Printed: in USA science. causes brain centers that control hunger and energy Copyright © 2019 Endocrine Society Insulin and leptin play very different roles in “ ” balance to believe the body is starving, and these This article has been published human physiology, and, accordingly, children centers drive unrestrained hyperphagia and weight gain under the terms of the lacking these hormones have starkly disparate despite increased adipose stores. Creative Commons phenotypes (Fig. )(, ). In ,anemaciated Despite insulin and leptin playing key roles in ad- Attribution License (CC BY; child with diabetes whose appearance suggested aptation to starvation, these hormones are quite distinct https://creativecommons.org/ starvation was transformed to normal appearance in other respects. The premise of this article is that much licenses/by/4.0/). Received: 19 July 2018 by daily injections of insulin [Fig. (a)] ( ). In can be learned by comparing and contrasting insulin and Accepted: 13 September 2018 , a massively obese child had his malady re- leptin—the scientific contexts within which their dis- First Published Online: versed by a course of daily leptin injections [Fig. coveries arose, their paths to discovery at the University 23 October 2018 doi: 10.1210/er.2018-00179 https://academic.oup.com/edrv 1 REVIEW ESSENTIAL POINTS · Insulin and leptin, discovered 73 years apart, are critical metabolic hormones that play distinct, nonredundant roles in regulating the physiologic switch between the fed and starved states · The paths to discovery of insulin and leptin were radically different, reflecting the state of biologic science in 1921 vs 1994, but collaboration was required in both cases, and in both cases, effective collaboration was followed by conflict within the teams · Insulin therapy for diabetes has been continuously enhanced and grown in application since its discovery, whereas leptin therapy is limited today to a very small group of patients lacking leptin and a somewhat larger group with lipodystrophy · Both insulin and leptin continue to be intensively studied, and although large amounts of new knowledge continue to accrue, key unanswered questions about the mechanisms of action and role in disease of these hormones remain unanswered of Toronto and Rockefeller University, their de- of their physiology, mechanisms of action, and velopment as therapeutics, and selected aspects pathophysiology. Scientific Context and Discoveries of Insulin including the discovery of the first hormone, se- and Leptin cretin, in (). Enter Frederick Banting, a scientifically untrained Diabetes and the discovery of insulin surgeon, recently returned from decorated surgical The discovery of insulin is among the most fasci- service in World War I, and seeking, with limited nating stories in the history of science, best success, to establish a surgical practice. After reading recounted in the book The Discovery of Insulin,by an article on the pancreas and diabetes in a surgical Canadian historian Michael Bliss (). Diabetes had journal, he became preoccupied by the idea that he been known as a disease since ancient times, when was capable of extracting the hypothesized factor sweet taste of the urine was identified as a cardinal from dog pancreas. Banting’s motivating idea was feature.Althoughitscausewasunknown,intheth that tying off the pancreatic duct of dogs to century several lines of evidence suggested a con- damage the exocrine pancreas would facilitate ff nection of diabetes to dysfunction of the pan- production of an e ective extract. This idea had creas. Most importantly, in , von Meering been proposed earlier by others, but Banting was and Minkowski reported that removal of the dog unaware of this ( ). Ironically, although the idea ’ pancreas caused blood sugar levels to rise, followed was logical and motivated Banting swork,duct by coma and death, resembling diabetes in humans. ligation was in the end not necessary for success of A number of scientists around the world then the project. By force of will, Banting convinced an appropri- sought to identify a pancreatic extract capable of ately skeptical Professor of Physiology at the Uni- lowering glucose levels after administration to ex- versity of Toronto, J. J. Macleod, to assist him. Macleod perimental animals. Despite some promising results, was an expert on metabolism who was familiar with none was definitive, and the hypothesis remained prior reported efforts to discover an antidiabetic unproven. pancreatic factor. Although highly skeptical of Bant- In , when Fred Banting initiated his quest to ing’s untutored approach and doubtful of his capacity find a pancreatic “internal secretion” in Toronto, to succeed, he nonetheless provided Banting access medical physiology was very early on the path to to a laboratory, a medical student assistant (Charles fi becoming a modern scienti c discipline, and it was Best), some dogs with which to initiate the experi- unrecognizable from its state today. There were few mental work, and suggestions (downplayed by Bant- physicians and scientists in universities, hospitals, ing) on analytical and extraction techniques. Banting’s and institutes trained to conduct experiments ca- approach to preparing tissue extracts was of course pable of interrogating physiology and disease. primitive by modern standards. Given the abundance Availabletoolswererudimentary,aswasunder- of proteolytic enzymes in pancreas, it is remarkable standing of biology at the level of molecules, cells, that he and Best obtained positive results, if only and systems. Physiology was relatively advanced erratically, in their diabetic dogs. It was even more among the scientific disciplines, so in spite of remarkable that in January of , an extract they limited tools and understanding, discoveries of prepared successfully lowered blood glucose in a di- lasting significanceweremadeduringthisera, abetic child. At a key moment during this period, when 2 Flier The History and Biology of Insulin and Leptin Endocrine Reviews, February 2019, 40(1):1–16 REVIEW Figure 1. (a) Before and after pictures of a child treated with insulin in 1922. From Bliss (1). (b) Before and after pictures of recombinant leptin treatment in a patient with congenital leptin deficiency. Before, 3 years old weighing 42 kg. After, 7 years old weighing 32 kg. [Reproduced with permission from Farooqi IS, O’Rahilly S. Twenty years of leptin: human disorders of leptin action. J Endocrinol 2014; 223(1): T63–T70. (2)] [© 2019 Illustration Presentation ENDOCRINE SOCIETY] the extraction procedure had become irreproducible, and he judged Macleod’s contribution to the discovery Macleod suggested that James Collip, an accomplished to have been important (). biochemist, be added to the team to improve the News of the therapeutic success of the extract in extraction procedure. Collip’sefforts
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