Drug Development Failure: How GLP-1 Development Was Abandoned in 1990.

Many factors determine whether and when a class of therapeutic agents will be successfully developed and brought to market, and historians of science, entrepreneurs, drug developers, and clinicians should be interested in accounts of both successes and failures. Successes induce many participants and observers to document them, whereas failed efforts are often lost to history, in part because involved parties are typically unmotivated to document their failures. The GLP-1 class of drugs for diabetes and obesity have emerged over the past decade as clinical and financial blockbusters, perhaps soon becoming the highest single source of revenue for the pharmaceutical industry (Berk 2023). In that context, it is instructive to tell the story of the first commercial effort to develop this class of drugs for metabolic disease, and how, despite remarkable early success, the work was abandoned in 1990. Told by a key participant in the effort, this story documents history that would otherwise be lost and suggests a number of lessons about drug development that remain relevant today.

Obesity and the vitality of food in Finland, ca. 1950-1970.

Mainstream and alternative nutrition doctrines have crucially shaped our understanding of the vital aspects of and forces in human nutrition. Drawing upon a diverse array of sources, this article delves into cultural, social, and scientific conceptions of vital nutrition and how they evolved in relation to the Finnish obesity discourse from the 1950s to the 1970s. The Association to Combat Obesity (ACO), which brought together nutrition scientists, food faddists and laypeople, was the driving force of these debates. In the context of this article, food was perceived to influence the vitality of individuals and nations through its effect on body weight. Obese bodies seemed to conflict with both utopian visions of bodily transcendence and the ideals of wellbeing in modern health sciences. This work highlights the ideological continuities between interwar and postwar nutrition debates as well as the persistent tensions between scientific advancements and alternative nutrition philosophies. They have molded the conceptions of vitality and attitudes towards obesity. Concludingly, we suggest that the social responses to obesity have been influenced by the condition's perceived adverse relationship to vitality, in which fat has acted as a persistent reminder of corporeality, death, and decay.

Belly fat or bloating? New insights into the physical appearance of St Anthony of Padua.

Over the centuries, iconographic representations of St Anthony of Padua, one of the most revered saints in the Catholic world, have been inspired by literary sources, which described the Saint as either naturally corpulent or with a swollen abdomen due to dropsy (i.e. fluid accumulation in the body cavities). Even recent attempts to reconstruct the face of the Saint have yielded discordant results regarding his outward appearance. To address questions about the real appearance of St Anthony, we applied body mass estimation equations to the osteometric measurements taken in 1981, during the public recognition of the Saint's skeletal remains. Both the biomechanical and the morphometric approach were employed to solve some intrinsic limitations in the equations for body mass estimation from skeletal remains. The estimated body mass was used to assess the physique of the Saint with the body mass index. The outcomes of this investigation reveal interesting information about the body type of the Saint throughout his lifetime.

História da obesidade na classificação internacional de doenças (CID): de 1900 a 2018 / History of obesity in the international classification of diseases (ICD): 1900 to 2018

O presente artigo teve como objetivo descrever o histórico da inserção da condição clínica denominada atualmente de "obesidade" nas onze revisões da Classificação Internacional de Doenças (CID), publicadas pela Organização Mundial da Saúde (OMS), entre os anos 1900 e 2018. Para tanto, buscou-se pela palavra-chave "obesity" nos documentos, realizando, posteriormente, uma descrição e uma análise da presença, modo de inserção e as mudanças ocorridas ao longo do tempo. Os resultados demonstraram que a condição já foi e continua sendo inserida como sintoma, morbidade, coREVSmorbidade, causa de mortalidade e/ou doença. Concluiu-se que há uma grande inconsistência lógica nos princípios que regem a classificação.

This article aimed at describing the history of insertion of the clinical condition currently referred to as "obesity" in the eleven revisions of the International Classification of Diseases (ICD) published by the World Health Organization (WHO) between 1900 and 2018. For this purpose, a search for the keyword obesity was performed in the documents, with subsequent description and analysis of the presence, mode of insertion, and changes occurring over time. The results demonstrated that the condition has been and continues to be inserted as symptom, morbidity, comorbidity, cause of mortality and/or disease. It can be concluded that there is a massive logical inconsistency in the principles that govern the classification.

A comprehensive account of insulin and LDL receptor activity over the years: A highlight on their signaling and functional role.

Insulin receptor (IR) was discovered in 1970. Shortcomings in IR transcribed signals were found pro-diabetic, which could also inter-relate obesity and atherosclerosis in a time-dependent manner. Low-density lipoprotein receptor (LDLR) was discovered in 1974. Later studies showed that insulin could modulate LDLR expression and activity. Repression of LDLR transcription in the absence or inactivity of insulin showed a direct cause of atherosclerosis. Leptin receptor (OB-R) was found in 1995 and its resistance became responsible for developing obesity. The three interlinked pathologies namely, diabetes, atherosclerosis, and obesity were later on marked as metabolic syndrome-X (MSX). In 2012, the IR-LDLR inter-association was identified. In 2019, the proficiency of signal transmission from this IR-LDLR receptor complex was reported. LDLR was found to mimic IR-generated signaling path when it remains bound to IR in IR-DLR interlocked state. This was the first time LDLR was found sending messages besides its LDL-clearing activity from blood vessels.

Framing the Latin American nutrition transition in a historical perspective, 1850 to the present.

This paper argues that many of the foundations and trends that led to the rise in obesity and other diet-related health problems in Latin America began to develop in the late nineteenth century. The tendency towards presentism in the nutrition transition literature provides a much abbreviated and limited history of changes in diet and weight. Whereas medical and nutrition researchers have tended to emphasize the recent onset of the crisis, a historical perspective suggests that increasingly global food sourcing prompted changes in foodways and a gradual "fattening" of Latin America. This paper also provides a methodological and historiographic exploration of how to historicize the nutrition transition, drawing on a diverse array of sources from pre-1980 to the present.

Framing the Latin American nutrition transition in a historical perspective, 1850 to the present / A constituição da transição nutricional latino-americana em uma perspectiva histórica, 1850 até o presente

Abstract This paper argues that many of the foundations and trends that led to the rise in obesity and other diet-related health problems in Latin America began to develop in the late nineteenth century. The tendency towards presentism in the nutrition transition literature provides a much abbreviated and limited history of changes in diet and weight. Whereas medical and nutrition researchers have tended to emphasize the recent onset of the crisis, a historical perspective suggests that increasingly global food sourcing prompted changes in foodways and a gradual "fattening" of Latin America. This paper also provides a methodological and historiographic exploration of how to historicize the nutrition transition, drawing on a diverse array of sources from pre-1980 to the present.

Resumo Este trabalho argumenta que fundamentos e tendências que levaram ao aumento da obesidade e de outros problemas de saúde relacionados à alimentação na América Latina começaram a surgir no final do século XIX. A propensão ao presentismo na literatura sobre transição nutricional produz uma história abreviada e limitada das mudanças em alimentação e peso. Embora pesquisadores médicos e nutricionistas enfatizem a recente instalação da crise, uma perspectiva histórica sugere que fontes alimentares crescentemente globalizadas resultaram em mudanças na alimentação e em gradual "aumento de gordura" na população latino-americana. O artigo propõe ainda a exploração metodológica e historiográfica de como historicizar a transição nutricional recorrendo a fontes pré-1980 até o momento.

Resting Energy Expenditure: From Cellular to Whole-Body Level, a Mechanistic Historical Perspective.

The basis of heat generated by the human body has been a source of speculation and research for more than 2,000 years. Basal heat production, now usually referred to as resting energy expenditure (REE), is currently recognized as deriving from biochemical reactions at subcellular and cellular levels that are expressed in the energy expended by the body's 78 organs and tissues. These organs and tissues, and the 11 systems to which they belong, influence body size and shape. Connecting these subcellular-/cellular-level reactions to organs and tissues, and then on to body size and shape, provides a comprehensive understanding of individual differences in REE, a contemporary topic of interest in obesity research and clinical practice. This review critically examines these linkages, their association with widely used statistical and physiological REE prediction formulas, and often-unappreciated aspects of measuring basal heat production in humans.

Diffusion of scientific concepts on obesity in the global context: a historical review / Difusão de conceitos científicos sobre obesidade no contexto mundial: análise histórica

ABSTRACT This article aimed to carry out a historical analysis of the dissemination of the scientific concepts on obesity, overweight and excess weight in the field of nutritional epidemiology in the world. The methodological procedures comprised: (1) Systematic search in the PubMed® database using single keywords and without date filter; (2) Documentary analysis of normative instruments on the websites of the World Health Organization, the Centers for Disease Control and Prevention and the World Obesity Federation; and (3) Analysis of the scientific production of scientists participating in the obesity classification of the International Obesity Task Force. The historical analysis showed that, considering the volume of publications on obesity, it appears that in the 1940-1949 decade the problem of obesity emerged on the world scenario. From the number of publications issued in the last 20 years, which corresponds to 85% of the investigated period, we can deduct that scientists' concern to investigate the subject as a phenomenon coincides with the World Health Organization declaration of obesity as a global epidemic issued in the year 2000. In accordance with normative procedures established by international organizations, there has been a hegemonic use of the concepts of obesity and overweight, in this order of priority, by scientists worldwide. The concept of excess weight has experienced a relative rise since the year 2000, but its use has been very restricted, expressing dissonance in face of the recommendations of international standardization organizations, a fact that suggests discussion and review of its use by the world scientific community.

RESUMO O artigo teve por objetivo realizar uma análise histórica da difusão dos conceitos científicos sobre obesidade, sobrepeso e excesso de peso no campo da epidemiologia nutricional no contexto mundial. Os procedimentos metodológicos compreenderam: (1) Busca sistemática na base PubMed® utilizando unitermos isolados e sem filtro temporal para data; (2) Busca e análise documental de instrumentos normativos nas páginas eletrônicas da Organização Mundial de Saúde, do Centers for Disease Control and Prevention e da World Obesity Federation e (3) Análise da produção científica de cientistas participantes da classificação de obesidade da International Obesity Task Force. A análise histórica mostrou que, pelo volume de publicações sobre obesidade, a emergência da problemática no cenário universal ocorreu na década de 1940-1949. Pelo número de publicações dos últimos 20 anos, que corresponde a 85% do período investigado, pode-se deduzir que a preocupação dos cientistas em investigar a temática é um fenômeno coincidente com a declaração de obesidade como epidemia global feita pela Organização Mundial de Saúde no ano 2000. Em concordância com procedimentos normativos estabelecidos pelas organizações internacionais, verificou-se uma hegemonia do uso dos conceitos de obesity e overweight, nessa ordem de prioridade, pelos cientistas no contexto internacional. O conceito de excess weight experimentou relativa ascensão desde os anos 2000, mas teve seu uso bem restrito, expressando dissonância frente às recomendações das organizações internacionais de normatização - o que sugere uma discussão e revisão de seu uso pela comunidade científica global.

[Obesity as a global challenge of the 21st century: clinical medical nutrition, prevention and therapy].

The article presents modern data on the prevalence of overweight and obesity, provides updated information on personalized programs for managing body weight, individual recommendations for a healthy diet, adequate physical activity and long-term lifestyle changes. It is shown that dietary therapy is the basic treatment method in weight loss programs and is aimed at long-term maintenance of a negative energy balance in the patient's organism by limiting the calorie intake. A significant place in the article is devoted to the use of diets modified by calorie value and macronutrient content which are recommended for obese patients. A strategy for the prevention of obesity and its associated diseases is presented.

The "discovery" of lipid droplets: A brief history of organelles hidden in plain sight.

Mammalian lipid droplets (LDs), first described as early as the 1880s, were virtually ignored for more than 100 years. Between 1991 and the early 2000s, however, a series of discoveries and conceptual breakthroughs led to a resurgent interest in obesity as a disease, in the metabolism of intracellular triacylglycerol (TAG), and in the physical locations of LDs as cellular structures with their associated proteins. Insights included the recognition that obesity underlies major chronic diseases, that appetite is hormonally controlled, that hepatic steatosis is not a benign finding, and that diabetes might fundamentally be a disorder of lipid metabolism. In this brief review, I describe the metamorphosis of LDs from overlooked globs of stored fat to dynamic organelles that control insulin resistance, mitochondrial oxidation, and viral replication.

Weighing on us all? Quantification and cultural responses to obesity in NHS Britain.

How do cultures of self-quantification intersect with the modern state, particularly in relation to medical provision and health promotion? Here I explore the ways in which British practices and representations of body weight and weight management ignored or interacted with the National Health Service between 1948 and 2004. Through the lens of overweight, I examine health citizenship in the context of universal health provision funded from general taxation, and track attitudes toward "overweight" once its health implications and medical costs affected a public service as well as individual bodies and households. Looking at professional and popular discourses of overweight and obesity, I map the persistence of a highly individual culture of dietary and weight self-management in postwar Britain, and assess the degree to which it was challenged by a new measure of "obesity" - the body mass index - and by visions of an NHS burdened and even threatened by the increasing overweight of the citizens it was created to serve.