Developing Sex: From Recremental Semen to Developmental Endocrinology.

During the 1890s, animal development became associated with glandular activity, with profound implications for pediatric nosology and treatment. The significance of this endocrinological turn of developmental physiology and pathophysiology in part hinges on an often-overlooked continuity with ubiquitous early modern medical thought concerning semen as a recrementitious (reabsorbed) nutrient or stimulant. Mid-19th-century interests in adult sexual physiology were increasingly nerve-centered and antihumoral. Scattered empirical, particularly veterinarian, interests in gonadal developmental functions failed to moderate these explanatory trends. While Brown-Séquard's rejuvenation experiments still offered no clear starting point for a developmental endocrinology, in 1892 Gaston Variot and Paul Bezançon more explicitly deduced a testicular developmental endocrinological function from various observations on testicular ectopy and a local form of animal "demi-castration." Ensuing interest in the thyroid, the thymus and in the testicles led to various working conceptions of their respective and putatively reciprocal developmental properties, including the idea of a thyroid-testis axis. From 1896, the pubertal affliction of chlorosis became the subject of multiple opotherapeutic approaches, providing an experimental basis for theories of ovarian internal secretion. Polyglandular therapy, piloted for divergent developmental conditions, remained routine until the 1930s despite the biological inefficacy of many endocrine products.

The discovery of insulin in Toronto: beginning a 100 year journey of research and clinical achievement.

There has been a great deal of controversy regarding priority of discovery of insulin. Indeed, many scientists made important and, in some cases, seminal contributions to identifying the endocrine role of the pancreas and the potential for pancreatic extracts to have a glucose-lowering effect. The purpose of this article is to describe the early experiences with respect to research leading to the discovery of insulin in Toronto (ON, Canada). The experiments conducted at the University of Toronto resulted in the first demonstration that a pancreatic extract could be prepared that would consistently lower glucose, reverse ketosis and arrest the catabolic effects of type 1 diabetes. The remarkably rapid commercial production of insulin soon followed. The Toronto story begins on 17 May 1921, when Frederick Banting and Charles Best began their summer research project in the laboratory of John James Rickard Macleod, and we are now celebrating the 100th anniversary of this landmark achievement. The article herein outlines the steps leading up to the discovery of insulin and provides an overview of some of the key developments in insulin therapy over the past 100 years.

The promising future of insulin therapy in diabetes mellitus.

The first therapeutic use of insulin by Frederick Banting and Charles Best in 1921 revolutionized the management of type 1 diabetes and considerably changed the lives of many patients with other types of diabetes. In the past 100 years, significant pharmacological advances took place in the field of insulin therapy, bringing closer the goal of optimal glycemic control along with decreased diabetes-related complications. Despite these developments, several challenges remain, such as increasing treatment flexibility, reducing iatrogenic hypoglycemia, and optimizing patient quality of life. Ongoing innovations in insulin therapy (e.g., new insulin analogs, alternative routes of insulin administration, and closed-loop technology) endeavor to overcome these hurdles and change the landscape of diabetes mellitus management. This report highlights recent advances made in the field of insulin therapy and discusses future perspectives.

100th anniversary of the discovery of insulin perspective: insulin and adipose tissue fatty acid metabolism.

Insulin inhibits systemic nonesterified fatty acid (NEFA) flux to a greater degree than glucose or any other metabolite. This remarkable effect is mainly due to insulin-mediated inhibition of intracellular triglyceride (TG) lipolysis in adipose tissues and is essential to prevent diabetic ketoacidosis, but also to limit the potential lipotoxic effects of NEFA in lean tissues that contribute to the development of diabetes complications. Insulin also regulates adipose tissue fatty acid esterification, glycerol and TG synthesis, lipogenesis, and possibly oxidation, contributing to the trapping of dietary fatty acids in the postprandial state. Excess NEFA flux at a given insulin level has been used to define in vivo adipose tissue insulin resistance. Adipose tissue insulin resistance defined in this fashion has been associated with several dysmetabolic features and complications of diabetes, but the mechanistic significance of this concept is not fully understood. This review focusses on the in vivo regulation of adipose tissue fatty acid metabolism by insulin and the mechanistic significance of the current definition of adipose tissue insulin resistance. One hundred years after the discovery of insulin and despite decades of investigations, much is still to be understood about the multifaceted in vivo actions of this hormone on adipose tissue fatty acid metabolism.

Peripheral and central regulation of insulin by the intestine and microbiome.

Blood glucose and insulin homeostasis is disrupted during the progression of type 2 diabetes. Insulin levels and action are regulated by both peripheral and central responses that involve the intestine and microbiome. The intestine and its microbiota process nutrients and generate molecules that influence blood glucose and insulin. Peripheral insulin regulation is regulated by gut-segment-dependent nutrient sensing and microbial factors such as short-chain fatty acids and bile acids that engage G-protein-coupled receptors. Innate immune sensing of gut-derived bacterial cell wall components and lipopolysaccharides also alter insulin homeostasis. These bacterial metabolites and postbiotics influence insulin secretion and insulin clearance in part by altering endocrine responses such as glucagon-like peptide-1. Gut-derived bacterial factors can promote inflammation and insulin resistance, but other postbiotics can be insulin sensitizers. In parallel, activation of small intestinal sirtuin 1 increases insulin sensitivity by reversing high fat-induced hypothalamic insulin resistance through a gut-brain neuronal axis, whereas high fat-feeding alters small intestinal microbiome and increases taurochenodeoxycholic acid in the plasma and the dorsal vagal complex to induce insulin resistance. In summary, emerging evidence indicates that intestinal molecular signaling involving nutrient sensing and the host-microbe symbiosis alters insulin homeostasis and action. Gut-derived host endocrine and paracrine factors as well as microbial metabolites act on the liver, pancreas, and the brain, and in parallel on the gut-brain neuronal axis. Understanding common nodes of peripheral and central insulin homeostasis and action may reveal new ways to target the intestinal host-microbe relationship in obesity, metabolic disease, and type 2 diabetes.

A Life's Journey Through Insect Metamorphosis.

This autobiographical article describes the research career of Lynn M. Riddiford from its early beginnings in a summer program for high school students at Jackson Laboratory to the present "retirement" at the Friday Harbor Laboratories. The emphasis is on her forays into many areas of insect endocrinology, supported by her graduate students and postdoctoral associates. The main theme is the hormonal regulation of metamorphosis, especially the roles of juvenile hormone (JH). The article describes the work of her laboratory first in the elucidation of the endocrinology of the tobacco hornworm, Manduca sexta, and later in the molecular aspects of the regulation of cuticular and pigment proteins and of the ecdysone-induced transcription factor cascade during molting and metamorphosis. Later studies utilized Drosophila melanogaster to answer further questions about the actions of JH.

Looking back on 25 years of the PSAD study group.

The year 2020 marks the 25th anniversary of the Psychosocial Aspects of Diabetes (PSAD) study group of the European Association for the Study of Diabetes. At the time, psychosocial diabetes research in Europe was steadily growing, but not well recognized. By establishing an official European Association for the Study of Diabetes study group, PSAD, for which purpose some hurdles had to be overcome, diabetes psychology became more visible and accessible to the scientific diabetes community. Over the years the PSAD study group has been successful in promoting the quality of research in the field through scientific meetings, mentoring, postgraduate education and publications. Looking back we can conclude that starting the PSAD study group signified an important moment in time, where researchers were joining forces to further the quality of the science, raise awareness of the importance of psychosocial aspects and promote the dissemination of psychological interventions in diabetes care.

Human reproductive behavior, life history, and the Challenge Hypothesis: A 30-year review, retrospective and future directions.

The Challenge Hypothesis (Wingfield et al., 1990) originally focused on adult male avian testosterone elevated in response to same-sex competition in reproductive contexts. The purpose of the present paper is to demonstrate how the Challenge Hypothesis has shaped ideas about human life histories. We conduct a citation analysis, drawing upon 400 Google Scholar citations in the human literature to identify patterns in this body of scholarship. We cover key factors, such as context and personality traits, that help explain variable testosterone responses such as winning/losing to adult competitive behavior. Findings from studies on courtship and sexual behavior indicate some variation in testosterone responses depending on factors such as motivation. A large body of research indicates that male testosterone levels are often lower in contexts of long-term committed partnerships and nurturant fathering and aligned with variation in male mating and parenting effort. As the Challenge Hypothesis is extended across the life course, DHEA and androstenedione (rather than testosterone) appear more responsive to juvenile male competitive behavior, and during reproductive senescence, baseline male testosterone levels decrease just as male life history allocations show decreased mating effort. We discuss how research on testosterone administration, particularly in older men, provides causal insight into effects of testosterone in humans, and how this "natural experiment" can be viewed in light of the Challenge Hypothesis. We synthesize central concepts and findings, such as an expanded array of costs of testosterone that inform life history tradeoffs between maintenance and reproductive effort, and we conclude with directions for future research.

Primary Aldosteronism: Where Are We Now? Where to from Here?

The past nine years have seen major advances in establishing the etiology of unilateral primary aldosteronism, and very possibly that of bilateral hyperaldosteronism, in response to somatic mutations in aldosterone synthase expressing cells. Though there have been important advances in the management of primary aldosteronism, in small but convincing studies, they represent minor changes to current guidelines. What has been totally absent is consideration of the public health issue that primary aldosterone represents, and the public policy issues that would be involved in addressing the disorder. In his introduction to PiPA 6, Martin Reincke calculated that only one in a thousand patients in Germany with primary aldosteronism were treated appropriately, an astounding figure for any disease in the 21st century. Towards remedying this totally unacceptable public health issue, the author proposes a radical simplification and streamlining of screening for primary aldosteronism, and the management of most patients by general practitioners. The second bottle-neck in current management is that of mandatory adrenal venous sampling for all but 1-2% of patients, a costly procedure requiring rare expertise. Ideally, it should be reserved - on the basis of likelihood, enhanced imaging, or peripheral steroid profiles - for a small minority of patients with clear evidence for unilateral disease. Only when costs are minimized and roadblocks removed will primary aldosteronism be properly treated as the public health issue that it is.

Progress in Primary Aldosteronism 2019: New Players on the Block?

Primary aldosteronism (PA) is characterized by hypertension caused by inappropriately high adrenal aldosterone secretion, consecutively low plasma renin, and an elevated aldosterone to renin ratio. It is nowadays the universally accepted main cause of endocrine hypertension. According to the most recent epidemiological data, PA is present in 5.8% of unselected hypertensives in primary care, 6-12% of hypertensives treated in hypertension centers, and up to 30% in subjects with resistant hypertension 1. Despite this high prevalence, a recent survey demonstrated that screening for PA is not universally followed. Renin and aldosterone measurements, the basis for PA screening, are currently performed by only 7% of general practitioners in Italy and 8% in Germany 2. Accordingly, the prevalence of PA was low with 1% among hypertensives in Italy and 2% in Germany. In a retrospective cohort study of 4660 patients with resistant hypertension in California the screening rate for PA was 2.1% 3. Based on these data, it is clear that we still miss the majority of PA cases, despite advances in diagnosis and therapy.

Continuous glucose monitoring for hypoglycaemia in children: Perspectives in 2020.

Hypoglycaemia in children is a major risk factor for adverse neurodevelopment with rates as high as 50% in hyperinsulinaemic hypoglycaemia (HH). A key part of management relies upon timely identification and treatment of hypoglycaemia. The current standard of care for glucose monitoring is by infrequent fingerprick plasma glucose testing but this carries a high risk of missed hypoglycaemia identification. High-frequency Continuous Glucose Monitoring (CGM) offers an attractive alternative for glucose trend monitoring and glycaemic phenotyping but its utility remains largely unestablished in disorders of hypoglycaemia. Attempts to determine accuracy through correlation with plasma glucose measurements using conventional methods such as Mean Absolute Relative Difference (MARD) overestimate accuracy at hypoglycaemia. The inaccuracy of CGM in true hypoglycaemia is amplified by calibration algorithms that prioritize hyperglycaemia over hypoglycaemia with minimal objective evidence of efficacy in HH. Conversely, alternative algorithm design has significant potential for predicting hypoglycaemia to prevent neuroglycopaenia and consequent brain dysfunction in childhood disorders. Delays in the detection of hypoglycaemia, alarm fatigue, device calibration and current high cost are all barriers to the wider adoption of CGM in disorders of hypoglycaemia. However, machine learning, artificial intelligence and other computer-generated algorithms now offer significant potential for further improvement in CGM device technology and widespread application in childhood hypoglycaemia.

Pancreatic Extracts for the Treatment of Diabetes (1889-1914): Acomatol.

BACKGROUND: Historical review on the early development of organotherapy for diabetes [pancreatic extracts (PE)] and its relationship with the social and political circumstances. AREAS OF UNCERTAINTY: The diagnosis of diabetes relied only in the presence of glycosuria and cardinal symptoms. Blood glucose determinations were not regularly available, requiring large volumes for sampling. Micromethods for glycemia were developed just in the last years of the investigated period. Hypoglycemia remains undiscovered. Isolation and purification of PE were difficult tasks due to the unknown chemical structure of the antidiabetic hormone. DATA SOURCES: (1) Berliner Medizinhistoriches Museum der Charité (Humboldt University). (2) GeDenKort Charité-Wissenschaft in Verantwortung. (3) Geheim Staatsarchiv Preußischer Kulturbesitz. (4) Archival Collections, University of Toronto: Thomas Fisher Rare Book Library. Academy of Medicine Collection, F. G. Banting Papers, C. H. Best Papers, J. J. R. Macleod Papers. (5) National Library of Medicine: Pubmed search for the topic of history of insulin. History of Medicine-on syllabus archive. (6) Selected books: The Discovery of Insulin (M. Bliss); Diabetes, Its Medical and Cultural History (D. von Engelhardt); Brown-Séquard (M. J. Aminoff); Diabetes: The Biography (R. Tattersall); The Endocrine Organs (E. Schäfer); The Internal Secretions (E. Gley); Health, race and German politics between national unification and Nazism, 1870-1945 (P. Weindling). THERAPEUTIC ADVANCES: Demonstration that diabetes is a pancreatic disease. The outstanding progress of medical physiology led to the birth of endocrinology and the key concepts of homeostasis. Experimental scientists designed new procedures for complete pancreatectomy and elaboration of PE containing the antidiabetic principle. Organotherapy achieved complete success in the treatment of myxedema and partial success in the treatment of experimental and clinical diabetes. CONCLUSIONS: The organotherapy of diabetes was an obliged step to facilitate the identification of the antidiabetic hormone. Organotherapy of diabetes was a paradigm for the integration of basic and applied knowledge about hormone action and development of endocrine pharmacology.

A 45-years journey within the reproductive brain of fish.

This article summarizes the scientific carrier of Dr. Olivier Kah, currently emeritus research director at the National Center of Scientific Research (CNRS) in France. Olivier Kah partly grew up in Africa where he developed a strong interest for animals. He studied biology in Paris and Bordeaux. He next received his PhD at the University of Bordeaux en 1978 and his Doctor of Science degree in 1983. He joined the CNRS in 1979 until his retirement in 2016. Olivier Kah dedicated his carrier to the study of reproduction, in particular to the roles of brain neuropeptides and neurotransmitters in the control of the reproductive axis in vertebrates, mostly fish. More specifically, Olivier Kah was specialized in the use of morphofunctional techniques that he implemented to the study of the organization of the hypothalamo-pituitary complex. He was also interested in the steroid feedback and studied intensively the expression and regulation of estrogen and glucocorticoid receptors in the rainbow trout and the zebrafish. In the last 10 years, Olivier Kah's team focused on the expression and regulation of aromatase in the brain and established that aromatase expression is restricted to a unique brain cell type, the radial glial cells, which serve as progenitors during the entire life of fish. He is also interested in the impact of endocrine disruptors using the zebrafish as a model and recently his team has developed an exquisitely sensitive in vivo assay to screen estrogenic chemicals on zebrafish embryos.

At the origin of "Endocrinology and Art": Woman's Head (third century BCE).

In 1911, the Danish physician Hans Christian Gram (1853-1938) sustained to have found signs of hyperthyroidism in a marble head of a Roman woman that he observed in the Ny Carlsberg Glyptotek in Copenhagen. It could be one of the first examples of a clinical diagnosis of an endocrine disease in an ancient statue.

Unveiling Charles II, the last King of the Habsburg Spanish Empire, in a portrait by Juan Carreño de Miranda (1685).

PURPOSE: Charles II (1661-1700) was the last King of the Habsburg dynasty. He was physically and mentally disabled and died at just 39 years old. Here, the authors attempt to investigate the correlations between his signs and symptoms and the physical appearance on the painting. METHODS: Charles II has been portraited by Juan Carreño de Miranda in a painting that may provide precious information about his premature death. RESULTS: It has been suggested that inbreeding beside other endocrinological disorders were of the major causes responsible for illness and ultimately his death. CONCLUSION: Possible endocrinological diseases have been hypothesized.

African statue with goiter.

INTRODUCTION: Representations of thyroid swelling, intended as an enlarged anterior neck in the artworks of various periods are sporadically reported in the literature. MATERIALS AND METHODS: An African statue belonging to the African Yoruba culture has been analysed. RESULTS: Members of Ogboni Society in Yoruba culture used this statues to represent a real subject and to communicate between the living and dead. CONCLUSION: The statue reported seems to represent a case of real goiter.

"La Toilette". When a doctor becomes a painter: Frederic Bazille.

PURPOSE: To find endocrinological disturbances in impressionism. PATIENTS AND METHODS: Analysis of "La Toilette" painting of Frederice Bazille. RESULTS: We present a masterpiece work of Frederic Bazille "La Toilette" where a large goiter is visible. Short description of Bazille's life and painting is included. CONCLUSION: Despite of unique painting technique, thyroid disorders are visible even in impressionism.