This article aims to describe several "ups and downs" in the tumultuous life of Charles-Édouard Brown-Séquard (1817-1894). The posthumous son of an American father and a French mother-whose surnames he combined-he was born and spent his youth on the island of Mauritius, then a British possession but largely French-speaking, before leaving for Paris, where he was advised to devote himself to medicine rather than literature, his first ambition. His medical studies were interrupted by the sudden death of his mother and a first, temporary return to Mauritius. When resumed in Paris, they culminated in a doctoral thesis on the physiology of the spinal cord. Despite precarious financial circumstances and a cholera epidemic (1848), Brown-Séquard continued his research on a wide range of subjects, including some rather unusual interspecific organ grafts. At the same time, he refined the description of the symptoms of the spinal cord lesion syndrome that still bears his name, demonstrated the crossing of sensory pathways within the spinal cord, and, through experiments on the rabbit's ear, showed the role of vasomotor innervation. Unable, because of his status as a British subject, to obtain a permanent position in France, he spent thirty years traveling and working abroad, particularly in the United States (with 60 transatlantic crossings), in Philadelphia, New York, and Richmond, and later in London or Dublin and Boston at Harvard. After the death of Claude Bernard, he obtained French naturalization, which allowed him to stand for the Chair of Medicine at the Collège de France, to which he was elected in 1878, as well as to the Académie des Sciences in 1886. Until his death in 1894, he devoted himself to describing the effects of regenerative treatments using extracts from glands or organs (organotherapy or opotherapy), anticipating in particular-through his work on the adrenal glands-the field that would later become endocrinology. Together with d'Arsonval, he promoted this method among physicians before the press and the general public took hold of it, giving him a somewhat controversial reputation. A tireless worker, extremely courageous, selfless, eccentric, and stubborn in both error and truth, Brown-Séquard emerges as a nineteenth-century scientist as singular as he was endearing. The Société de Biologie, which he helped to found in 1848 (along with several scientific journals) and which he later presided over (1887-1891), owes him this tribute (abstract établi avec l'aide de Chat GPT).
Incretins are hormones released from the gut that play a vital role in regulating postprandial metabolism. It has been 30 years since the first demonstration of the glucose-lowering effects of GLP-1 in people with type 2 diabetes. Here, we review the foundational science that led to an unparalleled development in the pharmacological treatment of diabetes. A first step was achieved with the discovery of inhibitors of the dipeptidyl peptidase-4 (DPP-4), which prevent the inactivation of GLP-1 and GIP, thereby prolonging their raised levels after meal ingestion. At the same time, several GLP-1 receptor agonists (GLP1-RAs) were engineered. The GLP1-RAs used clinically are based on exendin-4 and native GLP-1 and are now available as formulations for daily or weekly s.c. (exenatide, liraglutide, semaglutide) or oral administration (oral semaglutide). They mimic (better effectiveness) the action of native GLP-1 to reduce glucose levels through stimulation of insulin secretion and inhibition of glucagon secretion. They also demonstrated remarkable cardiovascular and weight-regulating benefits, including safety, leading to their prominent inclusion in current treatment recommendations for type 2 diabetes. Exciting advancements continue to emerge as the fundamental research efforts led to the development of monomeric multi-incretin receptor agonists: GLP-1/GIP (tirzepatide) dual receptor agonists and GLP-1/GIP/glucagon (retatrutide) triple receptor agonists which can achieve more than 20% weight loss in obesity as well as offering superior benefits in diabetes. This review also presents the promise of GLP1-RAs for more extensive application of this new class of drugs, in treating other metabolic disorders such as obesity, MASLD/NAFLD, cardio-vascular diseases and neurodegeneration.
Obesity now affects nearly one in five French people, and its prevalence has more than doubled since 1997. It is defined as a chronic, progressive disease responsible for numerous mechanical complications (osteoarthritis, low back pain, incontinence, gastroesophageal reflux disease), metabolic complications (diabetes, fatty liver disease, cardiovascular disease), and psychosocial complications (anxiety, depression, stigmatization), as well as an increased risk of numerous cancers. A new definition, developed in 2025, distinguishes preclinical obesity from clinical obesity by incorporating the Body Mass Index, organs damages and functional limitations, and encourages detailed phenotyping to personalize care. In France, the High Authority for Health (HAS) recommendations (2022, 2024) outline a stepwise care pathway [general practitioner, specialist, Specialized Obesity Center (CSO)] where the goal is not limited to weight but also addresses comorbidities, quality of life, and mobility. The foundation of treatment remains lifestyle modifications (nutrition, physical activity, psychological support) within a therapeutic education framework. Incretin agonists (GLP-1, GLP-1/GIP) are effective second-line pharmacological treatments, resulting on average in over 10% weight loss and a significant improvement in metabolic comorbidities. However, their use is limited by common gastrointestinal side effects, a risk of weight regain upon discontinuation, micronutrient deficiencies, muscle and bone loss, high cost, and often poor adherence in real-world settings. They must therefore be integrated into a comprehensive and sustainable treatment plan focused on nutritional guidance, physical activity, psychological support, and the prevention of deficiencies, in order to optimize long-term benefits beyond weight loss alone.
