Despite loss of responsiveness to exogenous leptin in obesity, endogenous leptin continues to restrain feeding, although the neural substrates that remain sensitive and mediate this effect remain unknown. Combining spatial transcriptomics with single-nucleus RNA sequencing in mice with diet-induced obesity (DIO), we here show that while most hypothalamic leptin receptor (Lepr)-positive neurons minimally respond to elevated leptin, a single subpopulation defined by glucagon-like peptide-1 receptor (Glp1r) co-expression retains robust leptin sensitivity. These Lepr+/Glp1r+ neurons project onto and inhibit orexigenic Agrp neurons. Lepr deletion from Lepr+/Glp1r+ neurons blocks the anorectic effect of exogenous leptin, reinstates hyperphagic responses normally suppressed in DIO, amplifies the obesogenic response to palatable diet, and unexpectedly attenuates hypothalamic microglial activation - a hallmark of DIO previously attributed to diet rather than leptin signaling. Hence, preserved leptin responses by a single neuronal population in the hypothalamus limit hyperphagia and weight gain, among other responses, during obesity.

Sarcopenia is a progressive skeletal muscle disorder characterised by reduced muscle strength, impaired muscle quantity or quality, and declining physical performance, with important consequences for falls, fractures, disability, and loss of independence. Whether sarcopenia prevalence itself is rising remains difficult to quantify because diagnostic frameworks and surveillance methods vary, yet a growing burden is plausible. Population ageing, increasing multimorbidity, obesity, hospitalisation, surgery, and incomplete recovery after musculoskeletal events are likely to increase the absolute number of people living with low musculoskeletal reserve. Osteoarthritis (OA) and osteoporosis (OP) are central to this problem because they amplify the functional consequences of weakness and reduced loading. OA may lead to strength loss through pain, inflammation, altered movement, and activity restriction, while OP increases the likelihood that falls or loading errors will result in fracture and subsequent deconditioning. Shared mechanisms for sarcopenia include mechanical unloading, adiposity-related metabolic dysfunction, inflammageing, mitochondrial stress, endocrine change, and nutritional insufficiency, although the strength of evidence differs across pathways. New weight-loss approaches using glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may substantially affect sarcopenia risk and therefore require careful consideration. Current diagnostic frameworks increasingly prioritise muscle strength and performance over lean mass alone, supporting pragmatic case-finding in older adults with severe OA, fragility fracture, recurrent falls, poor postoperative recovery, or weight loss. Current management should focus on progressive resistance and balance training, adequate energy and protein intake, guideline-based OP care, optimised OA treatment, and protection of mobility during transitions of care. The most immediate clinical gains are likely to come from integrating existing rheumatology, orthopaedic, fracture-prevention, rehabilitation, and nutritional services rather than from any osteosarcopenia-specific drug therapy.

The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the consensus statement on the management of type 2 diabetes in non-pregnant adults, published since 2006 and last updated In 2022. The target audience is the multidisciplinary healthcare team providing diabetes care in the USA and Europe. A systematic examination of publications since 2022 informed new recommendations. This update has broadened the focus from the management of hyperglycaemia to the holistic management of type 2 diabetes and its risk of associated multiple long-term conditions. Fundamental aspects of diabetes care include promoting healthy lifestyle behaviours (healthy eating, 24 h physical behaviours including sleep, and avoiding tobacco and substance use), alongside the provision of psychological support and weight management interventions. For the management of people living with type 2 diabetes, earlier use, potentially from diagnosis, of sodium-glucose cotransporter 2 (SGLT2) inhibitors or/and glucagon-like peptide-1 (GLP-1)-based therapies to offer organ protection and improve long-term outcomes in type 2 diabetes is advocated. Furthermore, earlier combination use of SGLT2 inhibitors and GLP-1-based therapies should be considered in people with concomitant CVD, chronic kidney disease and heart failure. Finally, the ability to transform outcomes for people living with type 2 diabetes is within our grasp through the consistent, equitable and systematic implementation of strategies and therapies that are already available.

The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the consensus statement on the management of type 2 diabetes in nonpregnant adults, published since 2006 and last updated in 2022. The target audience is the multidisciplinary health care team providing diabetes care in the U.S. and Europe. A systematic examination of publications since 2022 informed new recommendations. This update has broadened the focus from the management of hyperglycemia to the holistic management of type 2 diabetes and its risk of associated multiple long-term conditions. Fundamental aspects of diabetes care include promoting healthy lifestyle behaviors (healthy eating, 24-h physical behaviors including sleep, and avoiding tobacco and substance use), alongside the provision of psychological support and weight management interventions. For the management of people living with type 2 diabetes, earlier use, potentially from diagnosis, of sodium-glucose cotransporter 2 (SGLT2) inhibitors and/or glucagon-like peptide 1 (GLP-1)-based therapies to offer organ protection and improve long-term outcomes in type 2 diabetes is advocated. Furthermore, earlier combination use of SGLT2 inhibitors and GLP-1-based therapies should be considered in people with concomitant cardiovascular disease, chronic kidney disease, and heart failure. Finally, the ability to transform outcomes for people living with type 2 diabetes is within our grasp through the consistent, equitable, and systematic implementation of strategies and therapies that are already available.

Congenital hyperinsulinism (CHI) is a rare disorder resulting in hypoglycemia due to increased insulin secretion and is subdivided into focal and diffuse forms. CHI is associated with neurological damage due to hypoglycemia, making adequate blood glucose management crucial. Although subcutaneous octreotide injection can effectively treat CHI, frequent octreotide administration may be burdensome for patients and their families. Here, we describe a boy with early neonatal-onset persistent CHI treated with octreotide long-acting release (LAR). At first, he received treatment with continuous glucose infusion, diazoxide, and glucagon. Genetic analysis revealed the patient was a compound heterozygote for ABCC8, with diffuse form predicted. Although the focal form can be treated by surgery, the diffuse form requires long-term drug therapy. Therefore, he was treated with octreotide subcutaneous injections and subsequently transitioned to octreotide LAR to avoid the inconvenience of frequent injections. He has been receiving octreotide LAR for four years and has not experienced developmental delays or any apparent side effects, such as necrotizing enterocolitis. The dosing interval can be extended without increasing hypoglycemia. Octreotide LAR reduced the burden on the patient and his family. Octreotide LAR can be an effective long-term treatment for CHI. However, further cases are needed for verification.

The emergence of weekly, injectable glucagon-like peptide-1 (GLP-1) receptor agonists has revolutionized the obesity management landscape. Numerous studies have shown high efficacy as well as great variability in weight loss, highlighting the need for this mini review, summarizing current evidence about predictors of semaglutide-related weight loss. The first well-known determinant of semaglutide-induced weight loss is the presence of type 2 DM which is associated with significantly lower body weight reduction. The second predictor is sex, with females exhibiting a greater weight loss than males by a mean 6%. In addition, higher maintenance dose of 7.2 mg is superior to standard 2.4 mg dose in weight reduction by a mean 3%. There is no clear association of age and baseline body mass index with the magnitude of semaglutide-driven weight loss, except for the possibility of adolescence enhancing and overweight reducing this treatment effect. The potential impact of genetic polymorphisms of individual treatment response to semaglutide remains incompletely understood, limited so far to a modest effect of specific variants in GLP1 receptor gene. Another potential predictor of response could be obesity phenotype, with preliminary data supporting greater effectiveness of semaglutide in individuals with ''hungry gut'' phenotype. Type of lifestyle modification does not seem to have a significant effect on the variability of semaglutide-driven weight loss. Further studies are needed to expand knowledge about predictors of response to semaglutide, paving the way for validated predictive models in order to guide clinical decision-making and provision of personalized obesity care.

Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GIP/GLP-1 receptor agonists, have transformed obesity treatment by producing substantial weight loss and improving cardiometabolic outcomes. However, their therapeutic effects are accompanied by nutritional challenges, including reduced energy intake, gastrointestinal adverse effects, loss of lean mass or fat-free mass, and the risk of inadequate protein and micronutrient intake. This scientific statement of the Polish Society of Dietetics (PTD) summarizes current evidence and provides clinical guidance on nutritional care during incretin-based therapy for obesity. The statements were developed through multidisciplinary expert synthesis and consensus; direct nutrition-specific evidence remains limited, and no formal evidence-grading system was applied. The main features of evidence-informed nutritional care during incretin-based therapy include: 1) structured baseline nutritional assessment and ongoing monitoring of dietary intake, appetite, gastrointestinal tolerance, and body composition; 2) early identification of nutritional risk, including inadequate protein intake, micronutrient insufficiency, dehydration, and excessive loss of lean mass or fat-free mass; 3) individualized dietary strategies supporting adequate nutrient intake and treatment tolerance; 4) preservation of lean mass and muscle function through appropriate protein intake and regular resistance exercise; 5) use of Mediterranean, Dietary Approaches to Stop Hypertension (DASH), or appropriately planned plant-based dietary patterns adapted to individual clinical needs; 6) targeted rather than routine nutritional supplementation based on documented deficiency or increased clinical risk; and 7) integration of registered dietitians within multidisciplinary obesity care pathways. Future research should evaluate the effects of structured dietitian-led interventions on body composition, nutritional status, treatment adherence, and long-term clinical outcomes during incretin-based therapy.

The glucagon-like peptide-1 receptor (GLP-1R) is a critical therapeutic target for metabolic diseases. GLP-1 receptor agonists (GLP-1RAs) have been developed to treat type 2 diabetes and promote weight loss. In this study, Gaussian accelerated molecular dynamics (GaMD) simulations, MM-PBSA calculations, and conformational dynamic analyses were systematically employed to elucidate the binding mechanisms and dynamic stability of three representative agonists-native GLP-1, semaglutide, and tirzepatide-bound to the GLP-1R-Gs membrane protein complex. Molecular docking and trajectory analyses revealed that ligand binding significantly stabilizes the overall receptor structure, triggering conformational shifts in the extracellular domain (ECD) and transmembrane domain (TMD), particularly inducing long-range allosteric cross-talk with the intracellular Gs protein to downstream signal transduction. Compared to GLP-1 and semaglutide, tirzepatide demonstrated distinct conformational shifts, superior structural compactness, and the higher binding affinity with a significantly more negative binding free energy. Furthermore, micro-interfacial localization demonstrated that lipid bilayer interaction with basic and aromatic residues at the Zp interface synergistically stabilizes the active transmembrane conformation. These atomic-level insights highlight the unique structural advantages of tirzepatide and provide a solid theoretical foundation for the novel rational design of next-generation multi-target peptide therapeutics.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as pivotal agents in the treatment of type 2 diabetes (T2D) and obesity, with well-established metabolic and cardiovascular benefits that translate into improvement in quality of life and life expectancy. While a potential benefit may also be hypothesized in patients with metabolic disorders and malignancy, robust clinical evidence is still lacking. In recent years, attention has turned to their potential impact on cancer risk, although current evidence remains limited and, in some cases, conflicting. Several biological pathways, such as improvements in insulin sensitivity, reductions in chronic inflammation, modulation of cellular signaling, and changes in the tumor microenvironment, have been proposed as possible mechanisms through which GLP-1RAs might influence cancer development or progression. However, available data derive from preclinical or observational studies, and high-quality prospective clinical evidence is still lacking. While some reports suggest possible protective associations in specific cancer types, others raise concerns about potential risks, particularly in hormonally sensitive or receptor-expressing tissues. This position paper synthesizes available data on the oncologic safety and potential antitumor effects of GLP-1RAs, highlights key knowledge gaps, and discusses clinical implications, underscoring the need for further research to clarify their role in cancer prevention and treatment.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide have expanded from glucose-lowering therapy into cardiovascular medicine. In type 2 diabetes, several long-acting GLP-1RAs reduce major adverse cardiovascular events (MACE). SELECT extended this benefit to adults with established cardiovascular disease and overweight or obesity without diabetes, while SOUL demonstrated MACE reduction with oral semaglutide. SURPASS-CVOT established cardiovascular noninferiority of tirzepatide to dulaglutide but did not demonstrate superiority. Obesity-related heart failure with preserved ejection fraction (HFpEF) has emerged as a particularly responsive phenotype: semaglutide improves symptoms and physical function, whereas tirzepatide also reduces worsening heart failure events. FLOW further supports kidney and cardiovascular protection with semaglutide in type 2 diabetes and chronic kidney disease. Randomised human studies support effects on adiposity, haemodynamic burden, inflammation and cardiorenal outcomes, whereas endothelial, coronary microvascular and direct myocardial mechanisms remain less clinically validated. This Review integrates the current evidence, distinguishes randomised outcomes from observational and mechanistic signals, and provides a practical phenotype-directed treatment algorithm incorporating atherosclerotic cardiovascular disease, obesity, type 2 diabetes, chronic kidney disease, HFpEF, sodium-glucose cotransporter 2 inhibitor use and patient-specific treatment constraints. Current practice should be guided by indication-specific outcome evidence rather than weight-loss magnitude or indirect cross-trial comparisons.

Incretin-based pharmacotherapy has rapidly reshaped obesity management, influencing patient expectations, referral patterns, and treatment algorithms for metabolic and bariatric surgery (MBS). Framing pharmacologic and surgical therapies as competing modalities risks delaying definitive intervention and fragmenting longitudinal care. This narrative review synthesizes current evidence supporting the integrated use of glucagon-like peptide-1 (GLP-1)-based therapies and MBS within a chronic disease framework. Available data demonstrate that GLP-1-based therapies produce approximately 15%-21% total body weight loss in randomized clinical trials but require sustained administration to maintain effect. In contrast, MBS typically achieves 25%-35% total body weight loss with durable long-term metabolic benefits. Emerging evidence supports the use of GLP-1-based agents both preoperatively and postoperatively as adjuncts rather than substitutes for surgery, highlighting the complementary nature of these treatment modalities. Despite increasing adoption, key gaps remain regarding optimal timing, patient selection, duration of therapy, and cost-effectiveness of combined treatment strategies. Furthermore, fragmentation between medical and surgical obesity care continues to limit coordinated implementation. GLP-1-based pharmacotherapy and MBS should be conceptualized as integrated components of a longitudinal treatment strategy for obesity. Bariatric surgery programs are uniquely positioned to serve as the multidisciplinary "medical home," coordinating pharmacologic, endoscopic, and surgical therapies to optimize durability of outcomes and continuity of care.