GLP-1

Refining free fatty acid receptor agonism for metabolic control: Pharmacological and functional features of novel dual GPR40/GPR120 ligands.

Kashi Brunetti, Bruno Fassari, Elisabetta Catalani +11 more

Metabolic disorders require therapeutic strategies targeting complementary pathways beyond current incretin-based therapies. Free fatty acid receptors GPR40 (FFAR1) and GPR120 (FFAR4) regulate insulin and incretin secretion as well as lipid metabolism, supporting the development of dual agonists. Here, we characterized three novel compounds (DFL23914, DFL23915 and DFL24102) derived from a previously validated scaffold, combining in vitro pharmacology with in vivo functional analyses. All compounds exhibited low-micromolar agonist activity at human GPR40 and GPR120, activating both Ca²⁺-dependent and β-arrestin signaling pathways, with DFL24102 showing the most balanced dual-agonist profile. In Drosophila models of diet-induced metabolic dysfunction, chronic administration significantly improved locomotor performance, reduced body weight gain, and normalized hyperglycemia and triglyceride accumulation in both adult and larval stages, without affecting survival. In vitro assays demonstrated the significant stimulation of glucagon-like peptide-1 secretion by DFL23914, DFL23915, and DFL24102 as well as the absence of hepatotoxicity, while cells permeability and mouse pharmacokinetics revealed minimal systemic exposure, supporting a gut-restricted mechanism of action. Consistently, oral administration in mice improved glucose tolerance in an oral glucose tolerance test, with significant reductions in glycemic excursions, particularly for DFL23915 and DFL24102. Overall, these findings indicate that dual GPR40/GPR120 agonists of this chemical series exert robust metabolic benefits through coordinated receptor activation and local intestinal activity. This study further supports dual FFAR targeting as a promising pharmacological approach and identifies leading candidates for the development of innovative therapies for metabolic disorders.

Cardiovascular Risk Reduction With GLP-1 RA Drugs.

Marie Pigeyre, Hertzel C Gerstein

GLP-1 (glucagon-like peptide-1) receptor agonists (RAs) have emerged as a major therapeutic advance in cardiometabolic medicine. Initially developed as glucose-lowering therapies for type 2 diabetes, these agents have demonstrated broad benefits that extend well beyond glycemic control. GLP-1 RAs enhance glucose-dependent insulin secretion and reduce appetite, leading to improved glycemia and sustained weight loss. In addition, GLP-1 signaling exerts vascular and myocardial effects, including improved endothelial function, reduced inflammation and oxidative stress, and favorable changes in cardiac metabolism and remodeling. Large randomized cardiovascular outcomes trials have consistently shown that several GLP-1 RAs reduce major adverse cardiovascular events, including myocardial infarction, stroke, cardiovascular death, and heart failure. Benefits have been observed across diverse populations, including individuals with established cardiovascular disease and those with obesity but without diabetes. Emerging therapies targeting multiple incretin pathways, such as dual GIP (glucose-dependent insulinotropic polypeptide)-GLP-1 RAs, may further extend these benefits. Collectively, these findings suggest that GLP-1 RAs influence multiple cardiometabolic pathways and may shift the underlying metabolic milieu toward a more favorable physiological state. In this Clinical Primer, we review the physiology of GLP-1 signaling, the evidence supporting cardiovascular risk reduction, and practical considerations for the clinical use of incretin-based therapies.

Molecular, genetic, and pharmacological advances in type 2 diabetes (2015-2025).

Ricardo Romero

Type 2 diabetes (T2D) is a multifactorial metabolic disorder driven by the interplay of insulin resistance, β-cell dysfunction, and complex genetic and epigenetic factors. Over the past decade (2015-2025), advances in molecular biology, genomics, and pharmacology have reshaped our understanding of its pathogenesis and treatment. Large-scale GWAS and functional genomics have clarified genetic risk loci and epigenetic mechanisms, while novel biomarkers, including circulating microRNAs and metabolomic signatures, offer potential for early detection and risk stratification. Therapeutically, incretin-based drugs, especially GLP-1 receptor agonists and dual agonists, as well as SGLT2 inhibitors, have transformed outcomes by targeting both glycemic control and cardiovascular-renal protection. These insights have also informed prevention strategies, emphasizing weight reduction, microbiome modulation, and precision interventions based on genetic risk. Yet major gaps remain, including functional annotation of risk loci, understanding of β-cell dedifferentiation and recovery, and equitable implementation across diverse populations. This review synthesizes molecular, genetic, and pharmacological progress from 2015 to 2025, highlights clinical translation, and identifies priorities for the next decade of research.

The Effect of Fructose and FTO Gene Polymorphism on the Efficacy of GLP-1 and GIP Combination Therapies: A Narrative Review.

Douglas S Larner

This literature review examines how dietary fructose intake and fat mass and obesity-associated (FTO) gene polymorphisms may influence the efficacy of glucagon-like peptide-1 (GLP-1)- and glucose-dependent insulinotropic polypeptide (GIP)-based therapies in obesity and metabolic syndrome. The narrative review synthesizes evidence showing that incretin-based therapies, particularly GLP-1 receptor agonists and dual GLP-1/GIP agonists, produce substantial weight loss and metabolic improvement, but response varies considerably among individuals. A central theme is that high fructose consumption promotes hepatic steatosis, de novo lipogenesis, insulin resistance, oxidative stress, and systemic inflammation, thereby creating a metabolic environment that may contribute to variability in incretin responsiveness. In parallel, FTO risk alleles are associated with increased obesity susceptibility, altered appetite regulation, impaired leptin signaling, and greater vulnerability to metabolic dysfunction. The review proposes an integrated model in which FTO-mediated leptin resistance and fructose-induced hepatic and inflammatory stress converge to reduce the appetite-suppressive and metabolic benefits of GLP-1/GIP therapies. Furthermore, it discusses the clinical implications of this interaction, emphasizing dietary fructose reduction, combination pharmacotherapy, and precision medicine strategies such as FTO genotyping and individualized therapeutic selection. Overall, the evidence suggests that gene-diet interactions may meaningfully shape incretin treatment outcomes and that more personalized, multi-targeted approaches may improve weight-loss efficacy in patients with obesity and metabolic syndrome. However, direct clinical evidence linking FTO genotype and fructose intake to reduced GLP-1/GIP therapeutic efficacy remains limited.

Impact of incretin therapies on biochemical and imaging outcomes in metabolic dysfunction-associated steatotic liver disease.

Nicole Ann Tesoro, Frederick Berro Rivera, Nathan Ross B Bantayan +11 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver condition. Incretin therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and emerging dual agonists, have shown promise in improving steatohepatitis.

Efficacy and safety of incretin-based therapies in patients with type 2 diabetes mellitus: a network meta-analysis based on clinical trials.

Xichao Wu, Yujiao Yang, Xueyan Cui +2 more

This study systematically assessed the efficacy and safety of 15 incretin-based therapies (IBTs) for type 2 diabetes mellitus (T2DM), including mono- (GLP-1RA), dual- (GIP/GLP-1RA or GLP-1/GCGR), and triple- (GIP/GLP-1/GCGR) receptor agonists, and explored how dosage and treatment duration affect clinical outcomes to support individualized treatment decisions.

Integrating metabolic rehabilitation with incretin-based anti-obesity therapy: a narrative review of a multimodal strategy for sustainable weight loss.

Emmanuel Olumuyide, Katz Ariel, Ehimen Aneni

Obesity is a chronic condition associated with substantial cardiometabolic morbidity and mortality. Incretin-based anti-obesity therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists, have transformed obesity management by producing clinically meaningful weight loss and improvements in glycemic and cardiometabolic risk profiles. However, weight loss achieved with these agents includes reductions in lean tissue in many studies, and the clinical significance of these body-composition changes remains incompletely defined. Importantly, reductions in DXA-derived lean mass should not be assumed to represent impaired muscle quality, strength, or function, as no published clinical trial has demonstrated that incretin-based therapy impairs muscle function. Metabolic rehabilitation encompasses structured exercise training, nutrition optimization, and behavioral support that have independently demonstrated benefits in preserving lean mass, improving insulin sensitivity, and enhancing cardiopulmonary fitness. Emerging evidence suggests that combining incretin-based therapy with metabolic rehabilitation may provide additive and complementary benefits, promote sustainable fat loss, while mitigating adverse metabolic adaptations. Metabolic rehabilitation also addresses skeletal muscle quality, bone health, and functional capacity, domains not directly targeted by pharmacologic appetite suppression. This narrative review synthesizes current evidence on the physiological effects of incretin-based obesity pharmacotherapy and metabolic rehabilitation, explores the mechanistic rationale for their combined use, reviews available clinical data, and proposes a practical framework for integrated obesity care. Key knowledge gaps and future research priorities are highlighted.

Insulin Resistance as a Systemic Metabolic Risk State for Cancer: Mechanisms, Biomarkers, and Prevention.

Marijana Matek Sarić, Nataša Lisica Šikić, Tamara Sorić +4 more

Insulin resistance (IR) is traditionally viewed within the context of type 2 diabetes. However, it increasingly appears to represent a broader systemic metabolic risk state with potential relevance for carcinogenesis. Chronic hyperinsulinemia can activate insulin-like growth factor-1-dependent pathways, including phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin and mitogen-activated protein kinase signaling, promoting cellular proliferation while limiting apoptosis. At the same time, IR is closely linked to oxidative stress, chronic low-grade inflammation, and epigenetic alterations, together shaping a tumor-promoting microenvironment. Epidemiological studies report consistent associations between IR and increased cancer risk, particularly for endometrial, liver, and colorectal cancers. Yet causality remains uncertain and likely varies by tumor type. Notably, metabolic dysfunction may also occur in individuals with normal body mass index (BMI), underscoring the limitations of BMI-based risk assessment. Unlike previous reviews that primarily focused on individual mechanisms or epidemiological associations, this review examines IR as a systemic metabolic risk state by integrating molecular, epidemiological, biomarker-based, and prevention-oriented perspectives. Particular emphasis is placed on strategies for earlier risk identification using integrated biomarker approaches, including fasting glucose, homeostatic model assessment of insulin resistance, triglyceride-to-high-density lipoprotein ratio, high-sensitivity C-reactive protein, and insulin-like growth factor-1. Emerging tools such as continuous glucose monitoring and hepatokine profiling may further refine risk detection. Sustained lifestyle modification-diet, physical activity, sleep, and stress regulation-remains central to prevention. Pharmacological therapies, including glucagon-like peptide-1 receptor agonists and dual incretin agents, offer additional metabolic benefits, although their long-term impact on cancer risk is still unclear. Therefore, IR is best understood not as an isolated risk factor, but as a systemic metabolic risk state that may influence cancer development, with implications for prevention and early risk stratification.

Mediterranean Dietary Pattern in Type 2 Diabetes Management: Pathways and Clinical Evidence.

Dubravka Majić Milotić, Tomislav Bulum, Kristijan Peroš

The Mediterranean diet (MedDiet) has emerged as a promising dietary strategy for the prevention and management of type 2 diabetes mellitus (T2DM). This narrative review provides a comprehensive synthesis linking the biological pathways of the MedDiet with established clinical evidence. Adherence to this traditional dietary pattern-characterized by a high intake of fiber, complex carbohydrates, antioxidants, and healthy fats-has demonstrated significant benefits in terms of glycemic control, enhanced insulin sensitivity, and overall metabolic health. Mechanistically, the review explains how the MedDiet improves health by modulating key physiological processes, including anti-inflammatory and antioxidant pathways, the regulation of branched-chain amino acid metabolism, the enhancement of short-chain fatty acid production via gut microbiota modulation, and upregulated incretin effects. Importantly, this review explains how the MedDiet complements modern medications, including glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. By integrating molecular mechanisms with human clinical outcomes, this narrative review addresses multiple aspects of the MedDiet in both the prevention and management of T2DM including glycemic control, weight management, and cardiovascular risk reduction, rendering it a valuable dietary strategy for both the prevention and treatment of this chronic condition.

Targeting the GLP-1 receptor pathways for dual management of obesity and depression.

Ruchi Keswani, Shvetank Bhatt

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), initially developed for the treatment of diabetes mellitus, are now widely used in obesity management. Obesity and depression are interconnected and share common biological pathways, including inflammation, oxidative stress, neurotransmitter imbalance, mitochondrial dysfunction, adipocytokine alterations, as well as gut-brain and HPA-axis dysregulation. These mechanisms are mediated by the signaling pathways that involve the GLP-1 receptor and provide a therapeutic target in comorbid disorders. GLP-1RAs have an impact on glycemic levels, weight reduction, insulin sensitivity, appetite and satiety control. Recent studies also highlight their neuroprotective effects, including modulation of dopaminergic pathways, enhanced hippocampal neurogenesis and neuroinflammation reduction. Hence, this review focuses on the therapeutic potential of using GLP-1 receptor pathways in the dual treatment of obesity and depression.

HMB and Liraglutide Confer Complementary Protection Against Lipotoxic and Atrophic Alterations in High-Glucose Plus Free Fatty Acid-Treated C2C12 Myotubes.

Li-Yuan Chen, Shao-Hsing Weng, Hsin-Hua Li +7 more

Type 2 diabetes (T2D)-associated sarcopenia is characterized by impaired insulin signaling, lipotoxicity, oxidative stress, and progressive muscle loss. Although liraglutide improves glucose control and reduces lipid burden, its ability to preserve muscle integrity under diabetic lipotoxic conditions remains limited. This study investigated whether β-hydroxy-β-methylbutyrate (HMB) could enhance liraglutide-mediated protection against high-glucose plus free fatty acid (HG+FFA)-induced injury in skeletal muscle cells.

Effect of pasteurized Akkermansia muciniphila MucT on insulin sensitivity, body composition, and GLP-1 production in subjects with metabolic syndrome: impact of low baseline gut Akkermansia levels.

Peter Suenaert, Anneleen Segers, Leen Rymenans +4 more

Pasteurized Akkermansia muciniphila MucT was found to improve barrier function in preclinical models and a proof-of-concept study in obese and prediabetic adults. Here, we describe the results of a double-blind placebo-controlled multicenter (Ireland and Germany) trial in 142 adults with metabolic syndrome, with or without prediabetes. The primary endpoint of whole-body insulin sensitivity (Matsuda index) did not differ after 4-months of daily administration of capsules containing 30 billion cells of pasteurized A. muciniphila MucT compared to placebo in the intention-to-treat subjects. Subsequent exploratory analyses showed that 3-months intake of pasteurized A. muciniphila MucT already improved HOMA-based hepatic insulin sensitivity in prediabetic (12%; p = 0.05) and 63-y-or-older-age subgroups (p = 0.05) while increasing post-OGTT excursion of the insulinotropic hormone glucagon-like peptide 1 (GLP-1) over placebo (p < 0.01). Further analysis of the gut microbiota by deep metagenomic analysis showed minor effects of the intervention but revealed that the baseline microbial composition differed from that in matched healthy adults. We found that participants with low baseline Akkermansia gene counts experienced significant health improvements and GLP-1 excursion after 3-months of treatment with pasteurized A. muciniphila MucT over the placebo. These benefits included improved insulin sensitivity (as shown by Matsuda and HOMA-S indices) and GLP-1 excursion (post-OGTT) (p < 0.05), reductions in body weight (p = 0.06) and decreased trunk fat (p < 0.05). In conclusion, daily supplementation with pasteurized A. muciniphila MucT has the potential to improve health markers in overweight or obese normo- or dysglycemic adults with the most significant improvements in subjects with low baseline intestinal Akkermansia levels, who are apparently truly in need of this intervention. Clinical trial registration no.: NCT05114018 clinicaltrials.gov.

PROTAC-Mediated DPP-4 Degradation: A New Solution for Type 2 Diabetes.

Wei Zeng, Liangzhu Feng

Dipeptidyl peptidase-4 (DPP-4) is an important aggravating factor in the progression and exacerbation of type 2 diabetes mellitus (T2DM), a condition characterized by diminished insulin responsiveness because it rapidly degrades glucagon-like peptide-1 (GLP-1) and other peptide with similar physiological function. Although several small-molecule DPP-4 inhibitors have been developed for the clinical management of T2DM, their therapeutic benefits are only moderate, as the fail to achieve for sustained inhibition of DPP-4. Hence, targeted degradation of DPP-4 using proteolysis-targeting chimera (PROTAC) technology offers an alternative strategy for sustained glycemic control in T2DM.

From Satiety to Substance Use: Neural Mechanisms of GLP-1 Signaling in Appetite and Reward.

Caitlin Baumer-Harrison, Morgan Graham, Bart C De Jonghe +1 more

The central glucagon-like peptide-1 (GLP-1) system encompasses homeostatic and hedonic neural circuits. GLP-1-producing neurons within the brainstem project broadly to GLP-1 receptor (GLP-1R)-containing brainstem, hypothalamic, limbic, and mesolimbic nuclei. The diverse expression of the GLP-1R throughout metabolic and reward nuclei positions this system to integrate motivated behavior with physiological state. GLP-1 acts as a state-dependent "behavior-ending" signal that suppresses appetite, promotes satiety, and dampens hedonic and motivational reward value-effects that extends beyond palatable foods. GLP-1R agonists, which can partially cross the blood-brain-barrier, engage central GLP-1Rs via circumventricular organs and adjacent nuclei leading to polysynaptic relays that suppress feeding and drug-seeking behaviors. An abundance of preclinical and clinical evidence highlights the efficacy of GLP-1R agonists for the treatment of obesity and other metabolic disorders. Emerging evidence also indicates the therapeutic application may extend to other disorders characterized by reward-related maladaptive behaviors, including substance use disorders.

Changes in incretin hormone concentrations after pancreaticoduodenectomy: a systematic review and exploratory meta-analysis.

Oliwia Grząsiak-Kraj, Tomasz Kraj, Krzysztof Poznański +2 more

Pancreaticoduodenectomy (PD) removes the duodenum and proximal jejunum, alters nutrient transit, and may modify secretion of incretin hormones involved in glucose homeostasis.

Distinctive patterns of glucagon and incretin responses to oral and isoglycaemic intravenous glucose load in fibrocalculous pancreatic diabetes.

Shivendra Verma, Riddhi Dasgupta, Shajith Anoop +9 more

Fibrocalculous pancreatic diabetes mellitus (FCPD) is characterised by pancreatic calcification, intraductal calculi and severe insulin deficiency, yet abnormalities in glucagon regulation and incretin hormone responses remain incompletely understood. We evaluated the glucagon, incretins and oxyntomodulin secretory responses to oral and intravenous glucose administration in participants with FCPD. Participants with FCPD (cases; n = 9; mean age 34 ± 7.2 years) and healthy individuals (controls; n = 6; mean age 29.8 ± 7.7 years) underwent an extended oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion (IIGI). Serial measurements of plasma glucose, insulin, C-peptide, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), oxyntomodulin (OXM), and pancreatic polypeptide (PP) were done. Serial hormone responses were analysed using linear mixed-effects models, with area-under-the-curve analyses using trapezoidal rule, performed as secondary summaries. On primary mixed-model analysis, the participants with FCPD exhibited significantly higher fasting and post-OGTT glucagon concentrations with glucagon exposure being greater following OGTT than IIGI in the group with FCPD, whereas no route-dependent difference was observed in control participants. GLP-1 and OXM responses were similarly increased in participants with FCPD, particularly following, oral glucose tolerance test, while GIP responses were attenuated. In contrast, C-peptide and pancreatic polypeptide responses were profoundly suppressed during both OGTT and IIGI in FCPD, consistent with severe pancreatic endocrine failure. Despite matched glycaemic exposure, the incretin effect and gastrointestinal glucose disposal were reduced in the FCPD group. These findings demonstrate persistent hyperglucagonemia accompanied by a distinctive pattern of incretin secretion in FCPD, characterised by exaggerated L-cell-derived hormone secretion with attenuated K-cell (GIP) response and impaired pancreatic peptide responses, highlighting altered entero-pancreatic hormonal regulation in this condition.

Prescribing Trajectories in Type 2 Diabetes in the United States, 2019-2024.

Tobias S Lux, Dongkun Lee, Jeff M Phillips +12 more

Clinical guidelines for type 2 diabetes (T2D) provide population-level recommendations, but real-world treatment patterns evolve dynamically and vary across patients. Understanding longitudinal prescribing trajectories may reveal heterogeneity in care not captured by cross-sectional analyses.

Food-Derived Elastin Peptides Improve Glucose Metabolism and Protect Renal Vasculature in Stroke-Prone Spontaneously Hypertensive Rats Despite Modest Dipeptidyl Peptidase 4 Inhibition.

Kumiko Takemori, Yuki Nakamura, Kenji Sato +3 more

Elastin-derived peptides (EPs) from food sources may be multifunctional dietary components that support metabolic and vascular health. However, their in vivo physiological actions remain incompletely understood. This study investigated the effects of bonito bulbus arteriosus-derived EPs on glucose metabolism, GLP-1 elevation associated with enhanced early-phase insulin secretion, and renal vascular integrity in stroke-prone spontaneously hypertensive rats (SHRSP) with glucose intolerance.

sweelin®, a novel sweet protein, does not affect blood glucose and insulin levels - a double-blind, crossover, randomized study.

Yael Lifshitz, Rotem Saban, Shira Paz +5 more

A novel hyper-sweet protein, sweelin®, enables sugar reduction without compromising taste. This double-blind, randomized, crossover study evaluated the effect of sweelin® on blood glucose, insulin and GLP-1 levels compared to stevia and dextrose in healthy adults. In this study, subjects consumed sweelin® (0.051 g), stevia Reb-M (0.225 g) or dextrose (75 g) in beverages matched for sweetness levels. Blood samples were collected at baseline and during 120-min post consumption. Each participant (n = 19) consumed each of the three beverages in a randomized order. At every time point after consumption, as well as iAUC, glucose and insulin levels were significantly lower following sweelin® consumption compared to dextrose (p < 0.0001), and not different from stevia. Overall, the findings indicate that sweelin®, is well tolerated and does not increase blood glucose, insulin or GLP-1 levels in healthy individuals, and suggest that sweelin® may serve as a metabolically neutral alternative for individuals seeking to reduce sugar intake. This trial was registered at clinicaltrials.gov (identifier code: NCT06520293).

Erythritol, sucrose, and sucralose elicit similar reward responses after flavor preference learning in healthy humans.

Emilie Flad, Fabienne Teysseire, Aleksandra Budzinska +7 more

Utilizing artificial low-caloric sweeteners as sugar alternatives remains controversial, as they provide sweet taste and the associated rewarding responses but fail to stimulate satiation. Erythritol, a non-caloric bulk sweetener, is able to stimulate the release of gastrointestinal (GI) satiation hormones, yet its influence on reward responses is inconclusive. The aim of this study was to investigate reward responses to erythritol, sucrose, and sucralose during and after flavor preference learning, and to explore the potential involvement of GI satiation hormones. In this randomized, double-blind, crossover study, 20 healthy participants (10 women, 10 men; mean ± SD; age: 25.8 ± 7.5 years, BMI: 22.3 ± 1.8 kg/m2) rated the reward responses (explicit wanting and liking) of three novel, neutral flavored beverages before and after pairing with erythritol, sucrose, or sucralose. GI satiation hormones (cholecystokinin, glucagon-like peptide-1) and parameters of glycemic control (glucose, insulin) were measured. After conditioning, explicit wanting and liking ratings increased, with no differences between the sweeteners. The release of GI satiation hormones and changes in glucose and insulin concentrations had no effect on the reward responses, which therefore might not be associated with flavor-nutrient learning (FNL) but rather with flavor-flavor learning (FFL). To conclude, beverages previously paired with erythritol appear to be equally liked as sucrose and sucralose.

Differential Modulation of Postprandial Glycemic, Incretin, and Satiety Responses by Low-Digestible Carbohydrates in Humans: An Exploratory Investigation.

Jinsoo Noh, Hye Rim Kim, Jungsook Han +6 more

Effective postprandial glycemic regulation is essential for preventing metabolic disorders such as type 2 diabetes. While pharmacological interventions like GLP-1 (Glucagon-Like Peptide-1) receptor agonists are effective, dietary strategies using low-digestible carbohydrates (LDCs) may offer a sustainable and complementary approach.

Benefits of Incretin Therapy on Ovarian Function: A Scientific Literature Review.

Sandro La Vignera, Rosita A Condorelli

Incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have emerged as potentially promising therapeutic agents for improving ovarian function, especially in women with polycystic ovary syndrome (PCOS) and obesity-related reproductive dysfunction. This comprehensive review synthesizes evidence from 30 highly relevant studies examining the mechanisms of action, clinical outcomes, and safety profile of incretin therapies on ovarian function. The evidence suggests that GLP-1 RAs may exert beneficial effects through multiple molecular pathways, including FOXO1 signaling, modulation of steroidogenesis, and enhancement of insulin sensitivity, although most mechanistic data derive from animal models and in vitro studies without validation in human ovarian tissue. Clinical outcomes from randomized controlled trials and meta-analyses show improvements in menstrual regularity, hormonal profiles, and spontaneous conception rates, though evidence certainty is limited by small sample sizes, short duration, high heterogeneity, and restriction to overweight/obese populations. While preliminary safety data regarding inadvertent early pregnancy exposure are reassuring, animal studies suggest potential dose-dependent risks that warrant careful consideration. Importantly, GLP-1 RAs are not currently approved or guideline-recommended for fertility restoration, and substantial uncertainty remains regarding long-term reproductive safety, optimal patient selection, and clinical guidelines. This review provides a balanced synthesis of current evidence and identifies critical gaps requiring further investigation before routine clinical use can be recommended.

Lentiviral GLP-1 gene therapy elicits developmental stage-dependent β-cell regeneration in diabetic rats.

Ezgi Erbasan, Melike Aliciaslan, Fulya Erendor +4 more

Pancreatic β-cell differentiation and regenerative capacity differ markedly between developmental stages, with the neonatal pancreas exhibiting high plasticity that enables ongoing progenitor- and ductal-derived β-cell formation, whereas the adult pancreas demonstrates limited neogenic potential. Glucagon-like peptide-1 (GLP-1) promotes β-cell survival, proliferation, and differentiation; however, its developmental stage-specific effects on β-cell regeneration are not fully understood. To investigate this, we generated a third-generation HIV-based lentiviral vector encoding native GLP-1 (LentiGLP-1) under the control of cytomegalovirus (CMV) promoter using the Multisite Gateway® recombination cloning system. The vector's ability to modulate β-cell differentiation and proliferation was subsequently assessed in neonatal and adult diabetic rat models. Type 2 Diabetes (T2DM) was induced in neonatal rats by administering low-dose streptozotocin (STZ), exploiting the intrinsic plasticity of the developing pancreas, whereas in adult rats, a high-fat diet combined with low-dose STZ was used. LentiGLP-1 administration markedly promoted differentiation of ductal and progenitor cells into insulin-producing β-cells in neonatal rats, accompanied by enhanced β-cell proliferation, demonstrating effective engagement of developmental plasticity. In adults, LentiGLP-1 partially restored β-cell populations through activation of residual progenitors and stimulation of replication in existing β-cells, improving glycemic control and insulin sensitivity. Notably, acinar cells did not contribute to β-cell generation in either neonatal or adult models. These results indicate that GLP-1 exerts developmentally regulated effects on β-cell differentiation, facilitating neogenesis in neonates and partially restoring regenerative capacity in adults. Long term GLP-1 expression, thus represents a promising strategy to restore β-cell mass by proliferation and differentiation, providing insight into its therapeutic potential for diabetes.

Restoring Satiety After GLP-1/GIP Pharmacotherapy: Metabolic Stability, Diet Quality, and the Gut Microbiota.

Lidia Lasik, Natalia Ukleja-Sokołowska

GLP-1 receptor agonists and dual GLP-1/GIP agonists have significantly transformed the treatment of obesity, enabling clinically meaningful weight reduction and improvements in cardiometabolic parameters. However, clinical trial data indicate that cessation of therapy is associated with biologically driven weight regain and a partial loss of metabolic benefits. This phenomenon underscores the chronic nature of obesity and the limited durability of effects achieved through pharmacotherapy alone. Nevertheless, structured clinical frameworks describing how to maintain satiety and metabolic stability after GLP-1/GIP dose reduction or discontinuation remain limited. The aim of this narrative review is to discuss the mechanisms underlying weight regain following dose reduction or discontinuation of GLP-1/GIP pharmacotherapy and to present strategies supporting long-term metabolic stabilisation. Weight regain is driven in part by persistent metabolic adaptations, including a reduction in resting energy expenditure (adaptive thermogenesis), alterations in the hunger-satiety axis (increased ghrelin, reduced leptin signalling), and potentially incomplete restoration of adipose tissue and liver-related metabolic function, although direct evidence in this specific setting remains limited. Weight loss is often accompanied by a reduction in fat-free mass, which further lowers energy expenditure and increases susceptibility to a positive energy balance after treatment cessation. It remains unclear whether pharmacological suppression of appetite results in sustained normalisation of endogenous satiety regulation after treatment cessation, and its effects on gut microbiota function remain uncertain. In clinical practice, key priorities include preserving muscle mass (adequate protein intake, resistance training), maintaining dietary nutrient density, stabilising postprandial glycaemia, and ensuring sufficient intake of fermentable fibre to support short-chain fatty acid production and gut-brain signalling. GLP-1/GIP pharmacotherapy should be viewed as a component of an integrated model of obesity treatment. We propose that long-term weight stabilisation may require a transition from pharmacologically induced satiety to satiety supported by diet quality, preserved fat-free mass, and metabolic stability. Further research is needed to define optimal post-treatment strategies and to identify patients in whom therapy can be safely reduced or discontinued. This transition should be regarded as a conceptual framework and forward-looking hypothesis requiring validation in prospective studies.

Cost-effectiveness of iGlarLixi vs. IDegAsp in individuals with type 2 diabetes: a BRAVO model-based evaluation.

Jiali Qin, Man Tang, Xiaomei Wang +5 more

This study aimed to evaluate the long-term cost-effectiveness of insulin glargine/lixisenatide injection (iGlarLixi) vs. insulin degludec/insulin aspart (IDegAsp) in individuals with poorly controlled type 2 diabetes in China.

Semaglutide showed limited improvements in patients with Alzheimer's disease: Revisiting the evoke and evoke + clinical trials.

Christian Hölscher

BackgroundSemaglutide is a glucagon-like peptide-1 analog that is on the market to treat type 2 diabetes and weight loss (Ozempic, Wegovy). Two phase 3 clinical trials have been conducted, Evoke and Evoke+, testing the drug in patients with Alzheimer's disease. The trial management presented results of the intermediate readout at week 104 of the CDR-SB scores, which were negative. On the basis of that, the management decided to declare the trials a failure. However, data from week 130 and 156 had not been statistically analyzed.ObjectiveWhen evaluating time points 130 and 156, several results show a separation between drug group and placebo group with semaglutide showing better results.MethodsUsing the means, converting the SEMs to SDs and numbers of patients per group, I analyzed the results using the Welch T-test (two-tailed), which does not assume equal SD.ResultsThe ADCS-ADL-MCI test, Evoke trial, week 130, did show a significant difference, p = 0.0039. Other test such as the ADAS-cog-13 results show trends towards improvement by semaglutide at week 156. Cerebrospinal fluid biomarker analyses showed significant differences in some AD markers, too.ConclusionsThe results did show some limited drug effects at later time points of the trials. However, Semaglutide has been designed to stay in the blood for a long time and therefore does not cross the blood-brain barrier readily. Novel GLP-1 type drugs that can cross the blood-brain barrier easily may show superior protective effects in AD patients.

SGLT2 inhibitors and incretin-based therapies for metabolic dysfunction-associated steatohepatitis: a systematic review.

Artur Macedo Cruz, Bruna Carolyne Venancio Lima, José Erivelton Souza Maciel de Ferreira +1 more

In recent years, metabolic therapies originally developed to treat systemic metabolic disorders have been investigated as potential therapeutic strategies for Metabolic dysfunction-associated steatohepatitis (MASH).

Incretins for Type 2 Diabetes.

Esther Min, Andrew Goyette, Elaine Young +3 more

Type 2 diabetes (T2D) is a growing global health challenge. With prevalence projected to rise significantly in the coming decades, T2D is expected to contribute to increased healthcare costs due to associated morbidity and mortality. Characterized by insulin resistance and impaired pancreatic insulin secretion, T2D could be mediated by the effects of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Incretin-based therapies have, therefore, emerged as effective treatments for improving glycemic management and weight reduction in people with T2D. Since the approval of the first twice daily GLP-1 RA in 2005, advancements have led to the development of once-daily and once-weekly injectable formulations and an oral formulation. Furthermore, the approval of a dual GLP-1/GIP RA marked a significant milestone in incretin-based therapies. These agents have demonstrated glycemic-lowering benefits, weight loss, and reduced cardiovascular risk in high-risk populations. The most common adverse effects are gastrointestinal and can be partially mitigated with slow dose titration and patient education. Ongoing research into alternative dosing regimens, combination therapies, and strategies to improve access will be important for optimizing the long-term impact of incretin-based therapies in T2D management.

Adjunctive Treatment with GLP-1 and Dual GLP-1/GIP Receptor Agonists for People with Type 1 Diabetes: Consensus Report and Practical Guidelines for Safe Use.

Satish K Garg, Halis K Akturk, Samita Garg +29 more

Among the most impactful therapeutic advances in the management of diabetes over the past two decades has been the development of incretin-based therapies, specifically glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and in combination with glucose-dependent insulinotropic polypeptide (GIP) RAs. Since the introduction of exenatide in 2005, a growing number of these drugs has transformed the management of type 2 diabetes (T2D). Their pleiotropic effects include weight loss, reduced insulin resistance, improved glucose regulation, and reductions in known risk markers for diabetic kidney disease and cardiovascular disease. To date, these important noninsulin glucose-lowering therapies have only received regulatory approval for use in T2D, obesity, sleep apnea, and metabolic dysfunction-associated steatohepatitis with moderate-advanced fibrosis, supported by randomized controlled trials (RCTs) and real-world data that demonstrate efficacy and safety. Regulatory approval for use of weekly GLP-1 and GLP-1/GIP RAs in type 1 diabetes (T1D) has not yet been achieved, in part because of the limited number of inconsistent, small-scale, RCTs and real-world studies for glycemic impacts of these agents in T1D. Larger RCTs are ongoing or planned in participants with T1D. Potential safety risks include hypoglycemia and hyperglycemia-related ketosis in T1D after initiation of GLP-1/GIP RA drugs. While RCTs are ongoing to further investigate GLP-1 and GLP-1/GIP RA agents as adjunct therapy for people with T1D, access to these drugs is already possible, based on their use to treat overweight and obesity. However, without regulatory approval for the T1D indication, access and opportunities for people with T1D to engage with important education regarding the safety of GLP-1 and GLP-1/GIP RA therapy may be limited. This precludes support from diabetes health care professionals to optimize diabetes management of these agents alongside expected insulin dose changes. The purpose of this consensus report is to review the current literature and provide guidelines for diabetes clinicians and people with T1D to facilitate the safe use of GLP-1/GIP RAs in the management of T1D. This consensus statement has been endorsed by the following professional associations: Advanced Technologies & Treatments for Diabetes (ATTD), International Diabetes Federation-Europe, American Association of Clinical Endocrinologists (AACE), Breakthrough T1D, International Society for Pediatric and Adolescent Diabetes (ISPAD), Association of Diabetes Care and Education Specialists (ADCES).

A rationally designed 18-amino acid peptide with potential as GLP-1 receptor agonist.

Aditi Singh, Sucharita Shadangi, Soumendra Rana

Diabetes mellitus (DM) is a multifaceted disease etiologically characterised by dysregulation in glucose homeostasis. The World Health Organization (WHO) global report indicates that over 90% of DM cases are classified as Type 2 DM (T2DM), which is clinically characterized by chronic hyperglycemia. This systemic condition arises predominantly due to the interplay of two key components: (a) compromised insulin production by the pancreatic β-cells, and (b) the failure of insulin-sensitive tissues to react to insulin. Notably, it is well established that glucagon-like peptide-1 (GLP-1), an incretin hormone of the glucagon superfamily, contributes to glucose-dependent pancreatic β-cell insulin secretion. The insulinotropic impacts of secreted GLP-1 are facilitated by its interaction with GLP-1 receptor (GLP-1R), a class B G-protein-coupled receptor (GPCR). However, GLP-1 is proteolytically cleaved by dipeptidyl peptidase 4 (DPP-4), resulting in a plasma half-life of ∼2 minutes, which limits its therapeutic efficacy in patients with T2DM. Therefore, the exogenous administration of DPP-4-resistant GLP-1R agonists (GLP-1RAs) has proven to be a successful therapeutic strategy for managing T2DM. Notably, the currently marketed GLP-1RAs, such as Semaglutide, Liraglutide, and Lixisenatide, are long-chain GLP-1 mimetic peptides, ranging in length from 33 to 39 amino acids.

Sweet Killers: Animal Toxins that Mimic Glucoregulatory Hormones.

Isabela Gobbo Ferreira, Beatriz de Cássia da Silva Jacob, Emilly Regina Ramos +6 more

Glucose homeostasis is regulated by a complex interplay of endocrine signals, primarily involving insulin, glucagon, and incretin hormones, such as glucagon-like peptide-1 (GLP-1). Disruption of this balance underlies metabolic disorders like type 2 diabetes, a condition of growing global concern. In recent years, animal-derived toxins have emerged as a novel and underexplored source of bioactive compounds capable of modulating key pathways involved in glucose regulation. This review provides an overview of the endocrine control of glucose metabolism, followed by an in-depth examination of animal toxins that mimic or modulate the activity of insulin and GLP-1, as well as those that interfere with glucagon signaling, focusing on their pharmacological relevance. These naturally evolved molecules offer unique mechanisms of action and high target specificity, making them valuable leads for drug development. Several venom-derived compounds have already shown promise in preclinical and clinical studies, reinforcing their potential as templates for next-generation antidiabetic therapies. We also discuss the translational implications of these discoveries, highlight current challenges in their therapeutic development, and propose future directions for researches which crosstalk between Toxinology and Endocrinology.

Acute GIP and GLP-1 Administration Exerts Differential Metabolic Effects in Totally Pancreatectomised Individuals.

Liva S L Krogh, Maja B Hansen, Natasha C Bergmann +6 more

While being recognised for stimulating pancreatic insulin secretion, GIP and GLP-1 exert various extrapancreatic effects relevant in the context of incretin-based therapies. Here, we evaluated the extrapancreatic effects of GIP and GLP-1, separately and combined, on postprandial physiology in totally pancreatectomised individuals.

Targeting Inflammation and Fibrosis in Lipedema: The Potential Role of Glucagon-like Peptide-1 Receptor Agonist Therapies.

Yasmine Mohseni, Aria Vazirnia, Ardalan Minokadeh +2 more

Lipedema is a chronic disorder characterized by disproportionate accumulation of subcutaneous fat, most commonly affecting the extremities, and is associated with pain, inflammation, and fibrosis. Effective medical therapies are lacking, and liposuction remains the primary treatment. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrate metabolic and anti-inflammatory effects, but their role in lipedema remains unclear.

Associations of PYY, GLP-1 and LEAP2 with changes in feeding-related cognition, body weight and glucose homeostasis after bariatric surgery in non-diabetic women.

María F Andreoli, Pablo N De Francesco, Wei Zhou +6 more

Roux-en-Y gastric bypass (RYGB) is an effective surgical intervention for severe obesity, but the role of gastrointestinal hormones in its benefits remains unclear. We examined longitudinal pre-to-post-meal gastrointestinal hormone changes and their relationships with glucose homeostasis and feeding-related cognitive responses in women undergoing RYGB. Seventeen non-diabetic women were evaluated pre-RYGB (Visit 1, V1), 1-month post-RYGB (Visit 2, V2), and 1-year post-RYGB (Visit 3, V3). Plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), ghrelin, and liver-expressed antimicrobial peptide 2 (LEAP2) were measured before and after a breakfast in all visits. Appetite ratings and feeding-related cognitive performance were evaluated using visual analog scales, Ideal Portion Size, and Food Stroop tasks. At V3, RYGB induced weight loss (30.8%) and improved glucose homeostasis (p = .020), accompanied by reduced hunger (p = .042), smaller self-reported ideal portion size (p < .001), and improved cognitive control toward food-cues (p = .002). Fasting GLP-1 and PYY levels remained stable across visits but showed enhanced post-meal responses at V2 and V3 (GLP-1: p < .001; PYY: p = .013). Ghrelin levels increased post-RYGB (p = .010) without post-meal variation. LEAP2 concentrations remained stable. Fasting LEAP2 correlated positively with BMI at V1 (p < .001). Fasting PYY correlated inversely with BMI at V3 (p = .005), and its post-meal rise inversely correlated with ideal portion size at V1 (p = .022). GLP-1 increments negatively correlated with ideal portion size (p = .007) at all visits and glycemia (p = .017) at V1. In non-diabetic women, RYGB improves feeding-related cognitive processes. BMI is associated with LEAP2 only pre-surgery, and with PYY 1-year post-RYGB. Restoration of GLP-1 and PYY post-meal increments contributes to metabolic and behavioral improvements. Clinical Trial Registry: This study was registered at clinicaltrials.gov as NCT01815216. https://clinicaltrials.gov/study/NCT01815216.

Targeting Gut Microbiota by DPP-4 Inhibitors in Obesity: Mechanistic Insights and Therapeutic Implications.

Mansour Alanazi, Hayder M Al-Kuraishy, Ahmed A Mohamed +4 more

Obesity is a complex metabolic disorder driven by factors such as chronic inflammation, insulin resistance, and significant alterations in the gut microbiota. Dipeptidyl peptidase-4 (DPP-4), an enzyme primarily known for inactivating incretin hormones like glucagon-like peptide-1 (GLP-1), is now recognized as a critical link between metabolic dysfunction and gut microbiome dysbiosis. This review aims to examine the mechanistic role of DPP-4 and its inhibitors in obesity, specifically focusing on how they modulate the gut microbiome to influence host energy balance and metabolic health.

Oral GLP-1-Based Therapeutics in the Obesity-Metabolic Syndrome-Diabetes Continuum: Translational Advances, Clinical Barriers, and Emerging Strategies.

Syed Arman Rabbani, Manita Saini, Mohamed El-Tanani +5 more

The obesity-metabolic syndrome-diabetes continuum is driven by interconnected mechanisms including insulin resistance, dysfunctional adiposity, chronic inflammation and progressive cardio-renal-metabolic injury. This triggered a need for therapies that extend beyond glucose lowering alone. The benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as disease-modifying drugs include weight loss, cardiovascular risk reduction, glycemic control and renal protection. However, treatment burden, adherence issues and access restrictions may limit the long-term effects of injectable formulations. One significant translational development that aims to close this gap is oral GLP-1-based treatments. In this review, we examine the mechanistic rationale, formulation science and clinical development of oral GLP-1 RAs. Oral semaglutide is presented as the first validated proof of concept for systemic peptide delivery by the gastrointestinal route. The biological barriers to oral peptide absorption, including enzymatic degradation, low epithelial permeability, pharmacokinetic variability and epithelial safety constraints, are critically discussed. Enabling technologies such as SNAC-based gastric absorption, nanocarriers, mucoadhesive systems and stability-optimization platforms are evaluated. Evidence from the PIONEER program and related studies demonstrating meaningful glycemic and weight-loss efficacy, acceptable safety and clinical utility in patients with type 2 diabetes and chronic kidney disease is further synthesized. Beyond first-generation oral peptide platforms, we discuss the emerging landscape of non-peptide oral GLP-1 RAs, dual and triple incretin agonists, precision dosing strategies and model-informed drug development. Oral GLP-1-based therapeutics are shifting from a formulation breakthrough to a broader translational strategy for disease modification across the obesity-metabolic syndrome-diabetes continuum. Long-term renal outcomes, access and implementation barriers remain important priorities for future research.

Insulin and Incretin Receptor Agonists Reciprocally Alter Their Blood-Brain Barrier Permeabilities.

Angeline Fry, Alexis Rose, Riley Weaver +4 more

Incretin receptor agonists (IRAs) such as GLP-1-based therapies improve metabolic and cognitive outcomes and enhance brain insulin signaling. One way that IRAs could have these actions is by affecting the blood-brain barrier (BBB); however, IRA-BBB interactions are poorly studied. Here, we examined the ability of insulin and IRAs to affect each other's transport across the BBB in lean mice. We found that intracerebroventricular (ICV) administration of the insulin receptor antagonist S961 did not affect the blood-to-brain transport of the bioactive fragment of the IRA, 125I-dulaglutide (BAF). In contrast, 125I-dulaglutide (BAF) co-administered with intravenous (IV) insulin significantly enhanced 125I-dulaglutide (BAF) BBB transport into whole brain, olfactory bulb, parietal cortex, and pons, demonstrating insulin-dependent modulation of IRA BBB transport. Regional transport rates for 125I-dulaglutide (BAF) across the brain varied by ~2.5-fold, with the fastest transport into the olfactory bulb, frontal cortex, cerebellum, and pons. Co-administration of IV dulaglutide (BAF) did not alter 125I-insulin BBB transport rates (Ki) but did reduce reversible insulin binding (Vi) at the BBB by >50%, suggesting rapid effects on BBB insulin receptors. To explore the effects of chronic IRA administration, lean mice were treated with semaglutide for two weeks. Body weight and food intake were unchanged, but female mice showed reduced fasting levels of serum insulin and GLP-1 and decreased insulin transport into whole brain, while male mice showed a reduction in insulin binding at the BBB. Chronic semaglutide also reduced 125I-insulin BBB transport in female mice when studied with in situ perfusion, a procedure that removes the immediate influence of serum factors. Together, these findings demonstrate reciprocal and female-selective interactions between IRAs and insulin at the BBB. Acute insulin enhances the BBB transport of an IRA in female mice, whereas chronic IRA exposure selectively impairs insulin BBB transport in females, highlighting the BBB as a dynamic and hormone-sensitive interface with implications for long-term treatment in mouse models and potential for translation impact in humans.

Metabolic Dysfunction-Associated Steatotic Liver Disease and Incretin Receptor Agonists: A Metabolic Approach to Halting Liver Disease Progression.

Ludovico Abenavoli, Anna Giulia Loricchio, Ivo Lopez +4 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with metabolic abnormalities, shares pathophysiological pathways with metabolic syndrome, and has become a leading cause of chronic liver disease in industrialized nations. In the absence of approved pharmacological treatments and due to its high risk of progression to advanced fibrosis, MASLD represents a significant clinical challenge. Incretin-based therapies, originally developed for the treatment of type 2 diabetes mellitus and obesity, have recently gained attention as promising therapeutic strategies in hepatology. Among them, GLP-1 receptor agonists have shown efficacy in reducing hepatic steatosis, inflammation, and fibrosis-related biomarkers, primarily through weight loss and enhanced insulin sensitivity. Dual agonists targeting both GLP-1 and GIP receptors, such as tirzepatide, have demonstrated superior outcomes in improving hepatic and metabolic parameters. Emerging agents like cotadutide (a GLP-1/glucagon receptor agonist) and retatrutide (a GLP-1/GIP/glucagon triagonist) represent a novel therapeutic frontier, with early clinical data indicating potent hepatoprotective effects and favorable metabolic remodeling. This narrative review examines the hepatoprotective potential of incretin-based therapies, highlighting how targeted intervention on the underlying metabolic dysfunction may lead to significant improvements in MASLD. These therapies may also exert beneficial effects on fibrosis progression; however, the currently available evidence remains limited.

A randomised, double-blind, placebo-controlled trial to assess the postprandial dose-dependent effects of wild blueberries on metabolic and cognitive outcomes following a high-carbohydrate breakfast.

Lucy R Ellis, Dominic O'Connor, Haseena Khan +2 more

Despite equivocal human study data, anthocyanin-rich blueberries are associated with positive glycaemic effects which could benefit satiety and other cardiometabolic outcomes. The objective of this study was to examine the dose-dependent effects of freeze-dried wild blueberries on postprandial glucose response simultaneously with changes in satiety, blood pressure and cognitive function.

Response of Plasma Glucagon-Like Peptide 1 Concentration to Oral Administration of Lactose and Casein in Preweaning Calves.

Yudai Inabu, Midori Satoh, Taketo Obitsu +1 more

This study investigated the effects of orally administered sugars and casein, main components of whole milk, on plasma glucagon-like peptide 1 (GLP-1) concentration in preweaning calves. In Experiment 1, calves received water (CON), 2.37% (w/w) glucose (GLU), 2.37% galactose (GAL), or a mixed solution containing 2.37% each of glucose and galactose (GLU + GAL). In Experiment 2, calves received 4.5% (w/w) lactose (LAC), 3.0% casein (CAS), or a mixed solution containing lactose at 4.5% and casein at 3.0% (LAC + CAS). Because baseline plasma GLP-1 and α-amino nitrogen (AAN) concentrations varied greatly and correlated with postadministration mean concentrations, statistical analyses for these parameters included baseline values as covariates. In Experiment 1, glucose and insulin concentrations were higher in GLU and GLU + GAL than in CON (p < 0.001), whereas GLP-1 concentrations were lower in GAL than in other groups (p < 0.001). In Experiment 2, glucose and insulin concentrations were higher in LAC and LAC + CAS, AAN concentrations were higher in CAS and LAC + CAS, and GLP-1 concentrations were higher in LAC, CAS, and LAC + CAS compared with CON (p < 0.001). In conclusion, both lactose and casein promoted GLP-1 secretion in calves, although oral administration of glucose or galactose alone did not elicit a marked GLP-1 response.

A randomised clinical trial testing the safety of and metabolic responses to short-term duodenal infusion of recombinant RORDEP1 in healthy men.

Joachim Gæde, Yong Fan, Liwei Lyu +7 more

RUMTOR-derived peptides (RORDEPs) 1 and 2 are polypeptides synthesised by specific strains of the human gut commensal Ruminococcus torques. Preclinical studies have shown that RORDEPs lower blood glucose via an impact on plasma incretins and an improvement of hepatic insulin sensitivity. In a randomised, placebo-controlled, crossover trial, we here explore the safety and tolerability of, as well as any metabolic responses to, a duodenal infusion of recombinant RORDEP1 (r-RORDEP1) given to healthy men after oral intake of a liquid mixed meal.

Differences in physiological response to an oral glucose tolerance test in adult Maasai men and women.

Dirk Lund Christensen, Cathrine Olesen Emborg, Kaushik Laxmidas Ramaiya +9 more

Rural, agro-pastoralist Maasai in East Africa exhibit low prevalence of diabetes, yet little is known about their physiological response to glucose loads and whether sex has an impact on glucose metabolism, including incretin hormones.

Interactions between nutrition, GLP-1 secretion, and composition of the gut microbiome.

Afroditi Kouraki, Daniel McWilliams, Ana M Valdes

Glucagon-like peptide-1 (GLP-1) is a key incretin hormone regulating insulin secretion, appetite, and energy balance. Recent research highlights complex interactions between dietary composition, gut microbiome metabolism and GLP-1 secretion. Understanding these relationships is increasingly important given the widespread clinical use of GLP-1 receptor agonists for obesity and type 2 diabetes and the growing interest in microbiome-targeted nutritional strategies.

The novel GLP-1/GIP dual receptor agonist DA5-CH is superior to tirzepatide and exendin-4 in the 6-OHDA Parkinson rat model.

Zhang Lingyu, Feng Peng, Zhong Wanting +5 more

Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no cure. Diabetes is one of the risk factors for developing PD. Tirzepatide is a novel long-acting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist that is on the market as a treatment for diabetes. Importantly, two phase II trials in PD patients showed good effects with the GLP-1 receptor agonists Exendin-4 and Lixisenatide.

Progressive loss of glycemic control during chronic DPP-4 inhibitor therapy despite preserved β-cell function: a case report suggesting acquired incretin resistance.

Sai Prasad, Aarushi Ahuja, Shreya Sharma +4 more

Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely prescribed second-line agents for type 2 diabetes mellitus (T2DM). Secondary treatment failure with DPP-4 inhibitors is conventionally attributed to progressive β-cell dysfunction. Acquired resistance to DPP-4 inhibitor therapy, characterised by progressive glycemic deterioration despite preserved endogenous insulin secretion, remains an under-recognised and poorly documented clinical phenomenon. We report a case of secondary DPP-4 inhibitor failure with preserved β-cell function, raising the hypothesis of acquired incretin resistance as an alternative mechanism of treatment failure.

Converging neurotrophic-immune signaling in autism spectrum disorder: integrative roles of klotho, GDNF/GFRA-1, IGF-1 and GLP-1 pathways.

Janvi Verma, Rohit Kumar Singh, Supratim Paul +7 more

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by deficits in social communication and restricted, repetitive behaviors. Although traditionally linked to synaptic protein dysfunction and neurotransmitter imbalance, growing evidence suggests that broader intracellular signaling networks critically regulate the neurodevelopmental processes disrupted in ASD. This review synthesizes current evidence on four interconnected signaling pathways-Klotho, GDNF/GFRA-1, IGF-1, and GLP-1-and examines their potential roles in ASD pathophysiology within a unified mechanistic framework. These pathways regulate fundamental processes, including neuronal survival, synaptogenesis, dendritic maturation, myelination, modulation of oxidative stress, neuroinflammation, and metabolic homeostasis. Importantly, they converge on shared intracellular cascades such as PI3K/Akt, MAPK/ERK, mTOR, and Wnt/β-catenin, which are increasingly implicated in ASD-related abnormalities in synaptic plasticity and circuit organization. Experimental models demonstrate that dysregulation of these signaling systems can impair hippocampal function, alter excitatory-inhibitory balance, and disrupt structural connectivity. Among them, IGF-1 has shown promising translational potential in clinical trials for syndromic ASD, while GLP-1 receptor agonists and Klotho modulation represent emerging therapeutic avenues. The GDNF/GFRA-1 axis further highlights the importance of trophic support in maintaining synaptic integrity and neuronal resilience. By integrating molecular, preclinical, and clinical findings, this review proposes that convergent dysregulation of trophic and metabolic signaling pathways may contribute to ASD heterogeneity. A systems-level understanding of these interconnected mechanisms may facilitate biomarker development and support the advancement of stratified, pathway-targeted therapeutic strategies.

Maternal obesity and the metabolic syndrome in reproductive health: assessing incretin-based interventions.

Luisa Wallentowitz, Mariana G Garcia, Catalina Atorrasagasti +6 more

The global epidemic of overweight and obesity threatens gynecological and reproductive health, necessitating effective therapeutic strategies to improve maternal and fetal long-term health outcomes. This review provides an overview of weight loss interventions and discusses their use in the context of gestation, such as surgical interventions and anti-obesity medications. As the interest in incretin-based therapies has risen substantially, we discuss how incretin-based therapies, including glucagon-like peptide-1 (GLP-1) receptor agonists and GLP-1 receptor agonists and glucose-dependent insulinotropic polypeptide (GIP) dual agonists, might improve reproductive function and could interact with the physiological metabolic changes ensuring a healthy pregnancy. These metabolic adaptations during pregnancy arise from the integration of insulin signaling, lipid metabolism, placental endocrine function, mitochondrial remodeling and inflammatory regulation. Furthermore, we consider not only short-term consequences of maternal overweight and obesity but also focus on fetal long-term health trajectories following pregnancy-related metabolic disorders, as maternal obesity and gestational weight gain are considered risk factors for childhood obesity and overweight.

GLP-1 Receptor Agonist Treatment and Health Outcomes in Methadone-Treated Patients with Opioid Use Disorder and Diabetes.

Jane Y Pan, Igor Elman, Krisha Panchal +4 more

To investigate whether the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in methadone-treated patients with opioid use disorder (OUD) and type 2 diabetes (T2D) is associated with improved cardiometabolic and mental health outcomes.

Glucagon-like peptide 1 receptor agonists: anti-inflammatory effects in cardiovascular diseases.

Zorislava Bajic, Tanja Sobot, Miloš P Stojiljković +2 more

The potential therapeutic applications of glucagon-like peptide-1 (GLP-1) have led to the development of GLP-1 receptor agonists (GLP-1RAs), which replicate GLP-1's effects. The primary use of GLP-1RAs is the management of type 2 diabetes (T2DM) by stimulation of insulin secretion. In addition to its metabolic functions, GLP-1 exhibits significant anti-inflammatory effects through various molecular pathways, utilizing both direct and indirect mechanisms. Experimental studies have revealed that GLP-1RAs modulate multiple inflammatory pathways, including cytokine production, oxidative stress, glucotoxicity, lipotoxicity, and immune cell recruitment across multiple organs. They interact with their receptors on immune cells, thereby reducing the production of inflammatory cytokines and decreasing the infiltration of immune cells into tissues. There is considerable overlap among the pathways activated by GLP-1R in cardiovascular tissue, which can lead to anti-apoptotic, antioxidative, and anti-inflammatory effects. Clinical studies have confirmed the anti-inflammatory effects of GLP-1RAs in conditions such as acute myocardial infarction, left ventricular dysfunction, coronary artery disease, and ST-segment elevation myocardial infarction. Notably, GLP-1RAs are included in the European Society of Cardiology guidelines for managing cardiovascular disease in patients with T2DM.

GLP-1 Receptor Agonist Associated Unmasking of Insulinoma.

Eden Simonov, Rina Berger, Olga Shishkina +2 more

Insulinoma is a rare functional pancreatic neuroendocrine tumour and the most common cause of endogenous hyperinsulinaemic hypoglycaemia in adults. Diagnosis is frequently delayed due to non-specific and intermittent symptoms, and a high index of suspicion is needed.

Direct or Indirect Action? Mechanisms of the Antiatherosclerotic Effects of Glucagon-Like Peptide-1 Receptor Agonists.

Michał Zawadzki, Monika Karczewska-Kupczewska

Cardiovascular diseases (CVD) remain the leading cause of global mortality. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) significantly reduce major adverse cardiovascular events in patients with and without Type 2 diabetes, offering benefits that extend beyond glycemic control. This review summarizes proposed multifactorial mechanisms underlying these effects, categorizing them into indirect and direct pathways. Indirect mechanisms include, among others, improvements in lipid metabolism, insulin sensitivity, blood pressure, and renal protection. In addition to the previously described effects, GLP-1 RAs may exert direct vascular actions, including anti-inflammatory actions, suppression of oxidative stress, improved endothelial function, modulation of macrophage polarization, reduction of adhesion molecule expression, and inhibition of vascular smooth muscle cell proliferation and migration, as well as downregulation of matrix metalloproteinases and plasminogen activator inhibitor-1. Collectively, these processes contribute to plaque stabilization and reduced atherothrombotic risk. Although clinical evidence for cardiovascular risk reduction of GLP-1 RAs is robust, mechanistic insights are predominantly derived from preclinical or animal models. Therefore, further functional studies in humans are warranted to clarify the direct antiatherogenic actions of GLP-1 RAs.

Combination amino acids and glucose effects on insulin and GLP-1 secretion.

Kenneth H C Koh, Junhe Zhao, Sarah X Luo +3 more

Dietary nutrients such as amino acids possess an insulinogenic effect. However, not all amino acids were meticulously investigated for their effect on both insulin and incretin secretion, and the effect of amino acids given in different combinations remained incompletely characterized. In the present work, we reported the quantitative effect of individual and combinatorial amino acids in conjunction with low and high glucose, respectively, on insulin secretion from human islets and on glucagon-like peptide-1 (GLP-1) secretion from secretin tumor cell (STC-1). STC-1 cells were incubated with amino acid treatment solutions individually and in combinations at low and high glucose to investigate GLP-1 secretion. Batches of 15 islets were sequentially treated with 3 mM glucose, combinatorial amino acid treatment solutions at low and high glucose, and finally 25 mM KCl to quantify insulin secretion. Lysine, threonine, tryptophan, phenylalanine, and aspartic acid significantly increased GLP-1 secretion in STC-1 cells compared with negative control. Branched-chain amino acids (BCAAs) stimulated greater GLP-1 secretion only at high glucose and significantly induce insulin secretion in islets even in low glucose. Other amino acid combinations tested were able to augment GLP-1 secretion even in the absence of glucose but failed to further stimulate insulin secretion in human islets when given concurrently at higher glucose concentrations. In conclusion, the findings from our work could be used to infer the expected insulinogenic effect and glycemic response for proteins with different amino acid compositions.

Oat β-glucan reshapes gut microbiota to enhance glucose homeostasis via coordinated modulation of bile acid conjugation and succinate-dependent intestinal gluconeogenesis.

Yantong Meng, Siqi Li, Keyi Zhou +4 more

Dietary fibers-induced gut microbiota changes influence diabetes through bile acid metabolism. Oat β-glucan is a beneficial dietary fiber that improves glucose metabolism, but its mechanism of regulating gut microbiota-mediated bile acid metabolism and exerting hypoglycemic effects remains unclear. Here, we found that oat β-glucan improved glucose intolerance and insulin resistance and promoted glucagon-like peptide-1 (GLP-1) secretion in obese mice. The enhanced production of secondary bile acids such as lithocholic acid (LCA) and deoxycholic acid (DCA), which were associated with the enriched Faecalibaculum, norank_f_Muribaculaceae, Bifidobacterium and Akkermansia induced by oat β-glucan, were proven to promote GLP-1 secretion via inhibiting FXR. Simultaneously, succinic acid, which was elevated in fecal metabolites by oat β-glucan, was linked to enhanced intestinal gluconeogenesis and contributed to GLP-1 secretion. Overall, oat β-glucan modulated gut microbiota to increase secondary bile acids and succinic acid, thereby stimulating GLP-1 secretion to promote glucose metabolism in mice fed a Western diet.

Metabolic Benefits vs. Cardiovascular Uncertainty: A Critical Review of GLP-1 Receptor Agonists in Type 1 Diabetes.

Elżbieta Wójcik-Sosnowska, Adrianna Tabeau, Agnieszka Pawlik +2 more

Type 1 diabetes (T1DM) is associated with elevated cardiovascular (CV) risk, often exacerbated by the rising prevalence of obesity. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce CV risk in type 2 diabetes, but their role in T1DM is less well-defined. This umbrella review synthesizes evidence from systematic reviews, meta-analyses, and Mendelian Randomization (MR) studies to evaluate the metabolic efficacy and safety of GLP-1 RAs in T1DM. Adjunctive therapy, particularly with liraglutide and exenatide, was associated with clinically meaningful weight reduction (mean difference: -4.35 kg to -5.1 kg) and lower total daily insulin doses. HbA1c reductions were statistically significant but modest (0.2-0.3%), with no improvement in Time in Range. Secondary benefits included lower systolic blood pressure. Safety data were mixed: the risk of severe hypoglycemia was not increased, whereas Time Below Range and gastrointestinal adverse events were more frequent. Evidence on diabetic ketoacidosis (DKA) was inconsistent across studies. Overall, GLP-1 RAs improve weight and reduce insulin requirements in T1DM, potentially mitigating indirect CV risk factors; however their direct cardiovascular benefits remain unproven in the absence of dedicated outcome trials.

Incretin-Based Anti-obesity Medications in Polycystic Ovary Syndrome: The Evidence Map.

Mojca Jensterle, Andrej Janez

Polycystic ovary syndrome (PCOS) is a common, heterogeneous condition that is tightly linked to obesity, visceral adiposity and insulin resistance. Lifestyle intervention and off-label use of metformin provide only modest and unsustained weight loss, insufficient to reverse obesity-driven pathophysiology in most women with PCOS and obesity. Incretin-based anti-obesity medications, including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists (dual GIP/GLP-1RAs), offer a biologically plausible way to target adipose dysfunction, hyperinsulinemia and chronic inflammation that drive PCOS in a large subset of patients. In this narrative, product-segmented review, we map the evidence for liraglutide, semaglutide and tirzepatide in PCOS across mechanistic, clinical, and safety domains, and highlight key evidence gaps that limit current practice. Liraglutide has the densest PCOS-specific evidence, demonstrating reproducible weight loss across small and heterogeneous cohorts, reductions in visceral adiposity and hepatic fat, improved glycemia and inflammatory markers, and early signals for androgen and fertility benefits in selected phenotypes. Semaglutide data remain sparse but conceptually rich, demonstrating weight-loss efficacy and mechanistic insights, alongside preliminary signals of increased likelihood of natural conception. Tirzepatide currently has no PCOS-specific evidence and cannot be recommended beyond extrapolation from obesity and diabetes trials. Across all agents, reproductive outcomes, periconceptional and pregnancy safety, adolescent use, long-term cardiovascular-kidney-metabolic trajectories, obstructive sleep apnea, musculoskeletal health and phenotype-stratified response remain major evidence gaps. We propose a multidimensional, metabolic high-risk PCOS phenotype as the most rational current target for incretin therapy, while emphasizing that well-designed, PCOS-specific trials are essential before these drugs can be viewed as PCOS-modifying therapies rather than powerful, but still adjunctive, weight-loss agents.

Tirzepatide and semaglutide: different twins?

Arturo Cesaro, Vincenzo Acerbo, Paolo Calabrò

Incretin-based therapies currently represent one of the cornerstones in the management of type 2 diabetes mellitus and obesity, owing to their ability to integratively modulate cardiometabolic risk. Semaglutide, a selective agonist of the glucagon-like peptide-1 (GLP-1) receptor, has consolidated its clinical role through an efficacy profile that combines marked improvement in glycaemic control, substantial body weight reduction, and well-established cardiovascular and renal benefits. Tirzepatide, the first dual agonist of the glucose-dependent insulinotropic polypeptide and GLP-1 receptors, has introduced a new generation of incretin-based agents, characterized by a superior impact on weight loss and insulin sensitivity, with a potential expansion of therapeutic indications. Although both molecules share a remarkable ability to reduce body weight and HbA1c levels, they differ in their mechanisms of action, current therapeutic indications, and the robustness of available evidence on cardiovascular outcomes. Their integration into clinical practice therefore requires a personalized approach that balances metabolic efficacy, safety, and individual patient risk profiles. Within this context, the incretin revolution offers new perspectives for cardio-reno-metabolic prevention.

GLP-1, GIP, and Glucagon Excursions During a Mixed Meal Tolerance Test in Young and Lean South Asians Versus Europids.

Carlijn A Hoekx, Lisa B D Brinkman, Robin van Eenige +6 more

South Asians exhibit an unfavourable metabolic phenotype characterized by visceral obesity, insulin resistance and dyslipidemia. While various hormones play a critical role in regulating postprandial energy metabolism, it remains unclear whether they respond differently to food intake. We aimed to compare the meal-induced excursion of incretin hormones (GLP-1 and GIP) and glucagon between South Asians and Europids.

The molecular mechanisms of incretin resistance in Type 2 Diabetes Mellitus (T2DM).

Rawayh Muslim Albaghlany, Abbas Ali Mansour

Incretin hormones, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), serve as crucial mediators of postprandial glucose homeostasis by primarily enhancing glucose-stimulated insulin secretion. Research indicates that the incretin effect accounts for approximately 50% of insulin secretion in individuals without diabetes, which is significantly reduced to 30% or less in those with Type 2 Diabetes Mellitus (T2DM). The mechanisms underlying this incretin resistance have emerged as critical causes of postprandial hyperglycemia. Incretin-based therapies, including GLP-1 receptor agonists (GLP-1RAs) and DPP-4 inhibitors, have demonstrated efficacy in managing T2DM; however, intrinsic resistance mechanisms may limit their effectiveness. Understanding the processes by which T2DM affects incretin action, from hormone secretion to the modulation of signal transduction, is essential for optimizing current therapies and developing new interventions to enhance β-cell responsiveness and improve glycemic control. The concept of incretin resistance has a well-established history in literature, dating back to at least the early 1990 s. It is used to describe a reduced insulinotropic responsiveness to incretin hormones in individuals diagnosed with T2DM. This review examines how hyperglycemia, chronic inflammation, and genetic susceptibility collectively inhibit incretin signaling through distinct yet interconnected molecular pathways. This impairment exacerbates postprandial hyperglycemia and accelerates β-cell dysfunction. We propose novel hypotheses regarding selective β-arrestin signaling, enhancers, epigenetic regulation, interactions between gut microbiota and incretins, inflammation-induced endoplasmic reticulum (ER) stress, and genotype-specific therapeutic responses. The hypotheses presented in this review serve as a framework for future research and therapeutic development to combat the phenomenon of incretin resistance and improve the clinical management of T2DM.

High-amylose maize starch as a functional carbohydrate: Long-term regulation of glucose homeostasis following early-life intervention.

Zhiqiang Xu, Lingjin Li, Li Cheng +2 more

Carbohydrate intake in early life drives long-term host metabolic homeostasis. Maternal obesity is recognized as a risk factor for metabolic disorders in offspring. High-amylose maize starch (HAMS) is a functional carbohydrate with metabolic regulatory capabilities. However, its mechanisms and potential effects in improving glucose metabolism disorders in offspring with maternal obesity during early life remain unexplored. Here, we characterized the structural properties of HAMS and assessed its structural stability during gastrointestinal digestion. Subsequently, using a high-fat diet-induced maternal obesity model, we evaluated the long-term effects of early-life HAMS supplementation (3-8 weeks) on glucose metabolism in offspring and explored the potential mechanisms, focusing on hormone secretion, pancreatic islet function, and hepatic metabolomics. HAMS supplementation significantly improved glucose metabolism disorders in offspring with maternal obesity. Mechanistically, in vitro digestion experiments demonstrated that HAMS partially escaped gastrointestinal digestion and delivered increased amounts of fermentable carbohydrates to the colon. HAMS digestion products activated intestinal L-cells, restoring maternal obesity-induced reductions in serum glucagon-like peptide-1 (GLP-1) levels. HAMS also significantly increased GLP-1R, Ngn3, and Pdx1 gene expression, promoting pancreatic β-cell neogenesis and enhancing insulin secretion. Furthermore, hepatic metabolomics revealed that HAMS intake activated insulin signaling and energy metabolism-related pathways, including the AMPK, PI3K-Akt, and FoxO signaling pathways, and modulated amino acid metabolic networks in offspring with maternal obesity. This study provides new insights for investigating the regulatory role of HAMS in glucose metabolism and indicates that HAMS may serve as an effective dietary strategy in early life to improve glucose homeostasis in offspring with maternal obesity.

Glucagon-like Peptide-1 and Dual GIP/GLP-1 Receptor Agonists in Brain: Exploring the Expanding Role and Safety in Neuropsychiatry.

Ana Cristina Tudosie, Loredana-Maria Marin, Simona Georgiana Popa +1 more

Glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists, originally introduced for the management of type 2 diabetes mellitus and obesity, are increasingly recognized for their broader actions within the central nervous system, with emerging implications in neuropsychiatry and neurodegeneration. This review integrates current preclinical and clinical evidence, emphasizing their pharmacodynamic profile, central receptor distribution, and the molecular pathways linking metabolic signaling to neural function. Evidence suggests that GLP-1 receptor activation across key brain regions involved in energy balance and reward modulates multiple neurotransmitter systems, including dopamine and serotonin, as well as glutamatergic and GABAergic transmission, thereby influencing behavior, affective processes, and cognitive function. In parallel, these agents exhibit neuroprotective properties through improved neuronal insulin sensitivity, attenuation of neuroinflammatory pathways, and support of neuroplasticity, alongside effects on limiting pathological protein aggregation. Dual GIP/GLP-1 agonism may further potentiate these central actions through complementary metabolic and synaptic mechanisms. Although pharmacovigilance data have identified isolated neuropsychiatric adverse events, current clinical evidence does not support a consistent causal association. Collectively, incretin-based therapies represent a promising translational approach at the interface of metabolic and neuropsychiatric disorders, warranting further investigation into their long-term central safety, therapeutic efficacy, and clinical relevance.

A role for vagal activity in preventing the suppression of glucagon secretion by GLP-1 during hypoglycemia.

Carolina B Lobato, Amalie B E Nielsen, Jens J Holst

Glucagon-like peptide 1 (GLP-1) is generally safe against hypoglycemia, although it stimulates insulin and inhibits glucagon secretion. One explanation is that glucagon secretion is not inhibited by GLP-1 during hypoglycemia. We aimed at understanding the lack of suppression of glucagon secretion by GLP-1 by exploring the paracrine and neural regulation of pancreatic hormone secretion during hypoglycemia. Isolated rat pancreas (A) and an organ block comprising pancreas and stomach (B) were perfused. We performed 1) dose-response studies with GLP-1 (7-36) at hypoglycemia; 2) studies with GLP-1 (7-36) with and without blockage of somatostatin (SST) activity (with SST receptor antagonists); 3) and 4) dose-response experiments with acetylcholine at euglycemia and studies under hypoglycemia; and 5) finally, we studied the role of cholinergic signaling for modulation of GLP-1 activity under hypoglycemia. We measured glucagon, SST, and insulin levels. The secretion of SST was dependent on surgical preparation (A or B, P = 0.0006) and on cholinergic stimulation (P < 0.0001), rather than on glucose levels (P > 0.05). The infusion of SSTR antagonists in the isolated perfused rat pancreas blocked the paracrine effects of SST (P = 0.0041) and stimulated glucagon secretion (P = 0.0023). Cholinergic activity stimulated glucagon secretion during hypoglycemia through suppression of SST secretion. Cholinergic signaling delivered through the gastric intramural autonomic ganglia and/or vagus nerve efferents to the pancreas appears to be crucial for preventing GLP-1-induced inhibition of glucagon secretion during hypoglycemia.NEW & NOTEWORTHY Autonomic signaling suppresses somatostatin secretion, crucial for paracrine stimulation of glucagon secretion. SST mediates GLP-1-induced inhibition of glucagon secretion, but autonomic signaling may interfere with this mechanism. Activation of cholinergic pathways in a preparation with prepancreatic parasympathetic structures suppresses SST secretion in response to GLP-1 and potentiates glucagon secretion during hypoglycemia. These findings support the clinical importance of autonomic signaling in regulating pancreatic hormone secretion and hypoglycemia risk in some patients on GLP-1 receptor agonists.

Injectable thermosensitive hydrogel-based sustained delivery system for anti-diabetic peptides in type 2 diabetes mellitus therapy: A review.

Lam Quoc Vu, I-Hui Chiu, Cuong Thai Hoa Hoang +3 more

Injectable thermosensitive hydrogels have emerged as a promising class of biomaterials for the sustained delivery of drug. These smart systems undergo a sol-gel phase transition in response to physiological temperature, enabling minimally invasive injection and the formation of an in situ drug depot capable of controlled and sustained drug release. In recent years, thermosensitive hydrogels have drawn increasing attention in type 2 diabetes mellitus (T2DM) therapy, offering enhanced patient adherence, stable glycemic control, and reduced injection frequency compared with conventional formulations. Importantly, beyond glucose lowering, several hydrogel-based incretin therapies-particularly GLP-1 receptor agonists and dual GIP/GLP-1 agonists-have demonstrated clinically significant body-weight reduction and improved metabolic outcomes, addressing both hyperglycemia and obesity, two core components of T2DM pathophysiology. This review summarizes the classification, polymer composition, and drug release mechanisms of thermosensitive hydrogels. Special emphasis is placed on their use in the sustained delivery of insulin, GLP-1 receptor agonists and dual GIP/GLP-1 agonists. These hydrogel-based depots have demonstrated prolonged pharmacological efficacy, while preserving drug bioactivity, minimizing burst release, and achieving superior improvements in glycemic control and providing superior body-weight management with GLP-1 receptor agonists-loaded thermosensitive hydrogels, as compared with conventional injectable regimens. Finally, the challenges and future prospects of thermosensitive hydrogel systems are discussed, including the need for improved formulation stability, scalable manufacturing, and regulatory translation. With continued interdisciplinary advancements, injectable thermosensitive hydrogels hold strong potential as next-generation, long-acting, and patient-friendly delivery platforms for comprehensive diabetes management, encompassing both glycemic control and body-weight reduction in T2DM patients.

A comprehensive review of GLP-1 and aerobic training in cardiovascular disease management.

Negin Kordi, Rezvan KheirAndish, Peyman Akraminia +2 more

Secreted by enteroendocrine cells in the gastrointestinal tract, glucagon-like peptide-1 (GLP-1) is pivotal in the management of glycemic variability, as it promotes insulin secretion while concurrently suppressing glucagon release. This review investigates the neural circuits activated by both endogenous and pharmacological forms of GLP-1, with particular attention to the important cell types that express GLP-1 receptors (GLP-1R) and the pathways that relay both metabolic and non-glycemic signals linked to GLP-1. The examination includes the effects of GLP-1 on the benefits and adverse outcomes related to bariatric surgery, as well as its influence on islet function, appetite regulation, inflammation, and cardiovascular health. This review introduces both established and new concepts, identifies outstanding questions, and outlines future challenges in the development and optimization of GLP-1R agonists for the management of cardiovascular disease. The role of GLP-1 in enhancing endurance, muscle recovery, fiber type distribution, muscle mass, and energy efficiency is well-documented. Furthermore, GLP-1 influences various physiological components, including bile acids, short-chain fatty acids, L cells, and G-protein-coupled receptors. Increased levels of GLP-1 due to overexpression lead to higher glycogen concentrations, the development of endurance-oriented muscle fibers, augmented mitochondrial content, and improved glucose uptake in skeletal muscle. Exercise training has been shown to elevate GLP-1 levels, which may be beneficial for those suffering from metabolic syndrome. Nonetheless, additional research is necessary to clarify how exercise promotes GLP-1 secretion in individuals with cardiovascular diseases.

Expert meeting report: epidemiology and management of acquired hypothalamic obesity.

Hermann L Müller, Ute K Bartels, Christian Denzer +7 more

Acquired hypothalamic obesity (aHO) is a disease characterized by rapid, clinically significant, and persistent weight gain resulting from damage to hypothalamic structures. aHO is associated with substantial morbidity, increased mortality, and marked impairment in quality of life. Etiologies include craniopharyngioma and other space-occupying lesions of the sellar/parasellar region, neurosurgical procedures, cranial irradiation, and traumatic brain injury. A multidisciplinary panel comprising ten specialists in neuroendocrinology, neurooncology, and neurosurgery from Germany, Austria, and Switzerland convened in Frankfurt am Main, Germany, on November 10, 2025, to discuss contemporary challenges and advances in this field. aHO should be conceptualized and treated within the broader clinical entity of hypothalamic syndrome, a complex disorder involving multiple neuroendocrine deficiencies, disturbances of circadian regulation, impaired control of hunger, satiety, and thirst, altered thermoregulation, and a range of cognitive, sleep-related, and psychosocial dysfunctions. Long-term outcomes for affected individuals are frequently unfavorable, largely due to increased risks of metabolic syndrome, cardiovascular disease, profound reductions in health-related quality of life, and elevated rates of premature mortality. The management of hypothalamic syndrome remains particularly challenging. Pharmacological strategies, including dextroamphetamine and glucagon-like peptide-1 receptor agonists, have demonstrated potential benefits for weight and hyperphagia-related outcomes. Recently, preliminary findings from a prospective, randomized, placebo-controlled clinical trial (TRANSCEND) provided encouraging evidence for the efficacy of setmelanotide, a melanocortin-4 receptor agonist. This perspectives report reviews clinical advances in epidemiology, diagnostics, treatment, and follow-up of patients with aHO and outlines key directions for future research aimed at improving outcomes in this vulnerable population.

Gut-Derived GLP-1 Released by Rare Sugar d-Allulose Cooperates With Insulin to Activate Left-Sided Vagal Afferents and Enhance Insulin Sensitivity.

Kento Ohbayashi, Mamoru Tanida, Chikara Abe +6 more

Compared with glucagon-like peptide 1 (GLP-1) receptor agonists, the physiological roles and mechanisms of endogenous, short-lived GLP-1 in glucose metabolism remain poorly understood. We used the rare sugar d-allulose, a noncaloric GLP-1 secretagogue, as a tool to elucidate the physiological actions of endogenous GLP-1. d-allulose-induced intestinal GLP-1 release cooperates with insulin to activate left-side vagal afferents, enhancing insulin action rather than insulin secretion and thereby regulating glycemic control. Because this acute mechanism improved hyperglycemia in type 2 diabetes to an extent comparable to that observed with GLP-1 receptor agonists, targeting GLP-1/insulin-vagal signaling may inform novel therapies and dietary or nutritional interventions for type 2 diabetes.

Glucagon-like peptide-1 mimotopes screened from an Fv-antibody library.

Hyung Eun Bae, Dayoung Choi, Jeong Soo Sung +5 more

Glucagon-like peptide-1 receptor (GLP-1R) agonists treat type 2 diabetes and obesity by promoting insulin secretion and suppressing glucagon release. In this study, GLP-1 mimotopes with GLP-1R agonist activity were screened from the Fv-antibody library. The Fv-antibodies represented the hypervariable region of heavy-chain IgG, which included three CDRs and four FRs, and the library was produced by randomizing the CDR3 region with 11 amino acids through site-directed mutagenesis. The GLP-1 mimotopes with GLP-1R agonist activity were screened using monoclonal anti-GLP-1 antibodies and were synthesized into peptides and expressed as Fv-antibodies co-expressed with GFP. The binding affinity of GLP-1 mimotopes was analyzed using a surface plasmon resonance biosensor, and the activity of the GLP-1 mimotopes (expressed Fv-antibodies and synthesized peptides) was analyzed by measuring cyclic adenosine monophosphate (cAMP) production and hormone secretion in pancreatic α- and β-cells. The molecular docking simulations revealed that GLP-1 mimotopes interacted with GLP-1R by targeting key residues known to bind GLP-1, supporting their potential as functional receptor agonists. The effect on fatty acid accumulation was analyzed using hepatocyte cell lines (HepG2 and Huh7), and transcriptomic changes were analyzed by RNA sequencing. In addition, GLP-1R downstream signaling in β-cells was evaluated by western blot analysis of AKT and ERK1/2 phosphorylation. This approach offers a novel strategy to generate new GLP-1R agonists and expand molecular diversity for GLP-1R-targeted therapeutic design.

[Wheat bran reduces oxidative stress and promotes glucagon-like peptide-1 secretion in high-fat-fed rats].

Aisikaier Rukeye, Ting Shang, Kuerbanjiang Maierheba +5 more

This study aimed to investigate the effects of wheat bran intervention on oxidative stress status and glucagon-like peptide-1(GLP-1) secretion in rats fed a high-fat diet(HFD).

Evaluating the Use of GLP-1 Receptor Agonists in Wolfram syndrome Patients.

Laura Lee, Abby F Tang, Anna Asako +8 more

Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene, characterized by early-onset diabetes mellitus, optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and progressive neurodegeneration. The condition selectively affects pancreatic β cells and neurons via chronic endoplasmic reticulum (ER) stress, and no proven disease-modifying therapy currently exists. Diabetes mellitus is typically the first manifestation, presenting at a mean age of 6 years as an insulin-dependent phenotype with preserved C-peptide and negative diabetes-related autoantibodies. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well-established agents in the management of type 2 diabetes, augmenting glucose-dependent insulin secretion, suppressing glucagon, slowing gastric emptying, and promoting satiety. Preclinical evidence further suggests that GLP-1 RAs preserve β-cell mass, attenuate ER stress, and confer neuroprotective effects, properties of particular therapeutic relevance to Wolfram syndrome. We conducted a retrospective cohort study of 84 participants with genetically confirmed Wolfram syndrome and insulin-dependent diabetes mellitus enrolled in the Washington University Wolfram Syndrome International Registry and Clinical Study. Clinical data were extracted from medical records; for participants concurrently enrolled in the Tracking Neurodegeneration in Early Wolfram Syndrome study, longitudinal data were obtained from that source as well. Thirty-five percent of eligible participants had received a GLP-1 RA at some point during follow-up. We characterize the prevalence of GLP-1 RA use, documented rationale for initiation, observed effects on glycemic control and visual outcomes, adverse effects, and reasons for discontinuation. No statistically significant changes in hemoglobin A1c (HbA1c) or body mass index (BMI) were observed. Visual acuity declined significantly at two years, consistent with expected disease progression. Gastrointestinal adverse effects were common and contributed to frequent discontinuation. These observational data provide important clinical context and a foundation for future prospective trials evaluating GLP-1 RAs as a potential disease-modifying strategy in Wolfram syndrome.

Harnessing Herbal Power: A Systematic Review of Phytopharmaceuticals in Type 2 Diabetes Management.

Kamalika Chattopadhyay, Pankaj Kumar, Ravishankar Ram Mani +3 more

The Type 2 diabetes mellitus (T2DM) is one of the key health crises facing the world, with the prevalence expected to surpass 783 million adults by the year 2045. It causes premature disability, death and enormous social and economic costs. It is believed that the number of diabetes mellitus (DM) may increase to 592 million in 2035. Although there are conventional therapies, they are very expensive and limited. Despite the fact drugs that are produced synthetically are effective in controlling the disease, there are some side effects that are related with their long-term use. Consequently, the role of the traditional medicine such as plant extracts and pharmacological compounds derived out of plants is becoming very popular. The purpose of this review is to bring together the existing research on the effectiveness of herbal medicine in treating T2DM and especially phytochemicals based on in vitro, in vivo and clinical studies.

The critical role of gut-brain signalling in eating behaviour and obesity.

Guillaume de Lartigue, Daniel I Brierley, Hyung Jin Choi

The process of eating can be divided into three distinct phases of behaviour: food seeking, food consumption and non-prandial activities. The durations of, and transitions between, these behavioural phases are driven by underlying interoceptive phenomena of hunger, satiation and satiety. The gut-brain axis regulates all eating phases, with the vagus nerve a primary conduit for interoceptive feedback about gut-derived mechanical and chemical cues. This Review explores the mechanisms governing each phase, focusing on how gut-derived signals are peripherally and centrally integrated to shape hunger, satiation and satiety, food preferences, and food-related learning. Chronic exposure to high-fat, high-sugar diets disrupts these mechanisms, driving a maladaptive state characterized by hyperphagia, food choice biases and habitual overeating. We examine the mechanisms underlying this maladaptive state, including vagal fibre remodelling, altered gene expression and leptin resistance, which can impair gut-brain communication, diminishing the brain's capacity to appropriately control eating behaviour and maintain energy balance. Emerging therapies, including glucagon-like peptide 1 receptor agonists, are effective in promoting weight loss but typically do not reverse the underlying causes of gut-brain axis dysfunction. By examining the mechanisms of gut-brain signalling, this Review highlights the vagus nerve as a key, yet underappreciated, target for obesity treatment.

Pilot Trial of Vachellia farnesiana Pod Polyphenol Extract: Feasibility, Acute Postprandial Glycemic Response, and Incretin Hormone Modulation in Healthy Adults.

Yonatan Y Cariño-Cervantes, Martha Guevara-Cruz, Omar Noel Medina-Campos +9 more

Medicinal plants contain bioactive compounds with potential benefits for metabolic regulation, including glucose homeostasis. Vachellia farnesiana (VF) pods are rich in polyphenols, including quercetin, catechins, methyl gallate, prutin, and hydroxycinnamic acids; however, their clinical effects in humans remain underexplored.

Quantitative β-Cell Mass Imaging Redefines Disease Staging and Glycemic Control in Type 1 Diabetes.

Kentaro Sakaki, Takaaki Murakami, Hayao Yoshida +7 more

Noninvasive measurement of pancreatic β-cell mass remains an important unmet need in type 1 diabetes because conventional surrogate markers, such as C-peptide, often lack sensitivity in advanced disease. This study evaluated the glucagon-like peptide 1 receptor-targeted positron emission tomography tracer, 18F-labeled exendin-4-based probe conjugated with polyethylene glycol, [18F]FB(ePEG12)12-exendin-4 (18F-exendin-4), to determine its ability to visualize pancreatic β-cell mass. Positron emission tomography/computed tomography performed at 60 and 120 min after tracer injection in individuals with type 1 diabetes was compared with data from healthy control participants. No serious adverse events occurred. Pancreatic uptake was consistently lower in individuals with type 1 diabetes and showed clear separation between individuals with insulin-dependent diabetes and healthy control participants at 120 min. Pancreatic uptake at 120 min correlated with fasting C-peptide index and inversely with hemoglobin A1c and daily insulin dose per body weight. These findings support [18F]FB(ePEG12)12-exendin-4 positron emission tomography/computed tomography as a noninvasive approach for assessing β-cell mass and disease status.

Novel Small Molecule GLP-1R Agonists Based on 1H-Benzo[d]imidazole-5-Carboxylic Acid Scaffold.

Elena V Tolkacheva, Tagir L Salakhov, Alexandr Yu Saliev +7 more

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal endocrine L cells that activates the GLP-1 receptor (GLP-1R), leading to glucose-dependent insulin secretion and suppression of glucagon release. In recent years, GLP-1R agonists (GLP-1RAs) have become one of the leading therapeutic options for the treatment of type 2 diabetes mellitus; however, for a long time clinically approved GLP-1RAs were limited to peptide drugs unsuitable for oral administration. The discovery of the "first-in-class" small molecule agonist danuglipron in 2018 demonstrated the feasibility of orally available GLP-1RAs and stimulated the development of numerous danuglipron-like compounds, some of which showed increased efficacy over the prototype. In this study, we report the design and synthesis of novel GLP-1RAs based on a regioisomeric danuglipron scaffold, 1H-benzo[d]imidazole-5-carboxylic acid. A series of 35 compounds was synthesized and evaluated in vitro for cytotoxicity and GLP-1R agonistic activity using a cAMP accumulation assay. A potent lead compound 12r (pEC50 = 7.72, pCC50 < 3.60) was found which is a close structural analog of danuglipron with reduced cytotoxicity and excellent selectivity over two other class B GPCRs, including GCGR and GIPR. Despite decreased potency compared to danuglipron, the obtained results hold promise for further optimization and provide valuable structure-activity relationship insights.

The attenuated incretin effect is associated with glucose intolerance in patients with hepatitis B-related acute-on-chronic liver failure.

Meichuan Li, Han Hu, Yujuan Liu +6 more

The pathogenesis of glucose homeostasis disturbance in acute-on-chronic liver failure (ACLF) remains poorly defined. This study aimed to investigate the association between incretin effect (IE) and glucose intolerance in patients with hepatitis B virus-related ACLF (HBV-ACLF).

Nutritional Endocrinology in Dairy Cattle: Roles of the Ghrelin and Glucagon-Like Peptide Axis in Metabolic Adaptation and Developmental Programming.

Toshihisa Sugino, Rika Fukumori, Mabrouk Elsabagh +3 more

High-producing dairy cattle experience profound metabolic transitions during the periparturient and periweaning periods that influence health and long-term productivity. In ruminants, feed intake and metabolic adaptation reflect coordinated interactions among rumen fermentation, hepatic oxidative feedback, and gastrointestinal hormones. This review summarizes evidence on ghrelin and the glucagon-like peptide (GLP) axis and organizes recent findings within a hierarchical framework linking rumen-derived substrates, intestinal nutrient sensing, and systemic endocrine responses. Ghrelin increases during negative energy balance in early lactation and appears to support metabolic mobilization, whereas its orexigenic effect is constrained by ruminant-specific intake control. Evidence also indicates that postruminal amino acid supply and fatty acid profile can modulate ghrelin secretion, highlighting the importance of the digestive site and nutrient type. The GLP axis complements this regulation. GLP-1 links postruminal nutrient-related signals with insulin dynamics and satiety, whereas GLP-2 is more closely related to intestinal growth and adaptation during developmental transitions, including weaning. Notably, improvements in intestinal development in early life do not always coincide with large or sustained changes in circulating GLP-2. Overall, viewing dairy nutrition through endocrine responses, alongside nutrient supply, provides a basis to interpret variable outcomes in transition cows and calves and refine feeding strategies across physiological stages.

Evaluation of incretin levels in patients with prolactinoma.

Gökçe Altunay Vurğun, Nusret Yılmaz, Sebahat Özdem +1 more

Prolactin has been shown to play an important role in the regulation of glucose metabolism. The present study aimed toevaluate incretin hormones in patients with prolactinoma.

Obesity and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Literature Review on Pathophysiology and Treatment.

Michael Romanos, Juan M Garcia Cordova, Jose Villamarin +2 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a key hepatic manifestation of obesity and systemic metabolic dysfunction and is a leading cause of chronic liver disease worldwide. Obesity-driven mechanisms, including adipose tissue dysfunction, insulin resistance and increased free fatty acid flux to the liver, promote ectopic lipid accumulation and lipotoxic injury. These processes trigger mitochondrial and endoplasmic reticulum stress, inflammation, immune activation and disturbances in the gut-liver axis, driving disease progression from simple steatosis to metabolic dysfunction-associated steatohepatitis, fibrosis and cirrhosis. MASLD is a highly heterogeneous condition, with differences in fat distribution, body composition and genetic susceptibility giving rise to distinct clinical phenotypes, including lean and non-lean MASLD, which have important implications for disease risk, progression and therapeutic response. Clinical outcomes are determined primarily by fibrosis stage, which represents the strongest predictor of liver-related and all-cause mortality, underscoring the importance of early disease recognition and risk stratification. Therapeutic strategies, therefore, increasingly target upstream metabolic drivers rather than hepatic steatosis alone. Lifestyle interventions remain foundational but are often limited by challenges in long-term adherence. Pharmacologic therapies, particularly incretin-based agents such as glucagon-like peptide-1 receptor agonists and dual incretin agonists, as well as bariatric and endoscopic metabolic procedures, have demonstrated substantial metabolic and hepatic benefits. Recognition of disease heterogeneity supports phenotype-guided approaches that integrate metabolic risk, adiposity, body composition and fibrosis assessment to personalise treatment strategies and improve long-term outcomes across the MASLD spectrum.

Primary cilia regulate GLP-1 signaling in pancreatic β cells.

Isabella Melena, Jeong Hun Jo, Shannon E Townsend +5 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are mainstay therapies for diabetes and obesity, acting in part by enhancing glucose-dependent insulin secretion. While the primary cilium is a known signaling compartment for certain G-protein coupled receptors (GPCRs), its role in the β-cell response to incretins remains undefined. Here, we show that primary cilia are essential for full GLP-1R signaling. Loss of β-cell cilia in mouse and human islets severely impaired GLP-1-potentiated insulin secretion, an effect preceded by blunted whole-cell cAMP and Ca2+ responses. Immunofluorescence and immunogold scanning electron microscopy revealed endogenous GLP-1R localized to the primary cilium. Adenylyl cyclase immunostaining was also enriched within cilia, and targeted inhibition of ciliary PKA reduced insulin secretion. Critically, disrupting ciliary GPCR trafficking via Tulp3 knockdown - while preserving cilia structure - recapitulated the signaling and secretory deficits, demonstrating a specific requirement for the ciliary receptor pool. These findings establish the primary cilium as a non-redundant signaling compartment for GLP-1R and uncover a new layer of subcellular organization in incretin action in β cells.

Disparities in GLP-1 and GIP responses to small intestinal glucose infusion in individuals with well- and poorly-controlled type 2 diabetes.

Yixuan Sun, Cong Xie, Michelle Bound +6 more

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are key regulators of glucose homeostasis in health and type 2 diabetes (T2D). Whether their secretion is influenced by antecedent glycaemic control in T2D remains unclear. This study compared GLP-1 and GIP responses to intraduodenal glucose infusion between individuals with well- and poorly-controlled T2D.

GLP-1 Receptor Agonists.

Clifford J Rosen, Julie R Ingelfinger

Glucagon-like peptide-1 (GLP-1) receptor agonists are incretin analogues that promote glucose-mediated insulin release and are used to treat type 2 diabetes mellitus and obesity. GLP-1 receptor agonists and GLP-1 and glucose-dependent insulinotropic peptide agonists have several mechanisms of action, including reduction of gastric emptying, inhibition of glucagon secretion, beneficial changes in the intestinal microbiome, and direct effects on hypothalamic nuclei to enhance satiety (which promotes weight loss). Beyond the impressive effects of GLP-1 receptor agonists on blood glucose levels and body weight, large-scale randomized, controlled trials have shown that GLP-1 receptor agonists reduce cardiovascular risk and slow progression to renal failure in persons at high risk and those with type 2 diabetes. Adverse side effects from GLP-1 receptor agonists are mostly gastrointestinal but may also include loss of muscle and bone mass. Questions remain about long-term adherence, weight regain after discontinuation of treatment, and the functional implications of the loss of muscle and bone mass. Recent and ongoing targeted studies suggest the possibility of additional uses for GLP-1 receptor agonists.

Primary cilia regulate GLP-1 signaling in pancreatic β cells.

Isabella Melena, Jeong Hun Jo, Shannon E Townsend +5 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are mainstay therapies for diabetes and obesity, acting in part by enhancing glucose-dependent insulin secretion. While the primary cilium is a known signaling compartment for certain G-protein coupled receptors (GPCRs), its role in the β-cell response to incretins remains undefined. Here, we show that primary cilia are essential for GLP-1R signaling. Loss of β-cell cilia in mouse and human islets severely impaired GLP-1-potentiated insulin secretion, an effect preceded by blunted whole-cell cAMP and Ca²⁺ responses. Immunofluorescence and immunogold scanning electron microscopy revealed endogenous GLP-1R localized to the primary cilium. Critically, disrupting ciliary GPCR trafficking via Tulp3 knockdown - while preserving cilia structure - recapitulated the signaling and secretory deficits, demonstrating a specific requirement for the ciliary receptor pool. These findings establish the primary cilium as a non-redundant signaling compartment for GLP-1R and uncover a new layer of subcellular organization in incretin action in β cells.

Fatty acid regulation of feeding in Caenorhabditis elegans reveals the potential ancestral origin of a GLP-1-like multiagonist signaling system.

Feimei Zhu, Jorge Iván Castillo-Quan, Takafumi Ogawa +11 more

Regulation of food intake in mammals is complex and controlled by an interplay between hedonic and homeostatic signals, including hormones like leptin, which senses fat storage and suppresses food intake. Caenorhabditis elegans lack leptin and leptin receptors but still exhibit controlled eating. Here, we show that in C. elegans eating can be regulated by a balance between saturated and monounsaturated fatty acids interacting with transcriptional pathways regulating lipid synthesis, c-AMP response element binding protein and AMP kinase. This effect is mediated at the endoplasmic reticulum through formation of phospholipids and activation of the IRE-1 sensor in the nervous system, which controls behavior through neuronal serotonin and the G-protein-coupled ligand/receptor pair PDF-1/PDFR-1. We show that this peptide/receptor pair may be an ancestral precursor of the whole family of GLP-1/GIP-related peptides and their receptors. Indeed, administration of a 37 amino acid peptide derived from PDF-1 resulted in a reduction in body weight and improved insulin sensitivity in mice. In worms, signaling through this pathway induced food-leaving behavior on concentrated food and roaming behavior on dispersed food, a state we have termed "food-apathy," paralleling pharmacologic effects of GLP-1/GIP-related peptides in humans. These findings highlight the potential evolutionary origin of this family of hormones and their receptors, and its link to metabolic and neuronal responses in control of feeding behavior.

Semaglutide Plus Low-Dose Metformin Combination Therapy for the Treatment of Obesity and Prediabetes in a Woman with Partial Deletion of the X Chromosome Long Arm.

Vincenzo Marzolla, Stefania Gorini, Massimiliano Caprio +1 more

Background and Clinical Significance: Over the last two decades, glucagon-like peptide-1 (GLP-1) receptor agonists have dramatically improved the management of type 2 diabetes mellitus and obesity. Currently, little is known about the use of semaglutide (a second-generation GLP-1 receptor agonist) in patients with X chromosome abnormalities. Herein, we describe the therapeutic use of semaglutide in a woman with a partial deletion of the X chromosome long arm (partial Xq deletion) and comorbid obesity. We also conducted a narrative mini-review on overweight, obesity and common metabolic derangements in patients with partial Xq deletions and Turner syndrome. Case Presentation: A 65-year-old Italian woman with a partial Xq deletion, class 1 obesity, insulin resistance, prediabetes, hypercholesterolemia and metabolic dysfunction-associated steatotic liver disease (MASLD) was referred to our Institution for persistent difficulty in managing excess body weight despite regular adherence to different structured physical activity programs and hypocaloric diets. Therefore, we prescribed a combination therapy based on low-dose metformin (500 mg/day) and once-weekly subcutaneous semaglutide (as an adjunct to lifestyle intervention). At 5 months after initiation of the combination therapy, blood tests showed metabolic improvements, including improvement of prediabetes (0.3-percentage-point reduction in glycated hemoglobin [HbA1c] values) and normalization of markers of insulin sensitivity and insulin resistance (QUICKI, HOMA-IR and TyG index). At 8 months, the patient showed substantial weight loss, which amounted to 13.8 kg (percent total body weight loss: 20.95%), and was accompanied by a notable reduction in waist circumference (-14.1 cm). Moreover, body mass index (BMI)-based weight status improved from class 1 obesity to overweight: BMI value of 25.1 kg/m2 at 8 months vs. 31.8 kg/m2 at baseline (near-normalization of BMI values). Bioelectrical impedance analysis (BIA) revealed that the patient's overall weight loss consisted of 74.6% fat mass (FM) loss (-10.3 kg) and 25.4% fat-free mass (FFM) loss (-3.5 kg). Despite the expected FFM reduction in absolute terms, percent FFM increased at 8 months (+9.6%). This increase in percent FFM was accompanied by a reduction in percent FM at 8 months (-9.6%), indicating an overall improvement in body composition. Normalization of percent FM and FFM values (28.6% and 71.4%, respectively) was also achieved at 8 months. These body composition changes are in line with those observed in clinical trials investigating the use of semaglutide in patients with overweight or obesity. At 6 months, an abdominal ultrasound also showed the disappearance of the sonographic characteristics suggestive of mild-to-moderate hepatic steatosis. Low-dose metformin (500 mg/day) and subcutaneous semaglutide (up to a weekly dose of 1.7 mg) were well tolerated by the patient. Conclusions: To the best of our knowledge, this is the first case documenting the effective use of once-weekly subcutaneous semaglutide plus low-dose metformin combination therapy for the treatment of obesity and prediabetes in a woman with a partial Xq deletion. Large prospective cohort studies are warranted to better investigate the safety and efficacy profile of semaglutide (alone or in combination with metformin) in patients with numerical and structural X chromosome abnormalities, comorbid overweight/obesity and related metabolic disorders.

Glucagon-like peptide-1 agonists' effects on glycemic control, weight loss, and beta cells function in type 1 diabetes.

Hyder O Mirghani, Laila Albishi, Sawsan Mohmed Alblewi

Insulin is an effective treatment for type 1 diabetes mellitus (T1DM), and a significant proportion of patients are not controlled, develop hypoglycemia, and gain weight. Therefore, adjuvant therapies to mitigate the above are highly needed. Meta-analyses on the effect of glucagon peptide agonists (GLP-1 agonists) on weight loss and HbA1c are scarce. We aimed to assess the effects of GLP-1 agonists on HbA1c, weight, and C-peptide in patients with T1DM with obesity/overweight and normal weight.

Brainstem GLP-1 neurons modulate physiological satiation and drive sustained weight loss in obese mice.

Wanqing Jiang, Cecilia Skoug, Ian Rodrigues +6 more

Glucagon-like peptide-1 receptor (GLP-1R) activation in the brain strongly reduces appetite, but most brain GLP-1Rs are not accessible for systemically administered GLP-1R agonists. Acute activation of nucleus tractus solitarius (NTS) GLP-1 neurons, known as preproglucagon (PPG) neurons, strongly suppresses food intake separate from GLP-1R agonists. However, it is unknown if chronic stimulation of PPG neurons is a viable strategy for appetite suppression, or if obesity disrupts their function. Here we demonstrate that PPG neurons in the NTS and intermediate reticular nucleus (IRT) determine meal size, and that their total number is inversely correlated with bodyweight gain. We report that PPGNTS and PPGIRT neurons receive distinct monosynaptic inputs, but have convergent efferent projection targets throughout the brain, and that combined ablation of both populations delays the onset of physiological satiation to a degree sufficient to promote weight gain under ad libitum chow fed conditions. Crucially, chronic daily chemogenetic activation of PPGNTS+IRT neurons drives robust and sustained hypophagia and weight loss in obese mice without notable adverse effects, demonstrating their value as targets for obesity pharmacotherapy.

Acute interleukin-1β antagonism decreases systemic inflammation, increases GLP-1 release, and modulates insulin secretion in individuals with prediabetes.

Justus S Fischer, Matthias Hepprich, Marco Cattaneo +3 more

Metabolic stress in obesity and diabetes activates innate immunity. Chronic IL-1β antagonism improves insulin secretion in type 2 diabetes. However, it is unclear how rapidly this effect occurs, whether it is also present in individuals with prediabetes, and if IL-1β influences GLP-1 secretion. Therefore, we acutely antagonized IL-1β in patients with prediabetes overnight. Two injections of anakinra significantly reduced total leucocyte count (P < 0.001), neutrophils (P < 0.001), monocytes (P = 0.006), and CRP (P = 0.030) compared with placebo. Lymphocytes were slightly elevated (P = 0.045). A mixed meal tolerance tests showed a trend toward increased early insulin (P = 0.11) and GLP-1 responses (P = 0.055), with GLP-1 (P = 0.020) and glucagon (P = 0.003) levels being significantly higher at 120 min under anakinra. Cytokine analysis showed elevated baseline concentrations of IL-1β, IL-6, and IL-1Ra under anakinra (all P < 0.001), with IL-1β (P < 0.001) and IL-18BP (P = 0.048) decreased, and IL-6 increased (P = 0.059) after 60 min. Therefore, an acute injection of anakinra significantly reduces CRP and leucocyte counts in individuals with prediabetes, indicating effective innate immune modulation even after immediate treatment. Despite seeing no significant improvements in insulin secretion or glucose metabolism, we observed a trend toward earlier insulin secretion, along with increased release of IL-6 and GLP-1. We conclude that acute IL-1 antagonism dampens systemic inflammation in prediabetes, with the potential to improve insulin secretion via IL-6-induced GLP-1.NEW & NOTEWORTHY Acute IL-1 blockade with anakinra markedly reduced CRP and leukocyte counts within 12 h, demonstrating rapid anti-inflammatory efficacy. Anakinra induced a trend toward earlier insulin secretion and significantly increased postprandial IL-6 and GLP-1 levels. The study demonstrates that even short-term IL-1 blockade can modulate both immune and incretin responses in prediabetes. Early IL-1β antagonism may represent a preventive, anti-inflammatory approach to preserve GLP-1 secretion and β-cell function in individuals with prediabetes.

Type 2 Diabetes in Pregnancy: Management and Novel Therapies.

Gianna Wilkie

Type 2 diabetes mellitus (T2DM) is estimated to affect 2% of all pregnancies, and it is associated with numerous adverse perinatal outcomes. Glycemic monitoring and strict glycemic control are required to improve overall outcomes. Insulin is the mainstay of treatment, with limited data regarding newer medications like glucagon-like peptide 1 receptors agonists (GLP-1 RAs), dual incretin agonists like tirzepatide, sodium-glucose cotransporter-2 inhibitors (SGLT2i), and dipeptidyl peptidase-4 inhibitors (DPP-4i). This chapter will provide a review of the current available literature regarding T2DM management in pregnancy.

Pharmacological and metabolic effects of Bifidobacterium triple viable capsules and Five-animal Play in patients with impaired glucose tolerance.

Yu Yang, Xiangyong Gan, Qilin Xiao +9 more

Impaired glucose tolerance (IGT) is a reversible pre-diabetic condition characterized by early disruptions in insulin resistance and glucose control. Wingless-type MMTV integration site family member 5a/ secreted frizzled-related protein 5 (Wnt5a/Sfrp5) signaling and GLP-1 modulation have been identified as possible treatment approaches.

ARD-101, a gut-restricted TAS2R agonist, reduces hunger in adults and promotes weight loss in DIO mice with DPP-4 inhibition.

Zhenhuan Zheng, Jeremy H Pettus, Alexa Warner +8 more

Obesity management has limited oral pharmacotherapies. Bitter taste receptor (TAS2R) agonists may modulate hunger, satiety, and metabolism via gut-brain signaling. We evaluated denatonium acetate (DA), a gut-restricted TAS2R agonist, across preclinical and clinical settings, and explored its combination with sitagliptin (a dipeptidyl peptidase-4 [DPP-4] inhibitor).

Amycretin in obesity: Mechanisms, clinical efficacy, and future perspectives.

Linghua Fu, Rui Ding, Gaosi Xu +2 more

The global escalation of obesity necessitates therapeutic interventions that transcend the efficacy ceilings of current mono-target pharmacotherapies. Amycretin, a novel unimolecular co-agonist targeting glucagon-like peptide-1 (GLP-1) and amylin receptors, has emerged as a promising candidate for weight management. In this review, we examine the developmental rationale of amycretin, elucidating how its dual-agonist mechanism synergistically engages hindbrain-mediated satiety pathways and delays gastric emptying to overcome metabolic plateaus. We summarize pivotal findings from recent clinical trials, highlighting that amycretin elicits profound weight reduction-demonstrating up to 13.1% loss with oral administration (12 weeks) and 24.3% with subcutaneous delivery (36 weeks)-with a safety profile consistent with incretin-based classes. Furthermore, we explore the strategic potential of combining amycretin with insulin-independent agents, such as SGLT2 inhibitors, to optimize cardio-renal outcomes. These insights provide a theoretical framework for positioning amycretin in the future management of adiposity-based chronic diseases.

Intestinal neuroendocrine cells (STC-1 cells) exposed to skim milk powder with a high content of Maillard reactants show an attenuated secretion of incretins.

Mona Landin-Olsson, Birgitte Ekholm, Charlotte Erlanson-Albertsson +1 more

Incretins such as glucagon-like-peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play crucial roles in postprandial glucose management. GLP-1 and GIP stimulate insulin release in conjunction with meals and are responsible for up to 75% of the insulin secretion. Incretins are therefore very important for maintenance of normal blood glucose levels. Dairy foods are crucial for adequate nutrition at a young age, and skim milk powder in infant formula is frequently used. However, stored skim milk powder has been found to reduce the islet cell mass of the pancreas in experimental studies. The aim of this study was to investigate the potential effect of stored skim milk powder on incretin release from intestinal cells. Intestinal endocrine cells (STC-1 cells) were incubated with fresh and stored skim milk powder, the latter containing 70-fold higher amounts of Maillard reactants. The cells' viability, proliferation, and release of incretins were measured after 24 h. Both the viability and proliferation of the STC-1 cells decreased significantly during incubation with stored skim milk powder. The release of GLP-1 and GIP was suppressed in a dose-dependent manner by stored skim milk powder compared with fresh milk powder. The clinical significance for the development of diabetes and obesity, due to this observed weak release of incretins induced by stored skim milk powder containing high amount of Maillard reactants, requires further studies.

Renal Outcomes of GLP-1 Receptor Agonists and Tirzepatide Across CKD Stages and Metabolic Phenotypes (Type 2 Diabetes and/or Overweight/Obesity): A Scoping Review.

Jorge Rico-Fontalvo, Rodrigo Daza-Arnedo, Alicia Elbert +6 more

Diabetes mellitus is the leading global cause of chronic kidney disease (CKD) and end-stage renal disease. Although cardiovascular outcomes have improved substantially, renal risk remains high. Glucagon-like peptide 1 (GLP-1) receptor agonists and the dual GLP-1/GIP agonist tirzepatide have demonstrated potential cardiorenal benefits, but renal evidence has not been systematically mapped across CKD stages and metabolic phenotypes. This scoping review aimed to identify and describe clinical evidence on renal outcomes associated with GLP-1-based therapies in adults with type 2 diabetes and/or overweight/obesity, with or without CKD.

Temporal variation in incretin and insulin secretion in ponies in association with dietary macronutrients.

K E Andrews, P E M Sibthorpe, D M Fitzgerald +1 more

Equine insulin dysregulation (ID) is a common condition that predisposes to hyperinsulinaemia-associated laminitis. Improved pathophysiological understanding would enable better management of ID and reduce the risk of laminitis. The incretin peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), augment the insulin response to dietary glucose and GLP-1 has been implicated in the pathophysiology of ID. However, their temporal variation in response to a low-energy diet has not been reported. This study determined the variation in GLP-1, GIP and insulin in eight healthy ponies, in relation to both the fed and unfed state, over a 24 h period. The ponies were fed a high-fibre ration plus two types of forage. Blood samples were analysed for blood glucose, total protein, serum triglycerides, which were used as proxy measures for the dietary macronutrients, as well as GLP-1, GIP and insulin concentrations. All analytes varied throughout the study (P < 0.05) with the principal pattern being a peak after eating compared to the fasted state. Blood glucose, GLP-1 and insulin were strongly positively (ρ close to 1) and synchronously (ρ peaked at time shift (τ) 0) correlated over time. Plasma GIP concentration also peaked in the unfed state (P = 0.01) and was potentially positively correlated (r = 0.39; P = 0.08) with triglyceride concentration. This relationship was confirmed in a larger cohort of 30 ponies using archived samples (P = 0.03). These data indicate that GIP likely has a physiological role in lipid clearance and/or fat metabolism in ponies, as shown in other species. As obesity is an important component of equine metabolic syndrome, further studies on the role of GIP in metabolic dysfunction are warranted.

Heterogeneous effect of saxagliptin on glucose fluctuation and β-cell function in T1DM: a multicentre, randomised trial.

Yun Shi, Min Shen, Yong Gu +18 more

We aimed to explore whether saxagliptin, a dipeptidyl peptidase-IV inhibitor, could ameliorate glucose fluctuations and maintain β-cell function in T1DM.

The Benefits and Risks of Glucagon-Like Peptide-1 Receptor Agonists on Ocular Diseases: A Narrative Review.

Jacky Xiao Feng Huang, Joshua Wu, Hunain Ahmad +5 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin-based agents used in the management of type 2 diabetes mellitus (T2DM) and obesity. This class of medications mimics the action of the endogenous GLP-1 hormone, enhances insulin secretion, delays gastric emptying, causes early satiety, lowers systemic glycemic levels, and results in weight loss. There are emerging concerns about the use of GLP-1RAs, which may be an observational association with ocular pathologies, including retinal vascular occlusion (RVO), vitreous hemorrhage (VH), diabetic retinopathy (DR), non-arteritic ischemic optic neuropathy (NAION), and diabetic macular edema (DME). In contrast, there are beneficial impacts of GLP-1RAs on various conditions, including glaucoma and idiopathic intracranial hypertension. This narrative review aims to analyze current findings on the beneficial and adverse ocular effects of GLP-1RAs use, highlighting studies that elucidate the harmful causes, such as retinal microvascular dysregulation, inflammatory modulation, oxidative stress, osmotic dysregulation from sorbitol accumulation, and metabolic shifts. The literature search was conducted using PubMed, Elsevier, Embase, Google Scholar, Scopus, and Science Direct to retrieve relevant literature published in peer-reviewed journals from 2014 to 2025. Understanding the benefits and risks of GLP-1RAs in ophthalmology is crucial for clinicians to manage ocular conditions safely while a patient is using GLP-1RAs, and enables personalized ophthalmological screenings to minimize the risk of disease exacerbation.

Incretin and Glucagon Signalling in MASLD and MASH: Integrating Metabolic Pathways With Disease Progression.

Evangelia E Tsakiridis, Gregory R Steinberg

Metabolic dysfunction-associated steatotic liver disease (MASLD) arises from dysregulated interactions between nutrient delivery, adipose tissue lipid handling and liver lipid metabolism, which collectively coalesce to drive inflammatory signalling leading to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. Recent clinical success of incretin- and glucagon-based therapies in both diabetes and obesity has intensified interest into how these hormonal pathways modify liver disease progression. In this review, we integrate preclinical and clinical data to examine how glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon engage key pathogenic nodes, including the gut-liver and adipose-liver axes, hepatic lipid synthesis and oxidation, mitochondrial function and nonparenchymal inflammatory responses. GLP-1-based therapies consistently improve steatosis and steatohepatitis through reductions in nutrient flux to the liver, improved adipose tissue insulin sensitivity and weight-independent anti-inflammatory effects, despite limited direct action in hepatocytes. GIP signalling appears to modulate adipose tissue lipid handling and expandability, thereby limiting fatty acid spillover to the liver, although its role in hepatic inflammation remains incompletely defined. In contrast, glucagon receptor activation directly targets hepatocytes to enhance oxidative metabolism and reduce hepatocellular stress. Across studies, improvements in fibrosis appear secondary to sustained reductions in metabolic and inflammatory injury suggesting the addition of anti-fibrotic combination therapies may exert further benefits. Looking ahead, a key challenge will be defining how these hormonal pathways interact within distinct metabolic states and how this greater mechanistic understanding can be leveraged to rationally combine therapies and expand the proportion of patients who respond across the MASLD spectrum.

The Use of Glucagon-Like Peptide 1 Agonists Among Non-Diabetics: Evidence From Medicare Part D.

Minji Kim, Kieran Allsop, Joseph F Levy

To assess the extent of off-label glucagon-like peptide-1 receptor agonist (GLP-1) prescribing among individuals without diabetes in Medicare Part D.

Comparative Analysis of Efficacy and Safety of the Glucagon-Like-Peptide-1 Receptor Agonists Tirzepatide and Semaglutide in Solid-Organ Transplant Recipients.

Omar El Khatib, Maguy Chiha, Ola Jarad +5 more

Diabetes mellitus, including new-onset diabetes after transplant, is a prevalent complication in solid-organ transplant recipients, often necessitating complex glycemic management. Glucagon-like peptide-1 receptor agonists, including semaglutide and tirzepatide, have shown promising outcomes in the general population, but comparative data in solid-organ transplant recipients are limited. In this study, we evaluated and compared the efficacy and safety of semaglutide and tirzepatide in a diverse cohort of solid-organ transplant recipients.

Processing-induced structural remodeling enhances the hypoglycemic activity of Polygonatum cyrtonema Hua polysaccharides via gut microbiota-SCFA-GPR41/43 pathway.

Chuyao Deng, Jiaxin Zheng, Fei Xu +9 more

Type 2 diabetes mellitus (T2DM) poses a major health and socioeconomic challenge, and long-term use of conventional hypoglycemic agents often causes adverse effects such as impaired gastrointestinal function. Natural polysaccharides have emerged as promising alternatives due to their safety and bioactivity. In this study, polysaccharides from raw Polygonatum cyrtonema Hua (RPCP) and processed Polygonatum cyrtonema Hua (PPCP) were successfully extracted using enzyme-assisted hot water extraction. The purified fractions of RPCP (RPCP-P) and PPCP (PPCP-P) were structurally characterized by molecular weight determination, monosaccharide composition, FT-IR, methylation, and NMR analyses. Their hypoglycemic effects and underlying mechanisms were evaluated in high-fat diet and streptozotocin-induced T2DM mice. Both RPCP and PPCP significantly reduced fasting blood glucose, improved insulin sensitivity, and ameliorated lipid metabolism disorders. Mechanistically, the polysaccharides modulated gut microbiota composition, promoted short-chain fatty acid (SCFA) production, upregulated colonic GPR41/43 expression, and increased glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) secretion, thereby improving glucose homeostasis. Notably, PPCP exhibited superior antidiabetic effects to those of RPCP, which we attribute to its greater molecular heterogeneity and galactan-rich structure, suggesting that traditional steaming enhances polysaccharide bioactivity. These findings demonstrate that traditional processing enhances the functionality of Polygonatum cyrtonema polysaccharides through structure-dependent modulation of the gut microbiota-SCFA-host metabolic axis, providing a scientific basis for their development as functional food ingredients for glycemic regulation.

Med14 phosphorylation shapes genomic response to GLP-1 agonists.

Sam Van de Velde, Jungting Yu, K Garrett Evensen +4 more

Binding of GLP-1 to its receptor in pancreatic beta cells triggers activation of the cAMP pathway and phosphorylation of CREB, leading to induction of cellular target genes containing CREB binding sites. By contrast with their acute effects on beta cell gene expression, chronic exposure of beta cells to stable GLP-1 analogs like Exendin-4 stimulates sustained expression of beta cell-specific genes, leading to increases in beta cell viability and insulin secretion. In a proteomic screen for transcriptional coregulators that contribute to the transcriptional effects of GLP-1, we identified Med14, the scaffolding subunit of the conserved 30 subunit Mediator complex. Exposure to Exendin-4 and other GLP-1 receptor agonists stimulates sustained phosphorylation of Med14 at Ser983, which corresponds to a conserved PKA recognition site. Mutation of Med14 at Ser983 blocked Exendin-4 effects on cellular gene expression by interfering with CREB-mediated activation of beta cell-specific enhancers. Med14 mutation results in higher alpha-to-beta cell ratios and blunted gene regulation in response to Exendin-4 in Ser983-mutant primary mouse islets. Our work reveals how phosphorylation of a general transcription factor in response to GLP-1 analogs triggers a broad genomic response with salutary effects on beta cell function.

Nutritional Interventions in Type 1 Diabetes: Boosting Residual GLP-1 Responses-Is It an Option?

Maria Grammatiki, Xanthippi Tsekmekidou, Theocharis Koufakis +1 more

Type 1 diabetes (T1D) is characterized by autoimmune beta-cell destruction and lifelong insulin dependence, yet early-stage disease (Stages 1-2) retains residual beta-cell function that may still respond to incretin signaling. Incretin hormones-mainly glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)-enhance postprandial insulin secretion and suppress glucagon, and GLP-1 also exhibits beta-cell protective effects in preclinical models. Although the incretin effect is markedly reduced in established T1D, intestinal GLP-1 secretion is largely preserved, creating a mechanistic rationale for strategies that increase endogenous GLP-1 during the "residual function" window. This narrative review summarizes dietary and lifestyle interventions that may enhance endogenous GLP-1 responses and discusses their potential role as adjuncts to insulin therapy, particularly when combined with emerging beta-cell-preserving immunomodulatory approaches that may prolong early disease stages. Mechanistically, high-fiber diets may increase GLP-1 via microbiota-derived short-chain fatty acids acting on L-cell receptors; low-glycemic index carbohydrates may favor distal nutrient delivery and a GLP-1-dominant incretin profile; and Mediterranean dietary patterns may promote GLP-1 secretion through unsaturated fatty acids, fiber, and polyphenols, including potential DPP-4-modulating effects. This narrative review examines nutrition and lifestyle interventions modulating residual incretins to elongate early T1D stages and enhance glycemic control as insulin adjuncts, per Nutrients' Special Issue. Available evidence is strongest in non-T1D populations, with limited T1D-specific trials, highlighting the need for stage-targeted studies incorporating GLP-1 dynamics, C-peptide, glycemic variability, and microbiome outcomes.

GLP-1 Release by Rare Sugar D-Allulose Ameliorates Sucrose-Induced Obesity and Glucose Intolerance in Ovariectomized Mice.

Kengo Iba, Miharu Kyo, Hirotaka Ishihara +5 more

Estrogen deficiency after menopause promotes visceral fat accumulation and insulin resistance, thereby increasing the risk of type 2 diabetes. Although hormone replacement therapy is partially effective, its use is limited by increased risks of cardiovascular disease and breast cancer, underscoring the need for safer preventive strategies. The rare sugar D-allulose has been reported to stimulate secretion of glucagon-like peptide-1 (GLP-1), a gut hormone, and improve obesity and glucose metabolism, suggesting its potential as a novel intervention for postmenopausal metabolic dysfunction. Here, we examined whether D-allulose improves obesity and glucose intolerance in a GLP-1-dependent manner under sucrose-fed conditions, using ovariectomized (OVX) female C57BL/6J mice as a model of menopause. OVX mice, but not sucrose-fed sham mice, developed exacerbated visceral obesity and glucose intolerance in response to dietary sucrose, despite similar total energy intake. Daily oral administration of D-allulose for two weeks significantly suppressed visceral fat accumulation, improved insulin resistance, and ameliorated glucose intolerance in sucrose-fed OVX mice. These beneficial effects were markedly attenuated in GLP-1 receptor knockout mice. Taken together, we found that sucrose intake after ovariectomy exacerbates visceral obesity and glucose intolerance, and that D-allulose effectively ameliorates these metabolic abnormalities. GLP-1-stimulating dietary components such as D-allulose may represent a safe and promising preventive strategy for metabolic dysfunction associated with menopause.

The GLP-1-miRNA network: Epigenetic control of obesity and metabolic disorders.

Shihua Zhao, Ping Qin, Xin Wang +1 more

Glucagon-like peptide-1 (GLP-1) is a central incretin hormone with pleiotropic effects on glucose homeostasis, appetite regulation, and energy metabolism. Beyond its classical insulinotropic actions, GLP-1 enhances cardiovascular, renal, hepatic, and central nervous system (CNS) functions, thereby integrating multi-organ metabolic responses. Emerging evidence highlights the critical role of microRNAs (miRNAs) as epigenetic regulators of GLP-1 signalling, influencing receptor expression, β-cell survival, hypothalamic appetite circuits, and peripheral tissue metabolism. miRNAs act bidirectionally: they can attenuate GLP-1 receptor (GLP-1R) expression, contributing to 'incretin resistance' in obesity and type 2 diabetes (T2DM), or mediate GLP-1-induced transcriptional adaptations that enhance insulin secretion, lipid oxidation, and energy expenditure. This review synthesizes current knowledge of GLP-1 physiology, receptor signalling, and the miRNA-mediated regulatory network, with a focus on mechanisms underlying obesity and metabolic disorders. This review proposes an integrated GLP-1-miRNA framework that bridges molecular endocrinology with precision metabolic medicine.