GLP-1

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.