It has been proved that glucagon-like peptide-1 receptor (GLP1R) agonists have positive effects on renal outcomes in diabetic patients. However, it remains unknown whether GLP1R agonists could provide similar protection against other kidney diseases.

We performed two-sample Mendelian randomization (MR) analyses to determine the causal effects of GLP1R agonists on multiple kidney diseases. Exposure to GLP1R agonist was proxied by the available cis-eQTLs for GLP1R. Primary outcomes included the risk assessment for diabetic nephropathy, IgA nephropathy, membranous nephropathy, nephrotic syndrome, chronic kidney disease, acute glomerulonephritis, chronic glomerulonephritis and calculus of kidney/ureter. Type 2 diabetes and body mass index were used as positive control. Two-stage network MR analyses were conducted to assess the mediation effect of inflammatory proteins on the relationships between GLP1R agonists and kidney diseases.

After meta-analyses of both discovery and validation cohorts, genetically proxied GLP1R agonist was found to significantly associated with a decreased risk of diabetic nephropathy (OR = 0.72, 95%CI = 0.54-0.97, p = 0.031) and IgA nephropathy (OR = 0.58, 95%CI = 0.36-0.94, p = 0.027). Two-stage network MR revealed that there was an indirect effect of GLP1R agonist on IgA nephropathy through signaling lymphocytic activation molecule family member 1 (SLAMF1), with a mediated proportion of 34.27% (95% CI, 1.47-67.03%, p = 0.041) of the total effect.

The findings of current study presented genetic proof for the potential protective effects of GLP1R agonists in the development of diabetic nephropathy and IgA nephropathy, offering a novel sight for future mechanistic and clinical applications.

This study aims to compare adverse drug reaction patterns of liraglutide, semaglutide and tirzepatide-glucagon-like peptide-1 receptor agonists (GLP-1 RAs) approved for anti-obesity medications-to evaluate their real-world safety.

This disproportionality analysis utilized a case-control design with VigiBase. The study focused on reports of adverse events associated with liraglutide, semaglutide and tirzepatide, selected based on warnings in the US Food and Drug Administration approval labels for each drug. Data were restructured using unique identifiers to differentiate individuals affected by adverse drug reactions. Multivariable logistic regression models estimated adjusted reporting odds ratios (aRORs) with 95% confidence intervals (CIs) to assess the association between various adverse events and GLP-1 RAs, adjusting for age, sex, region, reporter qualification, reporting year and concomitant medication. The information component (IC) was analysed, and signals of adverse drug reactions were considered significant only when both aROR and IC were statistically significant.

Our analysis of targeted adverse drug reactions included 24 725 individuals using liraglutide, 21 454 using semaglutide and 11 538 using tirzepatide. Tirzepatide had fewer reports of adverse drug reactions compared with the other two drugs, and its pharmacovigilance association strength was the lowest. Semaglutide, however, was significantly associated with several unusual adverse events, including suicidal ideation and behaviour (IC, 1.53 [IC025, 1.28]; aROR, 2.52 [95% CI, 2.18-2.93]), hair loss (IC, 0.78 [IC025, 0.63]; aROR, 1.42 [95% CI, 1.30-1.55]) and vision loss (IC, 1.27 [IC025, 1.13]; aROR, 1.80 [95% CI, 1.66-1.97]).

Our findings emphasize the need for cautious prescribing and further research to ensure the safe use of these medications.

In late-stage type 2 diabetes mellitus (T2DM), impaired islet β cell function leads to absolute insulin deficiency, thereby disrupting blood glucose homeostasis. GLP-1, an incretin hormone, stimulates insulin secretion from islet β cells post-meals. This study investigated the effects of anthocyanin cyanidin-3-O-glucoside (C3G) on GLP-1 secretion using STC-1 (intestinal endocrine L cells) and NIT-1 (islet β cells). In a co-culture system, C3G treatment increased GLP-1 secretion in STC-1 cells, promoting insulin release in NIT-1 cells under high glucose. Mechanistically, C3G activated the PPARβ/δ-β-catenin-TCF-4 pathway in STC-1 cells, enhancing PG precursor transcription and GLP-1 synthesis.Inhibiting PPARβ/δ with GSK0660 blocked this C3G-induced upregulation. Overall, C3G stimulates GLP-1 secretion from intestinal L cells via this pathway, indirectly boosting insulin release from β cells. These findings enhance T2DM mechanism understanding and suggest the potential of C3G in GLP-1-based T2DM therapy.

Cells respond to the physical and geometrical tissue properties by multiple mechanotransduction mechanisms that can profoundly influence cells' decision-making, extending to cell metabolism. This review incorporates the most recent findings on this topic, organized along the idea that the mechano-metabolic connection serves three main functions, namely to inform systemic metabolism on the general functioning of a tissue/organ, to tune cells' energy production with the mechanical requirements imposed by their surroundings, and to coordinate cell metabolism with cell fate choices induced in response to mechanical cues. This connection highlights the pervasive influence of mechanical cues on cell activity, opens interesting questions on its physiological and pathological roles, and lays the foundations for exploiting the mechano-metabolism axis to design new therapeutic approaches.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have recently received Food and Drug Administration (FDA) approval for obesity management. However, the causal relationship between GLP-1RAs and psychiatric and neurodevelopmental conditions remains unclear.

We used Mendelian randomization (MR) to investigate the association between genetically proxied GLP-1RA exposure and 12 psychiatric and neurodevelopmental conditions. Genetic instruments were derived from cis-eQTLs for GLP-1R, and analyses were conducted using large-scale GWAS datasets. Type 2 diabetes was included as a positive control (107,133 cases, 656,672 controls). Findings were assessed across multiple independent datasets, including FinnGen, Psychiatric Genomics Consortium (PGC), and UK Biobank, and were synthesized through meta-analysis.

Genetically proxied GLP-1RA exposure was associated with a lower risk of schizophrenia (OR = 0.72, 95% CI [0.61-0.86]), bipolar disorder (OR = 0.91, 95% CI [0.88-0.94]), bulimia nervosa (OR = 0.34, 95% CI [0.23-0.52]), post-traumatic stress disorder (PTSD) (OR = 0.45, 95% CI [0.31-0.67]), and autism (OR = 0.55, 95% CI [0.32-0.93]), all P < 0.001. Conversely, higher GLP-1R expression was associated with an increased risk of obsessive-compulsive disorder (OCD) (OR = 2.30, 95% CI [1.26-4.22], P < 0.001). No significant associations were observed for anorexia nervosa, broad depression, major depressive disorder (MDD), or suicide and intentional self-harm. Sensitivity analyses and heterogeneity assessments supported the robustness of these findings across multiple cohorts.

GLP-1RAs reduced some psychiatric and neurodevelopmental conditions but lacked extensive evidence. Bulimia nervosa and PTSD evidence was limited to one database. Bipolar disorder and OCD results varied, with significant OCD findings in one database. The study's European ancestry focus limits generalizability. Rare disorders and disease progression were not examined. Future research needs diverse populations, long-term follow-ups, and treatment exploration.

Our study suggests that GLP-1RAs may decrease the risk of schizophrenia, anxiety disorders, bipolar disorder, bulimia nervosa, PTSD, and autism, but may increase the risk of OCD. Larger randomized controlled trials with long-term follow-up are necessary to confirm these associations and evaluate the risk-benefit ratios.

Not applicable.

Glucagon-like peptide-1 (GLP-1) receptor agonists (GRA) belong to a class of compounds that reduce blood glucose and energy intake by simulating actions of endogenous incretin hormone GLP-1 after it is released by the gut following food consumption. They are used to treat type 2 diabetes mellitus (T2DM) and obesity and have systemic effects on various organs, including the brain, liver, pancreas, heart, and the gut. Patients with T2DM have a higher risk of developing neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), accompanied by more severe motor deficits and faster disease progression, suggesting dysregulation of insulin signaling in these diseases. Experimental studies have shown that GRA have protective effects to modulate neuroinflammation, oxidative stress, mitochondrial and autophagic functions, and protein misfolding. Hence the compounds have generated enormous interest as novel therapeutic agents against NDs. To date, clinical trials have shown that three GRA, exenatide, liraglutide and lixisenatide can improve motor deficits as an add-on therapy in PD patients and liraglutide can improve cognitive function in AD patients. The neuroprotective effects of these and other GRA, such as PT320 (a sustained-released exenatide) and semaglutide, are still under investigation. The dual GLP-1/gastric inhibitory polypeptide (GIP) receptor agonists have been demonstrated to have beneficial effects in AD and PD mice models. Overall, GRA are highly promising novel drugs, but future clinical studies should identify which subsets of patients should be targeted as potential candidates for their symptomatic and/or neuroprotective benefits, investigate whether combinations with other classes of drugs can further augment their efficacy, and evaluate their long-term disease-modifying and adverse effects.

GLP-1 receptor agonists are valuable therapeutic agents for managing obesity and type 2 diabetes. The link between prostate cancer and obesity was described. The modulation of incretin hormone-dependent pathways may decrease the prostate cancer aggressiveness and progression.

The purpose of this study was to review and summarize the literature on the role of GLP-1 agonists in prostate cancer.

We performed a scoping literature review of PubMed from January 2002 to February 2025. Search terms included "glucagon-peptide like 1", "incretin hormone", "GLP-1 receptor agonist", and "prostate cancer". Secondary search involved reference lists of eligible articles. The key criterion was to identify studies that included GLP-1 receptor, incretin hormones, GLP-1 receptor agonists, and their role in prostate cancer development.

77 publications were selected for inclusion in this review. The studies contained in publications allowed us to summarize the data on the role of GLP-1 receptor and it's agonists in prostate cancer biology and development. The following review aims to discuss and provide information about the role of incretin hormones in prostate cancer pathogenesis and its clinical implication in patients with prostate cancer.

Incretin hormone-dependent pathways play an important role in prostate cancer pathogenesis. Moreover, GLP-1 receptor agonists seems to be a promising therapeutical agents when it comes to finding new therapies in patients with more aggressive and/or advanced stages of prostate cancer.

A chronic inflammatory condition of the colon called ulcerative colitis (UC) is characterized by mucosal surface irritation that extends from the rectum to the near proximal colon portions. The rationale of this work was to conclude if dulaglutide (Dula) could protect rats from developing colitis caused by exposure to acetic acid (AA). Rats were randomly divided into seven groups (each with eight rats): Normal control, Dula control, AA (received 2 milliliters of 3% v/v AA through the rectum), Sulfasalazine (SLZ); given SLZ (100 mg/kg) orally from day 11 to day 21 then AA intrarectally on day 22 and Dula groups ( pretreated with 50, 100 or 150 μg/kg subcutaneous injection of Dula - once weekly for three weeks and AA on day 22 to induce ulcerative colitis, colon tissues and blood samples were taken on day 23. By generating colonic histological deviations such as inflammatory processes, goblet cell death, glandular hyperplasia, and mucosa ulcers, Dula dropped AA-induced colitis. Additionally, these modifications diminished blood lactate dehydrogenase (LDH), C-reactive protein (CRP), colon weight, and the weight/length ratio of the colon. In addition, Dula decreased the oxidative stress biomarker malondialdehyde (MDA) and increased the antioxidant enzymes (total antioxidant capacity (TAC), reduced glutathione (GSH), and superoxide dismutase (SOD) concentrations). Dula also significantly reduced the expression of transforming growth factor-1 (TGF-β1), phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT) signaling pathway, and the inflammatory cytokines: nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), and interferon-γ (IFN-γ) in colonic cellular structures. In addition, Dula enforced the levels of glucagon-like peptide-1 (GLP-1) and trefoil factor-3 (TFF-3) that were crucial to intestinal mucosa regeneration and healing of wounds. By modulating TGF-β1 in conjunction with other inflammatory pathways like PI3K/AKT and NF-κB, regulating the oxidant/antioxidant balance, and improving the integrity of the intestinal barrier, Dula prevented AA-induced colitis in rats.

Semaglutide, a glucagon-like peptide-1 receptor agonist, has emerged as a pivotal therapeutic agent in the management of the cardio-renal-metabolic continuum. Initially developed for glycaemic control in Type 2 diabetes mellitus, its benefits extend far beyond glucose regulation. Clinical trials have demonstrated semaglutide's potential to reduce major adverse cardiovascular events, particularly in overweight/obese patients with high cardiovascular risk, as well as improving functional capacity in patients suffering from heart failure with preserved left ventricular function. Additionally, it has shown promise in improving renal outcomes, such as slowing the progression of albuminuria and reducing the risk of chronic kidney disease in diabetic populations. These effects are likely due to its multifaceted mechanisms, including anti-inflammatory properties, weight reduction, blood pressure lowering, and direct renal protection. This review synthesizes current evidence on semaglutide's role in the interrelated domains of cardiovascular, renal, and metabolic health.

A novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonist, tirzepatide (LY3298176, TZP), has been developed to treat Type 2 diabetes mellitus (T2DM). In ischaemic heart diseases, TZP is involved in cardiac metabolic processes. However, its efficacy and safety in treating heart failure (HF) following myocardial infarction (MI) remain uncertain.

Herein, 12 week C57BL/6J mice were subjected to MI surgery, followed by administration of TZP. The effects of TZP on cardiac function and metabolism were thoroughly assessed by physiological, histological, and cellular analyses. Downstream effectors of TZP were screened through untargeted metabolomics analysis and molecular docking. Construct a lower branched chain amino acid (BCAA) diet model to determine whether TZP's cardioprotective effect is associated with reducing BCAA levels. Our results demonstrated that TZP reduced mortality following MI, decreased the infarct area, and attenuated cardiomyocyte necrosis. Pathological evaluation of cardiac tissues demonstrated increased fibrosis repair and decreased inflammatory infiltration. Mechanistically, untargeted metabolomics analysis uncovered a positive correlation between TZP and the BCAA catabolism pathway. The molecular docking verified that TZP could bind with branched-chain keto acid dehydrogenase E1 subunit α (BCKDHA). TZP reduced BCKDHA phosphorylation at S293, enhanced BCAA catabolism, and inhibited the activation of metabolism by activating rapamycin (mTOR) signalling pathway. Furthermore, mice fed a low-BCAA diet post-MI demonstrated reduced cardiomyocyte necrosis, increased fibrosis repair, and decreased inflammatory infiltration. These cardioprotective effects were further enhanced when used synergistically with TZP.

Taken together, our findings provide new perspectives on the unrecognized role of TZP in cardiac protection. TZP enhanced BCAA catabolism and attenuated BCAA/mTOR signalling pathway in MI mice. Consequently, this study may present novel therapeutic options for patients with HF.

The development of chemical methods enabling site-selective incorporation of noncanonical amino acids into peptide backbones with precise functional tailoring remains a critical challenge. Particularly compelling is the use of underexplored endogenous amino acid hotspots, such as the N (in) of tryptophan, as versatile anchors for diversification. Herein, we report a chemoselective N(sp2)-H bond activation strategy targeting native tryptophan residues within peptide frameworks, exemplified by GLP-1 (7-37), using nickel metallaphotocatalysis under postsynthetic solid-phase conditions. This selective N (in)-arylation reaction proceeds efficiently within 3 h of light irradiation in highly functionalized heterogeneous environments, employing minimal excesses of electrophile and base, alongside catalytic quantities of nickel, ligand, and photocatalyst. The method affords homogeneous peptide products with high chemoselectivity and operational simplicity. We envision that this strategy could contribute to advancing the design of the next-generation long-acting class II G protein-coupled receptor agonist therapeutics.

The prevalence and rising use of alcohol, opioids, and stimulants have led to substance use disorders (SUDs) that are a significant public health challenge. Traditional treatments offer some benefit; however, they often limited by efficacy, side effects, and accessibility, highlighting the urgent need for novel therapeutics. This review explores the current literature surrounding three different classes of novel treatments: glucagon-like peptide-1 (GLP-1) receptor agonists, dopamine D3 receptor (D3R) antagonists, and corticotropin-releasing factor (CRF) antagonists. These therapeutics collectively target different aspects of the addiction process, such as stress and relapse prevention, reward modulation, and the reduction of drug-seeking behavior, leading to a combined multifaceted approach to treating SUDs. This review includes preclinical and clinical evidence supporting the use of these therapies, highlighting their potential to reduce substance use and prevent relapse to alcohol, opioid, and stimulant use. Despite the potentially promising findings of these treatments, further research is necessary to fully understand their mechanisms, optimize their application, and confirm their efficacy in clinical settings.

Fluorescent biosensors have advanced biomedical research by enabling direct live-cell measurements of signaling activities. However, current technology offers limited resolution and dimensionality, impeding our ability to resolve and interrogate spatiotemporally regulated networks of signaling activities. Here we introduce highly sensitive chemigenetic kinase activity biosensors that combine the genetically encodable self-labeling tag, HaloTag7, with far-red-emitting synthetic fluorophores. This technology enables both four-dimensional activity imaging and functional super-resolution imaging using stimulated emission depletion and other high-resolution microscopy techniques, permitting signaling activity to be detected across scales with the necessary resolution. Stimulated emission depletion imaging enabled the investigation of protein kinase A activity at individual clathrin-coated pits. We further demonstrate imaging of up to five analytes in single living cells, an increase in the dimensionality of biosensor multiplexing. Multiplexed imaging of cellular responses to the activation of different G-protein-coupled receptors (GPCRs) allowed quantitative measurements of spatiotemporal network states downstream of individual GPCR-ligand pairs.

Alcohol use disorder (AUD) is a prevalent neuropsychiatric disorder with serious health and social consequences. However, few licensed and successful pharmacotherapies exist for heterogeneous and complex disorders such as AUD, and these are poorly utilized. Preclinical and clinical findings suggest that the glucagon-like peptide-1 (GLP-1) system, a gut-brain peptide, is involved in the neurobiology of addictive behaviors. Additionally, the GLP-1 receptor (GLP-1R) has become a promising target for the treatment of AUD. Semaglutide, a novel GLP-1R agonist, has received clinical approval to treat type 2 diabetes in both subcutaneous and oral dosage forms. Studies have shown that it significantly reduces alcohol consumption and relapse of alcohol addiction in rats, suggesting its potential effectiveness for treating alcohol abuse in humans, particularly in overweight patients with AUDs. However, the use of semaglutide is associated with potential risks, such as gallbladder disease and clinical complications associated with delayed gastric emptying. This review evaluates the safety of semaglutide to inform its wider clinical application. Further extensive and in-depth studies on semaglutide are needed to reveal additional valuable clinical benefits.

G protein-coupled receptors (GPCRs) are the largest human membrane protein family that transduce extracellular signals into cellular responses. They are major pharmacological targets, with approximately 26% of marketed drugs targeting GPCRs, primarily at their orthosteric binding site. Despite their prominence, predicting the pharmacological effects of novel GPCR-targeting drugs remains challenging due to the complex functional dynamics of these receptors. Recent advances in X-ray crystallography, cryo-electron microscopy, spectroscopic techniques and molecular simulations have enhanced our understanding of receptor conformational dynamics and ligand interactions with GPCRs. These developments have revealed novel ligand-binding modes, mechanisms of action and druggable pockets. In this Review, we highlight such aspects for recently discovered small-molecule drugs and drug candidates targeting GPCRs, focusing on three categories: allosteric modulators, biased ligands, and bivalent and bitopic compounds. Although studies so far have largely been retrospective, integrating structural data on ligand-induced receptor functional dynamics into the drug discovery pipeline has the potential to guide the identification of drug candidates with specific abilities to modulate GPCR interactions with intracellular effector proteins such as G proteins and β-arrestins, enabling more tailored selectivity and efficacy profiles.

This study aimed to investigate the expression of glucagon-like peptide 1 receptor (GLP-1R) in the lacrimal gland and explore the effects of topical application of GLP-1R agonist on lacrimal gland function in a murine model of type 1 diabetes. Tear secretion was evaluated using phenol red threads, RNA sequencing was used to explore gene expression profiles associated with hyperglycemia-induced lacrimal gland injuries, and histologic analysis was conducted to evaluate the degree of damage. The expression of GLP-1R in the lacrimal gland was first identified, and a down-regulation trend associated with diabetes was observed. RNA-sequencing data from lacrimal gland tissues revealed that differentially expressed genes were enriched in inflammatory response pathways. Histologic analysis demonstrated persistent hyperglycemia-induced infiltration of inflammatory cells and progressive fibrosis in the lacrimal gland, resulting in atrophy and diminished tear secretion. Topical application of liraglutide effectively attenuated inflammation and alleviated fibrosis, thus promoting tear production in diabetic mice. Additionally, local intervention with liraglutide promoted autophagy degradation function in the lacrimal gland. This study represents the first validation of GLP-1R expression in the lacrimal gland and its down-regulation induced by diabetes. Additionally, these findings demonstrate that topical administration of liraglutide eye drops, a GLP-1R agonist, can effectively mitigate hyperglycemia-induced damage in the lacrimal gland while enhancing tear secretion.

Glucagon-like peptide-1 receptor (GLP1R) agonists and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists may help treat metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). However, their definitive effects are still unclear. Our study aims to clarify this uncertainty.

We utilised conventional Mendelian randomisation (MR) analysis to explore potential causal links between plasma GLP-1/GIP concentrations and MASLD and its related traits. Next, we conducted drug-target MR analysis using highly expressed tissue data to assess the effects of corresponding drug perturbation on these traits. Finally, mediation analysis was performed to ascertain whether the potential causal effect is direct or mediated by other MASLD-related traits.

Circulating 2-h GLP-1 and GIP concentrations measured during an oral glucose tolerance test showed hepatoprotective effects on MASLD risk (ORGLP-1 = 0.168 [95% CI 0.033-0.839], p = 0.030; ORGIP = 0.331 [95% CI 0.222-0.494], p = 6.31 × 10-8). GLP1R expression in the blood had a minimal causal effect on MASLD risk, whereas GIPR expression significantly affected MASLD risk (OR = 0.671 [95% CI 0.531-0.849], p = 9.07 × 10-4). Expression levels of GLP1R or GIPR in the blood significantly influenced MASLD-related clinical traits. Mediation analysis revealed that GIPR expression protected against MASLD, even after adjusting for type 2 diabetes or body mass index.

GLP-1/GIP receptor agonists offer promise in lowering MASLD/MASH risk. GIP receptor agonists can exert direct and indirect effects on MASLD mediated by weight reduction or glycemic control improvement.

Incretin-based medicines have considerably impacted the treatment of type 2 diabetes mellitus (T2DM), providing considerable advantages in glycemic regulation, weight control, and cardiovascular results. This narrative review examines progress in incretin medicines, encompassing glucagon-like peptide-1 (GLP-1) receptor agonists, dual-receptor, and triple-receptor agonists, while emphasizing their therapeutic advantages, obstacles, and prospective developments. The examined articles were sourced from databases including PubMed and Google Scholar, concentrating on publications predominantly from 2010 to 2024. Selective foundational papers released before this timeline were incorporated to furnish critical historical context about incretin processes and their discovery. Incretin-based medicines, despite their therapeutic efficacy, encounter hurdles including elevated treatment costs, patient compliance difficulties, and variability in response attributable to genetic and physiological variables. Moreover, there are still deficiencies in comprehending the long-term cardiovascular safety and cancer risks linked to these medicines. Emerging dual- and triple-receptor agonists demonstrate potential in overcoming the shortcomings of conventional GLP-1 receptor agonists, providing enhanced metabolic results and broader uses in intricate disease profiles. Future research must concentrate on economic obstacles, streamlined regimens, customized medicine, the integration of artificial intelligence, patient stratification, as well as the safety and efficacy of incretin-based medicines for holistic management of T2DM.

Conjugating two fatty acids (2FAs) to peptide drugs can improve pharmacokinetics and therapeutic effects. However, optimizing FA spacing, chain combination, and attachment site to simultaneously enhance albumin binding and drug efficacy remains challenging. We introduce a multiarm linker technology enabling precise control of 2FA spacing, composition, and attachment. By applying this technology to a modified glucagon-like peptide-1 (GLP-1) and screening various 2FA-GLP-1 conjugates differing in linkage, linker, and FA properties for improved albumin affinity, pharmacokinetics, and pharmacodynamics, TE-8105 emerged as a promising candidate. TE-8105 outperformed semaglutide, showing improved long-term glycemic control, weight loss, and liver health in diabetic mice, and dose-dependent weight loss and favorable body composition changes in obese mice. A distinct advantage of TE-8105 over semaglutide is its low-dose reduction of liver steatosis and improvement of liver health in nonalcoholic steatohepatitis mice. The multiarm linker technology provides a versatile platform for developing improved 2FA-peptide therapeutics.

Emerging evidence suggests that glucagon-like peptide-1 receptor (GLP1R) agonists may have potential benefits for mental illnesses. However, their exact effects remain unclear. This study investigated the causal relationship between glucagon-like peptide-1 receptor agonist (GLP1RA) and the risk of 10 common mental illnesses, including attention deficit and hyperactivity disorder, anorexia nervosa, anxiety disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, post-traumatic stress disorder, schizophrenia, cannabis use disorder, and alcohol use disorder. We selected GLP1RA as the exposure and conducted a Mendelian randomization (MR) analysis. The cis-eQTLs of the drug target gene GLP1R, provided by eQTLGen, were used to simulate the pharmacological effects of GLP1RA. Type 2 diabetes and BMI were included as positive controls. Using data from both the Psychiatric Genomic Consortium and FinnGen, we conducted separate MR analyses for the same disease across these two independent databases. Meta-analysis was used to pool the results. We found genetic evidence suggesting a causal relationship between GLP1RA and a reduced risk of schizophrenia [OR (95% CI) = 0.84 (0.71-0.98), I2 = 0.0%, common effects model]. Further mediation analysis indicated that this effect might be unrelated to improvements in glycemic control but rather mediated by BMI. However, the findings of this study provide insufficient evidence to support a causal relationship between GLP1RA and other mental illnesses. Sensitivity analyses did not reveal any potential bias due to horizontal pleiotropy or heterogeneity in the above results (p > 0.05). This study suggests that genetically proxied activation of glucagon-like peptide-1 receptor is associated with a lower risk of schizophrenia. GLP1R is implicated in schizophrenia pathogenesis, and its agonists may exert potential benefits through weight management. Our study provides useful information for understanding the neuropsychiatric effects of GLP1RA, which may contribute to refining future research designs and guiding clinical management. Moreover, our findings could have significant implications for overweight individuals at high risk of schizophrenia when selecting weight-loss medications. Future research should further investigate the potential mechanisms underlying the relationship between GLP1RA and schizophrenia.

Heart failure with preserved ejection fraction (HFpEF) is a major subtype of heart failure, primarily characterized by a normal or mildly reduced left ventricular ejection fraction along with left ventricular diastolic dysfunction. Recent studies have shown that the prevalence of HFpEF is higher in women than that in men, particularly in postmenopausal women. Concurrently, it has been observed that the incidence of risk factors contributing to HFpEF (such as obesity, hypertension, diabetes, and atrial fibrillation) also notably increases post-menopause, affecting the incidence of HFpEF. This review aimed to examine the relationship between estrogen and risk factors associated with HFpEF, clarifying the underlying mechanisms through which estrogen affects these risk factors from epidemiological and pathophysiological perspectives. This review also provides a comprehensive understanding of the association between estrogen and the risk factors for HFpEF, thus helping explore potential targets for HFpEF treatment.

Semaglutide is a glucagon-like peptide 1 (GLP-1) analog that binds to GLP-1 receptors (GLP-1R) on beta-cells and neuronal cells and is used for treating type 2 diabetes and obesity. Insulin-secreting pancreatic neuroendocrine neoplasms have been reported to express high levels of GLP-1R protein, raising the possibility that GLP-1 receptor agonists could promote tumor growth. Our goal was to quantify GLP-1R expression levels in 6 neuroendocrine neoplasm cellular models and determine their proliferative response to semaglutide treatment.

Gene expression of GLP-1R in neuroendocrine neoplasm cells (BON, GOT1, NT-3, NEC913, NEC1452, and NEC1583) was measured by quantitative polymerase chain reaction. Protein expression was determined by immunofluorescent staining and Western blotting. Neuroendocrine neoplasm cells were incubated with semaglutide, and cell growth was measured using a cell viability assay. Mice harboring GOT1 xenografts were treated with semaglutide, and tumor volumes were measured.

BON, NEC1452, and NEC1583 cells expressed significantly lower levels of GLP-1R transcript and protein than GOT1, NT-3, and NEC913 cells. GOT1 and NT-3 showed the highest response to semaglutide treatment, with a 19% and 22% increase in growth. Semaglutide promotes tumor growth in mice with GOT1 xenografts by 72%.

The impact of the GLP-1 receptor agonist semaglutide on neuroendocrine cancer growth is understudied. Our data revealed that 50% of neuroendocrine neoplasm cell lines tested expressed GLP-1R, and semaglutide treatment promoted their growth. These results indicate a potential risk in the use of semaglutide in patients with neuroendocrine neoplasms expressing GLP-1R. Investigations into a larger set of neuroendocrine neoplasms would be important because they are highly heterogeneous.

Bile acid diarrhea (BAD) is a chronic and socially debilitating disease characterized by abdominal pain, diarrhea, urgency, and fecal incontinence. Recently, in a 6-week randomized controlled trial, we showed that the glucagon-like peptide 1 receptor agonist (GLP-1RA) liraglutide is superior to bile acid sequestration (considered standard-of-care) using colesevelam in reducing BAD symptoms. The emergence of new, more potent, and longer-acting GLP-1RAs has spurred an interest in these treatments in BAD management. Here, we review the literature on different GLP-1RAs in BAD treatment and outline their potential mode of actions, highlight knowledge gaps, and outline the need for further clinical evidence generation.

Peptides are a powerful drug modality with potential to access difficult targets. This recognition underlies their growth in the global pharmaceutical market, with peptides representing ~8% of drugs approved by the FDA over the past decade. Currently, the peptide therapeutic landscape is evolving, with high-throughput display technologies driving the identification of peptide leads with enhanced diversity. Yet, chemical modifications remain essential for improving the 'drug-like' properties of peptides and ultimately translating leads to market. In this review, we explore two recent therapeutic candidates (semaglutide, a peptide hormone analogue, and MK-0616, an mRNA display-derived candidate) as case studies that highlight general approaches to improving pharmacokinetics (PK) and potency. We also emphasize the critical link between advances in medicinal chemistry and the optimisation of highly efficacious peptide therapeutics.

Obesity and diabetes mellitus (DM) pose challenges for patients undergoing total knee arthroplasty (TKA). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as agents for weight and DM management, but they affect multiple organ systems. Outcomes, trends, and demographics for perioperative GLP-1RA use in patients with TKA are not well understood.

A retrospective review of 13,751 primary, elective TKAs with at least 90 days of follow-up at an urban academic health system between 2012 and 2023 identified 865 patients who had perioperative GLP-1RA use. A 10:1 propensity score match based on sex, age, smoking status, American Society of Anesthesiologists classification, and body mass index created a control cohort of 8,650 TKAs with no GLP-1RA use.

The use of GLP-1RAs varied significantly by race, Medicaid insurance, Charlson Comorbidity Index, and presence of DM. Black and Latino patients and those covered by Medicaid were significantly less likely to receive GLP-1RAs. The GLP-1RA group had significantly shorter length of stay (2.1 versus 2.5 days, P < 0.001) and a higher rate of home discharge (91.7 versus 84.2%, P < 0.001). The GLP-1RA users had significantly higher rates of 90-day emergency department visits (5.9 versus 4.0%, P = 0.008), but no differences in 90-day readmissions (4.3 versus 3.6%, P = 0.168) or 2-year revision (2.3 versus 2.6%, P = 0.362) compared to matched controls. The GLP-1RA patients had significantly lower all-cause revision rates at the last follow-up (2.7 versus 3.9%, P = 0.034), but there was no significant difference in Kaplan-Meier implant survival (P = 0.311). Before TKA, GLP-1RA patients had an average decrease in body mass index of 0.4, compared to an average increase of 1.2 for matched controls.

Our results demonstrate that the use of GLP-1RAs is significantly lower for minority patients and those covered by Medicaid. Patients using GLP-1RAs have noninferior clinical outcomes with the potential for weight loss leading up to TKA.

III.

Glucagon-like peptide-1 receptor (GLP-1R) is an emerging critical target for the diagnosis and treatment of various diseases. Radiolabeled exendin-4 (Ex-4), a GLP-1R agonist, has been widely used as an imaging probe. However, its potential to induce hypoglycemia, especially in patients with insulinoma, limits its applicability. This study evaluated whether Ex-D3, a Glu3Asp substitution of Ex-4 with a higher internalization rate, could enhance the imaging efficacy of Ex-4 while reducing its hypoglycemic effects. We synthesized derivatives with an additional C-terminal Cys (Ex-D3-C40) for site-specific 125I labeling. Surface plasmon resonance analysis revealed that C-terminus modification did not significantly alter the binding affinity of Ex-D3-C40 to GLP-1R. In vivo studies in mice demonstrated that Ex-D3-C40 induced weaker hypoglycemic effects than Ex-4-C40. Biodistribution studies showed that 125I-labeled Ex-D3 ([125I]I-Ex-D3) achieved significantly higher pancreatic accumulation and higher pancreas-to-blood and pancreas-to-muscle ratios than [125I]I-Ex-4. Ex vivo autoradiography confirmed the binding specificity of [125I]I-Ex-D3 to GLP-1R-expressing pancreatic β-cells. These findings indicate that Ex-D3 is a promising parent peptide for the development of superior GLP-1R imaging probes with reduced hypoglycemic risk, highlighting the importance of considering pharmacological effects in designing molecular imaging probes.

Glucagon-like peptide-1 (GLP-1) is an incretin peptide hormone mainly secreted by enteroendocrine intestinal L-cells. GLP-1 is also secreted by α-cells of the pancreas and the central nervous system (CNS). GLP-1 secretion is stimulated by nutrient intake and exerts its effects on glucose homeostasis by stimulating insulin secretion, gastric emptying confiding the food intake, and β-cell proliferation. The insulinotropic effects of GLP-1, and the reduction of its effects in type 2 diabetes mellitus (T2DM), have made GLP-1 an attractive option for the treatment of T2DM. Furthermore, GLP-1-based medications such as GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, have been shown to improve diabetes control in preclinical and clinical trials with human subjects. Importantly, increasing the endogenous production of GLP-1 by different mechanisms or by increasing the number of intestinal L-cells that tend to produce this hormone may be another effective therapeutic approach to managing T2DM. Herein, we briefly describe therapeutic agents/compounds that enhance GLP-1 function. Then, we will discuss the approaches that can increase the endogenous production of GLP-1 through various stimuli. Finally, we introduce the potential of L-cell differentiation as an attractive future therapeutic approach to increase GLP-1 production as an attractive therapeutic alternative for T2DM.

Gene therapies and cell therapies require precise, reversible and patient-friendly control over the production of therapeutic proteins. Here we present a fully human nitric-oxide-responsive gene-regulation system for the on-demand and localized release of therapeutic proteins through clinically licensed nitroglycerin patches. Designed for simplicity and robust human compatibility, the system incorporates human mitochondrial aldehyde dehydrogenase for converting nitroglycerin into nitric oxide, which then activates soluble guanylate cyclase to produce cyclic guanosine monophosphate, followed by protein kinase G to amplify the signal and to trigger target gene expression. In a proof-of-concept study, human cells expressing the nitroglycerin-responsive system were encapsulated and implanted subcutaneously in obese mice with type 2 diabetes. Transdermal nitroglycerin patches applied over the implant enabled the controlled and reversible production of glucagon-like peptide-1 throughout the 35-day experimental period, effectively restoring blood glucose levels in these mice without affecting heart rate or blood pressure. The approach may facilitate the development of safe, convenient and responsive implantable devices for the sustained delivery of biopharmaceuticals for the management of chronic diseases.

This systematic review and meta-analysis aimed to examine the effect of Ramadan intermittent fasting on appetite-regulating hormones including leptin, ghrelin, insulin, gastrin, glucagon-like peptide-1, peptide YY, and cholecystokinin.

We searched the MEDLINE, Embase, Cochrane Library, CINAHL, Google Scholar, and Web of Science databases to identify relevant research on appetite-regulating hormones during Ramadan intermittent fasting, published until the end of March 2024.

Data from 16 eligible studies comprising 664 participants (341, 51.4 % male) with a mean ± standard deviation age of 33.9 ± 10.8 years were included. The meta-analysis included 12 studies with complete leptin data, showing no significant effect of Ramadan intermittent fasting on leptin concentrations (standardised mean difference - SMD = -0.11 μg/mL, 95 % CI: -0.36 to 0.14). Analysis of three studies with complete ghrelin data demonstrated a significant increase in ghrelin concentrations following Ramadan intermittent fasting (SMD = 0.31 pg/mL, 95 % CI: 0.03 to 0.60). Six studies examining insulin concentrations pre- and post-fasting revealed no significant effect on insulin concentrations (SMD = -0.24 μU/mL, 95 % CI: -0.54 to 0.02). Similarly, analysis of three studies with complete gastrin data showed no significant effect of intermittent fasting on gastrin concentrations (SMD = 0.23 pg/mL, 95 % CI: -0.71 to 0.99).

Ramadan intermittent fasting significantly increases ghrelin concentrations while showing no significant effects on leptin, insulin, and gastrin. While ghrelin findings were consistent across studies, the high heterogeneity in leptin studies suggests further research to better understand the effects of Ramadan intermittent fasting on appetite-regulating hormones.

The GLP-1 receptor, one of the most successful drug targets for the treatment of type 2 diabetes and obesity, is known to engage multiple intracellular signaling proteins. However, it remains less explored how the receptor interacts with proteins on the cell membrane. Here, we present a ligand-based proximity labeling approach to interrogate the native cell membrane interactome for the GLP-1 receptor after agonist simulation. Our study identified several unreported putative cell membrane interactors for the endogenous receptor in either a pancreatic β cell line or a neuronal cell line. We further uncovered new regulators of GLP-1 receptor-mediated signaling and insulinotropic responses in β cells. Additionally, we obtained a time-resolved cell membrane interactome map for the receptor in β cells. Therefore, our study provides a new approach that is generalizable to map endogenous cell membrane interactomes for G-protein-coupled receptors to decipher the molecular basis of their cell-type-specific functional regulation.

Cachexia is a multifactorial metabolic syndrome characterized by weight and skeletal muscle loss caused by underlying illnesses such as cancer, heart failure, and renal failure. Inflammation, insulin resistance, increased muscle protein degradation, decreased food intake, and anorexia are the primary pathophysiological drivers of cachexia. Cachexia causes physical deterioration and functional impairment, loss of quality of life, lower response to active treatment, and ultimately morbidity and mortality, while the difficulties in tackling cachexia in its advanced phases and the heterogeneity of the syndrome among patients require an individualized and multidisciplinary approach from an early stage. Specifically, strategies combining nutritional and exercise interventions as well as pharmacotherapy that directly affect the pathogenesis of cachexia, such as anti-inflammatory, metabolism-improving, and appetite-stimulating agents, have been proposed, but none of which have demonstrated sufficient evidence to date. Nevertheless, several agents have recently emerged, including anamorelin, a ghrelin receptor agonist, growth differentiation factor 15 neutralization therapy, and melanocortin receptor antagonist, as candidates for ameliorating anorexia associated with cancer cachexia. Therefore, in this review, we outline cancer cachexia-associated anorexia and its pharmacotherapy, including corticosteroids, progesterone analogs, cannabinoids, anti-psychotics, and thalidomide which have been previously explored for their efficacy, in addition to the aforementioned novel agents, along with their mechanisms.

The small intestine, including the endocannabinoid system (ECS), regulates the energy homeostasis. If maternal obesity modifies the intestinal ECS of the offspring favoring metabolic disorders throughout life is unexplored. Regardless maternal insults, overaction of the ECS has been related to obesity, mainly via type 1 cannabinoid receptor (CB1) signaling, while type 2 cannabinoid receptor (CB2) signaling and the endocannabinoid-like compounds, such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), have been associated with anti-inflammatory effects. We hypothesized that maternal obesity changes the ECS in the small intestine of weanling rat offspring in a sex-specific manner associated with altered fecal metabolites. Female rats received a control diet (C; 9% fat) or an obesogenic diet (OD; 37.2% fat, 11.8% sucrose) 9 weeks before mating, gestation and lactation. Offspring were euthanized at weaning. Maternal obesity increased CB2 protein content and mRNA levels of monocyte chemoattractant protein-1 in the small intestine in male offspring, while decreased fecal content of PEA and OEA in both sexes. Maternal obesity decreased gut permeability, but impaired glycemic homeostasis. Concerning fecal levels of γ-aminobutyric acid, amino acids and hypoxanthine, maternal obesity induced a fecal signature related to inflammatory and glycemic homeostasis impairment and dysbiosis. Maternal obesity induced intestinal inflammation and the signaling of CB2, PEA, and OEA might be part of a counter-regulatory response, contributing to reduced gut permeability, but not enough to avoid overweight and glycemic impairment in the offspring at weaning. Our findings provide molecular insights into the intestinal and fecal biomarkers for metabolic disorders.

Objectives: Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic disorder of the liver and affects many people worldwide. Intestinal bacteria are thought to be involved in the pathological progression of NAFLD; therefore, improving the intestinal microbiota may be important in controlling NAFLD. In this study, we assessed the effects of water-soluble cellulose acetate (WSCA) on the intestinal microbiota in a non-alcoholic steatohepatitis (NASH) mouse model. Methods: NASH model (STAM mice) was created by streptozotocin injection and feeding the mice a high-fat diet. The serum biochemical parameters were analyzed. Intestinal bacterial populations were analyzed using paired-end sequencing of 16S rRNA, 18S rRNA, and internal transcribed spacer gene. Results: Our findings indicated that WSCA administration tends to improve the serum alanine aminotransferase and glucose levels in STAM mice and decreased the alpha diversity and altered the beta diversity of their intestinal microbiota. Additionally, WSCA intake resulted in an increase in the abundance of Coriobacteriaceae_UCG-002 and a decrease in the abundance of Enterobacter. Conclusions: WSCA intake can alter specific microbial compositions to improve blood glucose levels and liver functions and may improve the pathogenesis of NAFLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently a pressing public health issue associated with adverse outcomes such as cirrhosis, malignancy, transplantation, and mortality. Lifestyle modifications constitute the most effective and fundamental management approach, but they often pose challenges in sustaining long-term clinical benefits. Hence, there is a critical need to enhance our understanding through pharmacological management, which unfortunately remains limited. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a leading treatment in the fields of diabetes and obesity, with recent preclinical and clinical studies indicating significant benefits in the management and treatment of MASLD. Our article begins by reviewing the beneficial therapeutic components of GLP-1RAs in MASLD. Subsequently, from a clinical research perspective, we concluded with the liver outcomes of current primary GLP-1RAs and co-agonists. Finally, we presented our insights on clinical concerns such as appropriate trial endpoints, management of comorbidities, and future developments. In conclusion, the benefits of GLP-1RAs in MASLD are promising, and background therapy involving metabolic modulation may represent one of the future therapeutic paradigms.

Metabolic peptides can influence metabolic processes and contribute to both inflammatory and/or anti-inflammatory responses. Studies have shown that there are thousands of metabolic peptides, made up of short chains of amino acids, that the human body produces. These peptides are crucial for regulating many different processes like metabolism and cell signaling, as they bind to receptors on various cells. This review will cover the role of three specific metabolic peptides and their roles in hyperinsulinemia, diabetes, inflammation, and neurodegeneration, as well as their roles in type 3 diabetes and dementia. The metabolic peptides glucagon-like peptide 1 (GLP-1), gastric inhibitor polypeptide (GIP), and pancreatic peptide (PP) will be discussed, as dysregulation within their processes can lead to the development of various inflammatory and neurodegenerative diseases. Research has been able to closely investigate the connections between these metabolic peptides and their links to the gut-brain axis, highlighting changes made in the gut that can lead to dysfunction in processes in the brain, as well as changes made in the brain that can lead to dysregulation in the gut. The role of metabolic peptides in the development and potentially reversal of diseases such as obesity, hyperinsulinemia, and type 2 diabetes will also be discussed. Furthermore, we review the potential links between these conditions and neuroinflammation and the development of neurodegenerative diseases like dementia, specifically Parkinson's disease and Alzheimer's disease.

Sleep spindles may be implicated in sensing and regulation of peripheral glucose. Whether spindle density in patients with type 2 diabetes mellitus (T2DM) differs from that of healthy subjects is unknown.

Our retrospective analysis of polysomnography (PSG) studies identified 952 patients with T2DM and 952 sex-, age- and BMI-matched control subjects. We extracted spindles from PSG electroencephalograms and used rank-based statistical methods to test for differences between subjects with and without diabetes. We also explored potential modifiers of spindle density differences. We replicated our analysis on independent data from the Sleep Heart Health Study.

We found that patients with T2DM exhibited about half the spindle density during sleep as matched controls (P < 0.0001). The replication dataset showed similar trends. The patient-minus-control paired difference in spindle density for pairs where the patient had major complications were larger than corresponding paired differences in pairs where the patient lacked major complications, despite both patient groups having significantly lower spindle density compared to their respective control subjects. Patients with a prescription for a glucagon-like peptide 1 receptor agonist had significantly higher spindle density than those without one (P ≤ 0.03). Spindle density in patients with T2DM monotonically decreased as their highest recorded HbA1C level increased (P ≤ 0.003).

T2DM patients had significantly lower spindle density than control subjects; the size of that difference was correlated with markers of disease severity (complications and glycemic control). These findings expand our understanding of the relationships between sleep and glucose regulation.

Glucagon-like-peptide-1 (GLP-1) agonists are commonly used to improve glycemic control and promote weight loss in individuals with type 2 diabetes mellitus (T2DM) and/or obesity. However, there is a paucity of evidence regarding GLP-1 agonist use in people with cystic fibrosis (pwCF). We present 11 people with CF (males: 3, females: 7; age range 24-47; BMI range 25.7-43.7) treated with GLP-1 agonists (semaglutide: 9,tirzepatide: 2) for variable duration (1-50 months). All experienced weight loss on GLP- 1 agonist therapy (median change in weight = -7.2 kg; change in BMI [kg/m2] = -0.9 to -8.1). Eight pwCF showed improvement in percent predicted forced expiratory volume in 1 second (ppFEV1) [change = -5 to + 18] and nine pwCF showed improvement in percent predicted forced vital capacity (ppFVC) [change= +1 to + 26]. Of the 7 pwCF with CFRD, all reduced their insulin quantity (mean, 31.5 % decrease in total daily insulin dose), and glucose time in range improved for most (mean, +11 % increase from baseline). Four pwCF stopped using GLP-1 agonists: 2 due to severe nausea/vomiting, 1 due to lack of perceived benefit, and 1 due to change in insurance coverage. This report is the largest published series to date of pwCF treated with GLP-1 agonist therapy. With the addition of GLP-1 agonists, all individuals experienced weight loss and a reduction in daily insulin dose, and most had improvement in pulmonary function. Future multi-center studies are needed to corroborate the efficacy and safety of these agents in the CF population.

Recombinant human B-type natriuretic peptide (rhBNP) has been extensively proven to be an effective mean of heart failure (HF) therapy, but its clinical application is limited by its very short half-life. This study aims to combine in vitro transcribed mRNA (IVT mRNA) and fusion protein technology to develop a rhBNP-Fc mRNA drug with long half-life, high efficiency and few side effects to treat HF.

The rhBNP-Fc fusion mRNA with IgG4-Fc sequence was produced by IVT technology. rhBNP-Fc mRNA was transfected into HEK293T cells to examine the expression in vitro. rhBNP-Fc mRNA encapsulated in LNP was injected into normal mice to detect the translation efficiency, half-life and negative effects in vivo. Finally, it was injected into doxorubicin-induced HF mice to screen the cardiac protective effect.

The rhBNP-Fc fusion mRNA extended the half-life of rhBNP, showing sustained expression in cell line for at least one day. rhBNP-Fc mRNA translation showed dose-dependent levels, and was still detectable 5 d after injection in vivo. In the HF mouse model, a single administration of rhBNP-Fc mRNA-LNP improved cardiac function, including improving heart ejection and reducing HF biomarkers expression. Additionally, rhBNP-Fc mRNA-LNP treatment mitigated myocardial damage, normalized cardiomyocyte structure, and reduced the levels of pro-inflammatory cytokines.

The rhBNP-Fc mRNA has the potential to serve as an alternative to traditional protein therapies, thereby reducing clinical dosages, injection frequencies, and treatment costs. Our findings offer new insights into the development and application of mRNA drugs, emphasizing their therapeutic potential in long-acting drugs.

The ingestion of macronutrients triggers the release of several incretin peptides from the gastrointestinal system, which have both insulinotropic and satiety-inducing properties. The effect of the meal's macronutrient content on the secretion of these peptides has not been adequately studied, particularly concerning the secretion of the newly characterized proglucagon-derived peptides (PGDPs). We aimed to examine the effect of a meal's macronutrient content, specifically its protein versus carbohydrate content, on postprandial PGDPs responses in healthy men.

Ten apparently healthy, normal-weight males completed a trial consisting of two interventions in a randomized, double-blind, crossover design. In one intervention, participants consumed an isocaloric high-protein breakfast (65 g of glucose, 60 g of protein), while in the other, participants consumed a carbohydrate-rich breakfast (125 g of glucose). Levels of all seven PGDPs, namely glucagon-like peptide-1 and -2 (GLP-1 and GLP-2), oxyntomodulin, glicentin, major pro-glucagon fragment (MPGF), glucagon and proglucagon, as well as glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide total and total plus (GIP total and GIP total plus) levels were measured at baseline, every 15 minutes for the first hour and every 30 minutes for the second and third hours after each meal.

The two interventions produced similar glycemic and insulinemic responses, while total amino acids increased more over time in response to protein administration. Levels of proglucagon (F(8) = 4.114, p = 0.001) and the primarily pancreas-secreted glucagon and MPGF (F(8) = 3.088, p = 0.005) rose significantly during the protein intervention. GIP total and GIP total plus increased in response to carbohydrate ingestion. No major overall differences were observed for the primarily intestinally secreted GLP-1, oxyntomodulin and glicentin between the two arms of the trial, although their levels tended to increase earlier in response to carbohydrates and later in response to protein administration, especially in the case of GLP-2 levels.

The carbohydrate vs. protein content of a meal differentially increases the levels of GIP and PGDPs during the postprandial period. Dose-response studies and comparisons with lipid intake may further advance our knowledge of the physiology of these clinically important molecules and their implications in energy homeostasis.