GLP-1 receptor agonists (GLP-1-RA) are emerging as promising agents beyond their established role in type 2 diabetes mellitus (T2DM) and obesity treatment, showing significant nephroprotective effects. The FLOW study demonstrated that semaglutide significantly slows the progression of chronic kidney disease (CKD) in T2DM patients. The nephroprotective mechanisms are multifactorial, including improved glycemic control, blood pressure reduction, antifibrotic, and anti-inflammatory effects. Early studies suggest that GLP-1-RA may also benefit patients without T2DM. Additionally, their combination with SGLT2 inhibitors is gaining relevance. Current evidence suggests that GLP-1-RA could play a key role in CKD management. Future studies will determine whether they can be established as a standard therapy to optimize care for high-risk patients.

Tirzepatide is a novel dual gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) for type 2 diabetes or obesity. To explore the safety profile of tirzepatide in real-world clinical applications.

A retrospective analysis of adverse events (AEs) reports associated with tirzepatide was conducted from the second quarter of 2022 through the fourth quarter of 2023, utilizing the FDA Adverse Event Reporting System (FAERS) database. Signal mining utilized the reporting odds ratio (ROR) method, and onset time was analyzed utilizing the Weibull Shape Parameter (WSP).

We identified 25,215 AE reports related to tirzepatide, predominantly in the 65 to 85 age group. Four positive signals were found at the system organ classes level. Additionally,109 AEs at the preferred terms level with positive signals were indicated. Included among these are novel signals, such as the presence of thyroid mass, medullary thyroid carcinoma, and conditions affecting the reproductive system and breast. Most AEs occurred within the first 30 days. The WSP was 0.66, indicating a propensity for early failure type.

This study identified several novel AE signals for tirzepatide, highlighting the need for careful monitoring, especially in the early stages of treatment.

Glucagon (GCG) like peptide 1 (GLP-1) has emerged as a powerful player in regulating metabolism and a promising therapeutic target for various chronic diseases. This review delves into the physiological roles of GLP-1, exploring its impact on glucose homeostasis, insulin secretion, and satiety. We examine the compelling evidence supporting GLP-1 receptor agonists (GLP-1RAs) in managing type 2 diabetes (T2D), obesity, and other diseases. The intricate molecular mechanisms underlying GLP-1RAs are explored, including their interactions with pathways like extracellular signal-regulated kinase 1/2 (ERK1/2), activated protein kinase (AMPK), cyclic adenine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC). Expanding our understanding, the review investigates the potential role of GLP-1 in cancers. Also, microribonucleic acid (RNA) (miRNAs), critical regulators of gene expression, are introduced as potential modulators of GLP-1 signaling. We delve into the link between miRNAs and T2D obesity and explore specific miRNA examples influencing GLP-1R function. Finally, the review explores the rationale for seeking alternatives to GLP-1RAs and highlights natural products with promising GLP-1 modulatory effects.

Diabetes and bone disease are common in cystic fibrosis (CF) and primarily occur alongside exocrine pancreatic insufficiency (PI). "Incretins," glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), augment insulin secretion and regulate bone metabolism. In CF, PI dampens the incretin response. Loss of the insulinotropic effect of GIP in CF was recently identified, but effects on bone are unknown.

Determine effects of incretins on bone resorption markers in adults with PI-CF.

Secondary analysis of a mechanistic double-blinded randomized placebo-controlled crossover trial including adults ages 18-40 years with PI-CF (n = 25).

Adults with PI-CF received either GIP (4 pmol/kg/min) or GLP-1 (1.5 pmol/kg/min) infusion, followed by double-blind randomization to either incretin or placebo infusion. Non-CF healthy controls received double-blind GIP (4 pmol/kg/min) or placebo. Serum C-terminal telopeptide (CTX), a bone resorption marker, was assessed during the infusion over 80 (GIP) or 60 (GLP-1) minutes.

CTX (mg/dL) concentrations.

In PI-CF, CTX decreased during GIP infusion, but not during placebo (time-by-treatment interaction P < 0.01). GLP-1 did not affect CTX. In non-CF healthy controls, time-by-treatment interaction was not significant (P = 0.23), but CTX decreased during GIP (P = 0.02) but not placebo (P = 0.47).

GIP evokes a bone anti-resorptive effect in people with PI-CF. Since the incretin response is perturbed in PI-CF, and an infusion of GIP lowers bone resorption, the "gut-bone axis" in CF-related bone disease requires attention.

Obstructive sleep apnea (OSA) is a prevalent global health issue, with recent advances in pharmacotherapy expanding treatment options. Tirzepatide, a dual GLP-1 and GIP receptor agonist, has been newly approved by the FDA for managing moderate to severe OSA, following promising results from major randomized trials. Initially indicated for type 2 diabetes mellitus, Tirzepatide promotes glycemic control and weight loss through incretin-mediated insulin secretion and appetite suppression. As its use becomes more widespread, perioperative physicians and head-neck surgeons must be familiar with its pharmacokinetics and associated risks. Notably, delayed gastric emptying, a dose-dependent side effect, raises concerns of pulmonary aspiration during general anesthesia. Preoperative gastric ultrasound, diet modification, and individualized glycemic management are recommended strategies. Given the limited high-quality data, a multidisciplinary, institution-specific approach remains essential in managing patients on Tirzepatide in the perioperative setting.

Obesity, a widespread global health issue affecting millions, is characterized by excess fat deposition and metabolic dysfunction, significantly elevating the risk of comorbidities like type 2 diabetes, cardiovascular disease, and certain cancers, all of which contribute to rising rates of preventable morbidity and mortality. Current approaches to obesity, including lifestyle modifications, and pharmacotherapy, often face limitations such as poor long-term adherence, side effects, and insufficient targeting of the complex, multifactorial pathways underlying the disease. Herein we report a dual, RNA-mediated combinatorial approach using targeting lipid nanoparticles (LNP) for the treatment of obesity. LNPs were co-encapsulated with mRNA encoding Interleukin-27 (mIL-27) to coactivate PGC-1α, PPARα, and UCP-1, thereby promoting adipocyte differentiation and enhancing adaptive thermogenesis within adipocytes, and siRNA targeting Dipeptidyl peptidase-4 (siDPP-4) to silence the primary inhibitory enzyme of GLP-1, and GIP within the incretin system, effectively restoring glucose homeostasis. Following post translational silencing of DPP-4 and upregulation of IL-27 in a diet-induced obesity (DIO) mice model, increased expression of thermogenic biomarkers PGC-1α, PPARα, and UCP-1 was observed at the molecular, protein, and tissue level, and insulin sensitivity was restored. Importantly, this gene modulation led to a 21.1 % reduction of bodyweight after treatment in the DIO model. These findings demonstrate for the first time a dual RNA-mediated combinatorial approach, leveraging liver targeting LNP delivery with synergistic effects from incretin system regulation and induction of adipocyte differentiation and thermogenesis after codelivery of siDPP-4 and mIL-27. This innovative strategy provides a promising alternate framework for addressing obesity and its associated metabolic dysfunction.

Suicide is a global public health concern, accounting for nearly 700,000 deaths annually. Although well-established risk factors, including mental health disorders, are widely recognized, emerging concerns have surfaced regarding a potential association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs), the dual Gastric Inhibitory Polypeptide (GIP)/GLP-1 Receptor Agonist tirzepatide and suicidal behavior. This systematic review aims to synthesize the available evidence on the potential association between these drugs and suicidal behavior.

This review was conducted following PRISMA guidelines. A systematic search was performed in MEDLINE, Embase, and APA PsycInfo up to September 24, 2024, using terms related to GLP-1 RAs/GIP/GLP-1 RAs and suicidal behavior.Three independent reviewers conducted article screening and data extraction. Risk of bias was evaluated using the Newcastle-Ottawa Scale for cohort studies and ROB2 for RCTs.

The review identified 16 studies published between 2017 and 2024, consisting of 5 observational studies, 2 randomized controlled trials, 8 pharmacovigilance analyses, and 1 post-hoc analysis of RCTs. No consistent evidence indicated an increased suicide risk among GLP-1 RA users. Pharmacovigilance analyses produced mixed findings; while some disproportionality analyses reported higher rates relative to other antihyperglycemic drugs, no causal link was confirmed. Cohort studies involving diabetic and obese populations generally did not demonstrate a significant increase in suicidal behavior.

Although current data do not warrant changes in prescribing practices, further research is needed before definitive conclusions can be drawn. Moreover, the generalizability and reliability of these findings should be interpreted in light of the methodological limitations of the included studies.

In the SURPASS J-mono trial, tirzepatide demonstrated significant improvements in bodyweight and several metabolic parameters in Japanese participants with type 2 diabetes. This post hoc analysis evaluated the potential relationships between weight loss and metabolic improvements in SURPASS J-mono.

Metabolic parameter data from tirzepatide-treated participants were analyzed by weight loss subgroups and compared to dulaglutide 0.75 mg. Correlations between changes from baseline to week 52 in weight loss and each metabolic parameter were assessed; Pearson correlation coefficients were derived. Mediation analyses were conducted to evaluate weight loss-associated and -unassociated effects of tirzepatide vs dulaglutide 0.75 mg.

This analysis included 548 participants (tirzepatide: n = 411, dulaglutide: n = 137). Weight loss subgroups showed greater improvement in metabolic parameters with greater bodyweight loss. Significant (P < 0.05) but weak correlations between changes in bodyweight and triglycerides (r = 0.18-0.25), high-density lipoprotein cholesterol (r = -0.37 to -0.29), and systolic blood pressure (r = 0.19-0.41) were observed across treatment groups; in diastolic blood pressure in the tirzepatide 5-mg (r = 0.28), pooled tirzepatide (r = 0.20), and dulaglutide 0.75-mg (r = 0.23) groups; and in fasting serum glucose in the dulaglutide 0.75-mg (r = 0.18) and pooled tirzepatide (r = 0.13) groups. Weight loss was associated with treatment differences between tirzepatide and dulaglutide 0.75 mg to varying degrees across metabolic parameters, with improvements in fasting serum glucose having the lowest association with weight loss (36.6%-43.5%).

In this post hoc analysis, non-glycemic and glycemic parameter improvements appeared differentially associated with weight loss, suggesting both weight loss-associated and -unassociated effects of tirzepatide.

Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP.

In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases.

Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders.

Glucagon-like peptide-1 receptor (GLP-1R), a class B1 G protein-coupled receptor, plays critical roles in glucose homeostasis. Recent structural pharmacology studies using cryogenic electron microscopy, X-ray crystallography, mass spectrometry, and functional analyses, have provided valuable insights into its activation by endogenous hormones and mono- or dual agonists like semaglutide and tirzepatide, highly effective in treating type 2 diabetes and obesity. They highlight significant conformational changes in the extracellular and transmembrane domains of GLP-1R that drive receptor activation and downstream signal transduction. Additionally, allosteric modulators, supported by emerging structural information, show great promises as an alternative strategy. Future research investigating unexplored effector interactions, biased signaling, weight rebound mechanisms, and personalized therapy strategies will be critical for developing better therapeutic agents targeting GLP-1R.

Glucagon-like peptide-1 receptor agonists (GLP1RA), initially approved for glycemic control in type 2 diabetes mellitus (T2DM), have emerged as agents for weight loss, cardiovascular and kidney protection. This review summarizes the evidence supporting the benefits of these therapies on cardiorenal outcomes.

Clinical trials have consistently demonstrated reductions in major adverse cardiovascular events with GLP1RA treatments. Recently, the FLOW trial revealed that semaglutide reduced the composite outcome of kidney failure, at least 50% decline in estimated glomerular filtration rate, kidney or cardiovascular mortality by 24% in patients with T2DM, thereby establishing GLP1RA as a pillar of therapy in this population. New evidence suggests favorable effects on kidney endpoints in nondiabetic individuals with overweight or obesity. Dedicated trials have also provided evidence for reduction in the risk for heart failure hospitalization and improvement in symptoms in individuals with heart failure with preserved ejection fraction. Subgroup analyses have suggested that GLP1RAs confer additive cardiorenal benefits irrespective of background medication use.

There is increasing evidence that GLP1RA reduces the risk for cardiovascular events, chronic kidney disease progression, and heart failure hospitalizations. Further data on the effect of dual and triple GLP1-based therapies on cardiorenal outcomes is required.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are peptide-derived analogs that were initially investigated to treat type 2 diabetes. Recently, a drug targeting the receptors of both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) (tirzepatide) has been introduced to the market, and its indications have expanded to include treating obesity. Here, we review the pharmacokinetics, pharmacokinetic drug-drug interactions (DDIs), and pharmacokinetic modeling approaches of four currently available GLP-1 RAs (exenatide, liraglutide, dulaglutide, and semaglutide) and tirzepatide. To address the extremely short half-life (2 min) of native human GLP-1, structural modifications have been applied to GLP-1 RAs and a dual GLP-1/GIP RA. These include amino acid sequence substitutions, fatty acid conjugation using a linker, and fusion with albumin or the IgG fragment crystallizable (Fc) region, resulting in minimal metabolism and renal excretion. Due to their diverse structures, the pharmacokinetic profiles vary, and a prolonged half-life may be associated with an increased risk of adverse events. Clinically significant drug-metabolizing enzyme- and transporter-mediated DDIs are yet to be reported. Mechanism-of-action-mediated DDIs are currently limited to those involving delayed gastric emptying, and most studies have found them to be clinically insignificant. However, significant changes in exposure were observed for oral contraceptives and levothyroxine following the administration of tirzepatide and oral semaglutide, respectively, indicating the need for close monitoring in these instances. Thirty models have been developed to predict pharmacokinetics and physiologically based pharmacokinetic modeling can be useful for assessing mechanism-of-action-mediated DDIs. Alterations in the volume of distribution and clearance resulting from other mechanisms of action (eg, reduced fat mass, changes in cytochrome P450 activity, and glomerular filtration rate) are key factors in determining pharmacokinetics. However, the DDIs mediated by these factors remain poorly understood and require further investigation to ensure that GLP-1 RAs can be safely used with concomitant medications.

Tirzepatide is an approved drug that is used to treat type 2 diabetes. Tirzepatide is a peptide comprised of 39 amino acids and activates glucose-dependent insulinotropic polypeptide receptors (GIPR) and glucagon-like peptide-1 receptors (GLP-1R). Via GIPR and GLP-1R, tirzepatide stimulated in cell culture adenylyl cyclases (AC) and thereby elevated the cellular content of 3':5' cyclic adenosine monophosphate (cAMP). We tested the hypothesis that tirzepatide augmented the force of contraction (FOC) in isolated electrically driven (1 Hz) human right atrial preparations (HAP) obtained during open heart surgery from adult patients. Cumulatively applied tirzepatide, starting at nanomolar concentrations, raised FOC in a concentration-dependent manner and a time-dependent manner (p < 0.05). The positive inotropic effects (PIE) of tirzepatide were attenuated by about a quarter by a GIPR antagonist (100 nM, Pro3-GIP) and by about three quarters by a GLP-1R antagonist (100 nM, exendin9-39) in HAP. Tirzepatide (1 µM) was less effective than 1 µM isoprenaline in raising FOC in HAP. The inhibitor of the cAMP-dependent protein kinase called H89 reversed the PIE of tirzepatide. We suggest that tirzepatide probably acts via stimulation of GIPR and GLP-1R to exert a PIE in HAP.

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the treatment of type 2 diabetes and obesity. While their metabolic benefits are well-established, their potential effects on vestibular function remain unexplored. This study investigated the association between GLP-1RA use and the risk of vestibular disorders. Methods: Using the TriNetX research network (accessed 3 November 2024), we conducted a retrospective cohort study of adults prescribed semaglutide (n = 419,497) or tirzepatide (n = 77,259) between January 2018 and October 2024. Cases were matched 1:1 with controls using propensity scores based on demographics and comorbidities. The primary outcome was new-onset vestibular disorders, analyzed at 6 months, 1 year, and 3 years after treatment initiation. Results: Both medications were associated with an increased risk of vestibular disorders. Semaglutide users showed a higher cumulative incidence (0.12% at 6 months to 0.41% at 3 years) compared to controls (0.03% to 0.16%, p < 0.001), with hazard ratios ranging from 4.02 (95% CI: 3.33-4.86) at 6 months to 4.95 (95% CI: 4.51-5.43) at 3 years. Tirzepatide users demonstrated similar patterns but lower absolute rates (0.10% at 6 months to 0.19% at 3 years vs. controls 0.04% to 0.15%), with hazard ratios from 3.19 (95% CI: 2.11-4.81) to 4.55 (95% CI: 3.43-6.03). The direct comparison showed a higher risk with semaglutide versus tirzepatide (RR 1.53-2.04, p < 0.001). Conclusions: GLP-1RA therapy is associated with an increased risk of vestibular disorders, with a higher risk observed with semaglutide compared to tirzepatide. These findings suggest the need for vestibular symptom monitoring in patients receiving these medications and warrant further investigation into underlying mechanisms.

Obesity is a growing global health challenge, necessitating effective treatment options beyond lifestyle interventions. This narrative review explores established and emerging pharmacotherapies for weight management, including parenteral agents like Liraglutide, Semaglutide, Setmelanotide, and Tirzepatide, as well as peroral medications such as Phentermine, Phentermine/Topiramate, Bupropion/Naltrexone, Orlistat, and Metformin. Newer treatments like Cagrilintide and Bimagrumab show promise for enhancing weight loss outcomes. Parenteral GLP-1 receptor agonists demonstrate superior efficacy compared to traditional peroral medications, with gastrointestinal side effects being the most common. Artificial intelligence presents intriguing opportunities to enhance weight loss strategies; however, its integration into clinical practice remains investigational and requires rigorous clinical validation. While current anti-obesity medications deliver significant benefits, future research must determine the efficacy, safety, and cost-effectiveness of AI-driven approaches. This includes exploring how AI can complement combination therapies and tailor personalized interventions, thereby grounding its potential benefits in robust clinical evidence. Future directions will focus on integrating AI into clinical trials to refine and personalize obesity management strategies.

The development of long-acting incretin receptor agonists represents a significant advance in the fight against the concurrent epidemics of type 2 diabetes mellitus (T2DM) and obesity. The aim of the present review is to examine the cellular processes underlying the actions of these new, highly significant classes of peptide receptor agonists. We further explore the potential actions of multi-agonist drugs as well as the mechanisms through which gut-brain communication can be used to achieve long-term weight loss without negative side effects.

Several unimolecular dual-receptor agonists have shown promising clinical efficacy studies when used alone or in conjunction with approved glucose-lowering medications. We also describe the development of incretin-based pharmacotherapy, starting with exendin- 4 and ending with the identification of multi-incretin hormone receptor agonists, which appear to be the next major step in the fight against T2DM and obesity. We discuss the multi-agonists currently in clinical trials and how each new generation of these drugs improves their effectiveness. Since most glucose-dependent insulinotropic polypeptide (GIP) receptor: glucagon-like peptide- 1 receptor (GLP- 1) receptor: glucagon receptor triagonists compete in efficacy with bariatric surgery, the success of these agents in preclinical models and clinical trials suggests a bright future for multi-agonists in the treatment of metabolic diseases. To fully understand how these treatments affect body weight, further research is needed.

Albumin and albumin-based biomaterials have been explored for various applications, including therapeutic delivery, as therapeutic agents, as components of tissue adhesives, and in tissue engineering applications. Albumin has been approved as a nanoparticle containing paclitaxel (Abraxane®), as an albumin-binding peptide (Victoza®), and as a glutaraldehyde-crosslinked tissue adhesive (BioGlue®). Albumin is also approved as a supportive therapy for various conditions, including hypoalbuminemia, sepsis, and acute respiratory distress syndrome (ARDS). However, no other new albumin-based systems in a hydrogel format have been used in the clinic. A review of publicly available clinical trials indicates that no new albumin drug delivery formats are currently in the clinical development pipeline. Although albumin has shown promise as a carrier of therapeutics for various diseases, including diabetes, cancers, and infectious diseases, its potential for treating blood-borne diseases such as HIV and leukemia has not been translated. This review offers a perspective on the use of albumin-based drug delivery systems for a broader range of disease applications, considering the protein properties and a review of the currently approved albumin-based technologies. This review supports ongoing efforts to advance biomedical research and clinical interventions through albumin-based delivery systems.

Glucagon-like peptide 1 receptor agonists and dual agonists have changed the treatment landscape of obesity and type 2 diabetes (T2D), but significant limitations have emerged due to their gastrointestinal side effects, loss of lean mass, and necessity for ongoing subcutaneous injections. Our objective was, therefore, to test a novel small molecule as a different and potentially better tolerated oral medications to improve obesity-associated impairment in glucose homeostasis.

High-fat diet (HFD)-fed mice or severely obese, leptin-deficient ob/ob mice were randomly assigned to serve as controls or receive oral TIX100, a novel thioredoxin-interacting protein (TXNIP) inhibitor just approved by the FDA as an investigational new drug for type 1 diabetes (T1D). The TIX100 effects on glucose intolerance and weight control were then assessed.

TIX100 protected against HFD-induced glucose intolerance, hyperinsulinemia, and hyperglucagonemia. TIX100 also reduced diet-induced adiposity resulting in 15% lower weight in treated mice as compared with controls on HFD (p <0.05), while preserving lean mass. Even though the TIX100 weight effects were lost in ob/ob mice, TIX100 improved glucose control leading to a dramatic 2.3% reduction in HbA1C (p <0.05), independent of any weight loss. This is consistent with the beneficial effects of TIX100 in non-obese diabetes models and its protection against elevated TXNIP and islet cell stress common to all diabetes types.

Thus, TIX100 may provide a novel, oral therapy for T2D that targets underlying disease pathology including islet cell dysfunction and hyperglucagonemia and promotes metabolic health and weight control without aggressive weight loss.

Background: Tirzepatide (TZP), a unimolecular dual agonist targeting glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, is a promising weight loss agent in obesity. The preservation of metabolically active fat-free mass (FFM), muscle strength (MS), and resting metabolic rate (RMR) is essential for optimizing fat mass (FM) reduction. Although TZP is typically combined with a low-calorie diet (LCD), its impact on FFM is uncertain, and studies on MS and RMR are lacking. Evidence suggests that Low-Energy Ketogenic Therapy (LEKT) may reduce FM while preserving FFM, MS, and RMR. Therefore, this study aimed to compare the effects of an LEKT and an LCD, both combined with TZP, on body weight (BW), FM, FFM, MS, and RMR in patients with obesity. Methods: We prospectively compared the effects of TZP combined with either an LCD or LEKT in 60 patients with obesity (n = 30 per group) over 12 weeks. BW, FM, FFM, MS, and RMR were measured at baseline and after 12 weeks. Clinical parameters, an assessment of dietary compliance, and side effects were also evaluated. Results: At 12-week follow-up, both groups showed a significant BW reduction from baseline (TZP+LEKT, p = 0.0289; TZP+LCD, p = 0.0278), with no significant intergroup difference (p = 0.665). Similarly, FM decreased significantly in both cohorts (TZP+LEKT, p < 0.001; TZP+LCD, p = 0.0185), with the TZP+LEKT group achieving a greater FM loss (p = 0.042). However, the TZP+LCD group exhibited significant declines from baseline in FFM (p = 0.0284), MS (p = 0.0341), and RMR (p < 0.001), whereas we did not observe any significant changes in FFM (p = 0.487), MS (p = 0.691), and RMR (p = 0.263) in the TZP+LEKT group. Intergroup direct comparisons confirmed that the TZP+LCD group experienced significantly greater reductions in FFM (p = 0.0388), MS (p = 0.046), and RMR (p = 0.019). Conclusions: Based on the findings of these preliminary data, we are able to support the hypothesis that TZP+LEKT seems to be superior to TZP+LCD in promoting FM reduction while preserving FFM, MS, and RMR in patients with obesity.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the leading causes of chronic liver disease globally. Based on the 2023 definition, MASLD is characterized by the presence of metabolic dysfunction and limited alcohol consumption (<140 grams/week for women, <210 grams/week for men). Given the significant burden of MASLD in Latin America, this guidance was developed by the Latin American Association for the Study of the Liver (ALEH) Working Group to address key aspects of its clinical assessment and therapeutic strategies. In Latin America, ultrasonography is recommended as the initial screening tool for hepatic steatosis due to its accessibility, while Fibrosis-4 (FIB-4) is preferred for fibrosis risk stratification, with further evaluation using more specific techniques (i.e., vibration-controlled transient elastography or Enhanced Liver Fibrosis [ELF] test). A Mediterranean diet is advised for all MASLD patients, with a target of 7-10% weight loss for those with excess weight. Complete alcohol abstinence is recommended for patients with significant fibrosis, and smoking cessation is encouraged regardless of fibrosis stage. Pharmacological options should be tailored based on the presence of steatohepatitis, liver fibrosis, excess weight, and diabetes, including resmetirom, incretin-based therapies, pioglitazone, and sodium-glucose cotransporter-2 inhibitors. Bariatric surgery may be considered for MASLD patients with obesity unresponsive to lifestyle and medical interventions. Hepatocellular carcinoma screening is advised for all cirrhotic patients, with consideration given to those with advanced fibrosis based on individual risk. Finally, routine cardiovascular risk assessment and proper diabetes prevention and management remain crucial for all patients with MASLD.

Glucagon-like peptide-1 (GLP-1) and glucagon (GCG) are polypeptides derived from a common precursor (preproglucagon) that modulates the activity of numerous cell types involved in regulating glucose and energy homeostasis. GLP-1 and GCG exert their biological functions via binding to specific G protein-coupled receptors (GLP-1Rs and GCGRs). Ligand-activated GLP-1Rs and GCGRs preferentially activate the heterotrimeric G protein Gs, resulting in increased cytosolic cAMP levels. However, activation of the two receptors also leads to the recruitment of β-arrestin-1 and -2 (βarr1 and βarr2, respectively) to the intracellular surface of the receptor proteins. The binding of β-arrestins to the activated receptors contributes to the termination of receptor-stimulated G protein coupling. In addition, receptor-β-arrestin complexes can act as signaling nodes in their own right by modulating the activity of many intracellular signaling pathways. In this Review, we will discuss the roles of βarr1 and βarr2 in regulating key metabolic functions mediated by activated GLP-1Rs and GCGRs. During the past decade, GLP-1R agonists have emerged as highly efficacious antidiabetic and antiobesity drugs. Moreover, dual agonists that stimulate both GLP-1Rs and GCGRs are predicted to offer additional therapeutic benefits as compared to GLP-1R agonist monotherapy. We will summarize and try to synthesize a series of studies suggesting that the development of G protein-biased GLP-1R and/or GCGR agonists, which do not lead to the recruitment of β-arrestins, may lead to even more efficacious therapeutic agents.

G protein-coupled receptors (GPCRs) form one of the largest drug target families, reflecting their involvement in numerous pathophysiological processes. In this Review, we analyse drug discovery trends for the GPCR superfamily, covering compounds, targets and indications that have reached regulatory approval or that are being investigated in clinical trials. We find that there are 516 approved drugs targeting GPCRs, making up 36% of all approved drugs. These drugs act on 121 GPCR targets, one-third of all non-sensory GPCRs. Furthermore, 337 agents targeting 133 GPCRs, including 30 novel targets, are being investigated in clinical trials. Notably, 165 of these agents are approved drugs being tested for additional indications and novel agents are increasingly allosteric modulators and biologics. Remarkably, diabetes and obesity drugs targeting GPCRs had sales of nearly US $30 billion in 2023 and the numbers of clinical trials for GPCR modulators in the metabolic diseases, oncology and immunology areas are increasing strongly. Finally, we highlight the potential of untapped target-disease associations and pathway-biased signalling. Overall, this Review provides an up-to-date reference for the drugged and potentially druggable GPCRome to inform future GPCR drug discovery and development.

Diabetes and obesity increase risk of death after lung transplantation. Optimal treatment of diabetes and obesity may improve post-transplant outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are FDA-approved to treat diabetes and obesity and demonstrate improvement in renal and cardiovascular outcomes in the general population. However, side effects may limit tolerability in lung transplant recipients. We hypothesized that GLP-1RA would be stopped due to side effects in a higher proportion of lung transplant recipients compared to the general population but result in weight loss for those who were able to tolerate them.

We performed a single-center case series of lung transplant recipients initiated on a GLP-1RA post-transplant between April 1, 2005 and December 31, 2023. We assessed side effects and complications during GLP-1RA use. Weight was assessed at time of GLP-1RA initiation and 3-, 6-, and 12-months postinitiation.

Fifty-nine lung transplant recipients initiated a GLP-1RA during the study period with a median (IQR) total time of use of 590 (280-891) days. Thirty-seven percent (22/59) stopped the medication due to side effects, with nausea and vomiting being most common. The median (IQR) percent change in weight at 12-months post-GLP-1RA initiation was -2.5% (-8.7% to 1.5%).

We report the largest study evaluating GLP-1RA use in lung transplant recipients. Discontinuation rates are higher and weight loss is lower than in the general population. However, most lung transplant recipients tolerated long-term use of GLP-1RA. Further work is required to identify which recipients are most likely to benefit and how to optimize tolerability.

Obesity pharmacotherapy represents a promising approach to treating obesity and may provide benefits beyond weight loss alone. Maintaining or even increasing muscle mass during weight loss is important to overall health, metabolic function and weight loss maintenance. Drugs such as liraglutide, semaglutide, tirzepatide, and naltrexone/bupropion have shown significant weight loss effects, and emerging evidence suggests they may also have effects on body composition, particularly a positive influence on muscle mass. However, further research is needed to fully understand the mechanism of action of these drugs and their effects on muscle mass. Clinicians should consider these factors when developing an obesity treatment plan for an individual patient.

No meta-analysis has been published comparing the efficacy and safety of tirzepatide vs once-daily basal insulins in subjects with type 2 diabetes (T2D) inadequately controlled with oral anti-hyperglycemic drugs. This meta-analysis was conducted to address this knowledge gap.

Randomized controlled trials involving subjects with T2D inadequately controlled with oral anti-hyperglycemic drugs and receiving tirzepatide in intervention arm and basal insulins in control arm as add-on therapy were searched throughout the electronic databases. The primary outcome assessed was the change from baseline in hemoglobin A1c (HbA1c).

Three randomized controlled trials involving 4339 subjects met the inclusion criteria. Compared to basal insulins, tirzepatide arms achieved greater reductions from the baseline in HbA1c (tirzepatide 5 mg: mean difference (MD) -0.89% [95% CI: -1.23, -0.54]; tirzepatide 10 mg: MD -1.11% [95% CI: -1.42, -0.79]; and tirzepatide 15 mg: MD -1.23% [95% CI: -1.48, -0.97]; P < .00001 for all). Additionally, the proportions of patients achieving HbA1c levels below 7.0%, 6.5%, and 5.7% were significantly greater in the tirzepatide groups than in the basal insulin group. Greater body weight and blood pressure reductions were observed with tirzepatide than with basal insulins. Moreover, tirzepatide had a more favorable impact on lipid profile. Hypoglycemia was less frequent with tirzepatide. Gastrointestinal adverse events (AEs) were more frequent with tirzepatide (all doses) than basal insulin, although serious AEs were comparable between the 2 groups.

Tirzepatide outperformed basal insulins in controlling blood glucose, body weight, blood pressure, and lipids in subjects with T2D and is generally well-tolerated except for its higher gastrointestinal AEs.

Tirzepatide, a long-acting, glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor agonist, reduced urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) decline in people with type 2 diabetes and high cardiovascular risk in the SURPASS-4 trial. To examine the generalizability of these findings, we assessed change from baseline in UACR for tirzepatide (5, 10, and 15 mg) compared with active and placebo treatment in a broad population from the SURPASS-1-5 trials.

This post hoc analysis examined data from the overall pooled SURPASS-1-5 population and subgroups defined by baseline UACR ≥30 mg/g. A mixed model for repeated measures was used to analyze on-treatment data from baseline to the end-of-treatment visit. Study identifier was included in the model as a covariate.

The adjusted mean percent change from baseline in UACR for tirzepatide 5, 10, or 15 mg compared with all pooled comparators was -19.3% (95% CI -25.5, -12.5), -22.0% (-28.1, -15.3), and -26.3 (-32.0, -20.0), respectively, at week 40/42. Results were similar across pooled placebo, active, and insulin comparator studies. UACR lowering appeared more pronounced in subgroups with UACR ≥30 mg/g. Mediation analysis findings suggested that approximately one-half of the reduction in albuminuria associated with tirzepatide may be weight loss related. There was no difference in eGFR between tirzepatide and pooled comparators at week 40/42.

In this post hoc analysis in people with type 2 diabetes, including those with chronic kidney disease, tirzepatide was associated with a clinically relevant decreased UACR versus comparators, suggesting a potential kidney-protective effect.

Hypertension is a frequent comorbidity of obesity that significantly and independently increases the risk of cardiovascular and renal events. Obesity-related hypertension is a major challenge to the healthcare system because of the rapid increase in obesity prevalence worldwide. However, its treatment is still not specifically addressed by current guidelines. Weight loss (WL) per se reduces blood pressure (BP) and increases patient responsiveness to BP-lowering medications. Thus, a weight-centric approach is essential for the treatment of obesity-related hypertension. Diet and physical activity are key components of lifestyle interventions for obesity-related hypertension, but, in real life, their efficacy is limited by poor long-term patient adherence and frequently require pharmacotherapy implementation to achieve target BP. In this context, first-generation anti-obesity drugs such as orlistat, phentermine/topiramate, and naltrexone/bupropion are poorly effective, whereas second-generation incretin receptor agonists, including the GLP-1 receptor agonists liraglutide and semaglutide, and in particular the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) co-agonist tirzepatide, substantially contribute to effective WL and BP control in obesity. SGLT2 inhibitors are weak body weight and BP-lowering medications, but clearly synergize the benefits of these medications. Bariatric surgery remains the gold standard treatment for severe "pathological" obesity and related life-threatening complications. Renal denervation is a valuable rescue treatment for drug-resistant hypertension, commonly related to obesity. Integrating a multifaceted weight-based approach with other strategies, such as antihypertensive drugs and renal denervation, could specifically target the main neuro-hormonal and renal pathophysiological mechanisms of obesity-related hypertension, including sympathetic-nervous and renin-angiotensin-aldosterone systems overactivity, salt retention, and volume expansion. This comprehensive strategy can provide a personalized algorithm for managing hypertension in obesity within the context of "precision medicine" principles.

GLP-1-based therapies have changed the treatment of overweight/obesity. Liraglutide 3.0 mg daily, the first GLP-1 RA approved for treatment of overweight, induced a weight loss of 6-8%, Semaglutide 2.4 mg once weekly improved weight loss to about 12-15%, while the dual GIP/GLP-1 receptor agonist tirzepatide once weekly has induced a weight loss of about 20% in obese people without diabetes.

This review describes results obtained with GLP-1 mono-agonists, GLP-1/GIP dual agonists, GLP-1/glucagon co-agonists, and the triple agonist retatrutide (GIP/GLP-1/glucagon), which have shown beneficial effect both on body weight and steatotic liver disease. A combination of semaglutide (a GLP-1 agonist) and cagrilintide (a long-acting amylin analogue) for weekly administration is currently in phase III development, and so is oral semaglutide and several non-peptide small molecule GLP-1 agonists for oral administration. The adverse events with the GLP-1-based therapies are primarily gastrointestinal and include nausea, vomiting, obstipation, or diarrhea, which often can be mitigated by slow up titration.

The GLP-1-based therapies will change the treatment of obesity and its comorbidities including steatotic liver disease in the future. Outstanding question is maintenance of the weight loss, possibly pharmacological treatment needs to be life-long.

The incidence of diabetes is growing at an alarming rate globally. Most of these projected individuals will develop type 2 diabetes (T2DM), raising their risk of cardiovascular disease and chronic kidney disease. This mini-review examines current noninsulin and noninjectable pharmacotherapy focused in T2DM, highlighting the effect on glycemic control and importance of cardiovascular and renal outcomes.

We included population level data and searched the PubMed database for recent systematic reviews, meta-analyses, and original research articles.

There is a pharmacologic menu of noninsulin-based medications for the treatment of diabetes. Through varying mechanisms, all agents ultimately lead to glycemic improvement to varying degrees. Only a select number of agents are shown to improve important clinical cardiovascular and renal outcomes. Of note, sodium-glucose cotransporter-2 inhibitors have improved cardiovascular mortality and time to dialysis in people with diabetes. Likewise, incretin-based therapies have improved important cardiovascular and renal composite outcomes in those with diabetes and cardiovascular disease. As a result, agents with proven cardiovascular and renal benefits should be prioritized based on patient risk.

Despite the availability of new medications and technology, published clinical guidelines, and treatment algorithms, most people with diabetes remain above glycemic targets. We encourage clinicians to follow the guidelines and use appropriate medications to lower cardiovascular risk, delay progression of chronic kidney disease, reach glycemic targets, and manage weight.

This review discusses findings related to neurological disorders, gut microbiota, and bariatric surgery, focusing on neurotransmitters, neuroendocrine, the pathophysiology of bacteria contributing to disorders, and possible therapeutic interventions. Research on neurotransmitters suggests that their levels are heavily influenced by gut microbiota, which may link them to neurological disorders such as Alzheimer's disease, Parkinson's disease, Multiple sclerosis, Depression, and Autism spectrum disorder. The pathophysiology of bacteria that reach and influence the central nervous system has been documented. Trends in microbiota are often observed in specific neurological disorders, with a prominence of pro-inflammatory bacteria and a reduction in anti-inflammatory types. Furthermore, bariatric surgery has been shown to alter microbiota profiles similar to those observed in neurological disorders. Therapeutic interventions, including fecal microbiota transplants and probiotics, have shown potential to alleviate neurological symptoms. We suggest a framework for future studies that integrates knowledge from diverse research areas, employs rigorous methodologies, and includes long-trial clinical control groups.

To compare the risk of primary open-angle glaucoma (POAG) and ocular hypertension in patients with obesity taking glucagon-like peptide 1 receptor agonists (GLP-1RAs) versus alternative weight loss medications.

A retrospective cohort study of the TriNetX research network was conducted by analyzing international electronic health record data from January 2004 through December 2024.

Patients without diabetes who had a diagnosis of being overweight or obesity who were treated with either GLP-1RAs or alternative weight loss medications, including orlistat, phentermine-topiramate, bupropion-naltrexone, or setmelanotide.

Patients were assessed for outcomes at 3 and 5 years. Propensity score matching (PSM) was conducted between cohorts matched for baseline demographics, comorbidities, and medication use. Risk ratios (RR) and 95% confidence intervals (CIs) were calculated subsequently.

Risk of POAG and ocular hypertension.

After PSM, both cohorts comprised 61 057 patients. The risk of both POAG and ocular hypertension were significantly lower in the GLP-1RA group at both 3 and 5 years of follow-up. A 50.4% lower risk at 3 years (RR, 0.496; 95% CI, 0.371-0.664) and a 58.5% lower risk at 5 years (RR, 0.415; 95% CI, 0.316-0.545) for POAG developing was noted. Lower risks of 55.9% at 3 years (RR, 0.441; 95% CI, 0.318-0.611) and 65.8% at 5 years (RR, 0.342; 95% CI, 0.250-0.466) for ocular hypertension developing were noted.

In patients without diabetes, the use of GLP-1RAs exhibited a significantly lower risk of POAG and ocular hypertension compared with alternative weight loss therapy at 3-year and 5-year intervals.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Glucagon-like peptide-1 (GLP-1), derived from enteroendocrine cells, is a pivotal hormone crucial for blood glucose regulation. Menin, encoded by the MEN1 gene and known for its tumor suppressor role, is abundantly expressed in the intestine. Previous research has demonstrated that acute Men1 excision reverses preexisting glucose intolerance in high-fat diet-fed mice. However, its impact on GLP-1 expression in enteroendocrine cells has not been investigated. In the present study, both the knockdown of Men1 and the administration of the MI-463 menin inhibitor increased GLP-1 expression in glucose-stimulated STC-1 cells. Additionally, administering MI-463 to obese mice significantly elevated GLP-1 levels in both ileal epithelial cells and serum. Mechanistically, menin inhibition enhanced the nuclear accumulation of β-catenin, allowing it to bind TCF7L2, thereby increasing glucagon gene (Gcg) transcription. Furthermore, compared with control mice, mice with intestinal epithelial cell-specific Men1 knockdown exhibited significant improvements in glucose tolerance under fat challenge, which was correlated with elevated GLP-1 levels. These findings suggest that menin-mediated regulation of GLP-1 expression may be an important mechanism through which menin inhibiton alleviates type 2 diabetes.

The objective of this study is to quantitatively compare the weight loss effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in adult patients with no diabetes and type 2 diabetes (T2D). PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase have been used as data sources from database inception to January 6, 2024. A total of 137 trials, encompassing 310 treatment arms, 17 GLP-1RAs, and 56,683 patients, were included in the analysis. The included trials were divided into three groups based on the characteristics of the populations: nondiabetic overweight or obesity group (NDOOG), type 2 diabetes Caucasian group (T2DCG), and type 2 diabetes Asian group (T2DAG). The effects of covariates were further evaluated, patients with a higher baseline body weight tend to have better weight loss outcomes, and patients with a higher baseline glycated hemoglobin (HbA1c) tend to achieve better blood sugar control. Five mathematical models were subjected to longitudinal analysis. In terms of Δ body weight, retatrutide (12 mg qw) was the most effective treatment (mean difference = -26.56% [95% confidence interval: -43.89% to -3.01%]). Tirzepatide (15 mg qw) demonstrated good weight loss ability in all three ΔBW models, ΔBW-NDOOG (-22.76% [-26.45% to -18.50%]), ΔBW-T2DCG (-11.09% [-12.39% to -9.44%])), and ΔBW-T2DAG (-4.97% [-5.84% to -4.12%]). In the aspect of ΔHbA1c, tirzepatide (10 mg qw) and oral orforglipron (10 mg qd) were the most effective drug, respectively. GLP-1RAs demonstrated effective weight management in both nondiabetic and T2D populations. Retatrutide achieved the most pronounced weight reduction, followed by tirzepatide. GLP-1RAs also significantly improved glycemic control for patients with T2D, with tirzepatide performing the best for glycemic control.

Animal venoms, distinguished by their unique structural features and potent bioactivities, represent a vast and relatively untapped reservoir of therapeutic molecules. However, limitations associated with comprehensively constructing and expressing highly complex venom and venom-like molecule libraries have precluded their therapeutic evaluation via high-throughput screening. Here, we developed an innovative computational approach to design a highly diverse library of animal venoms and "metavenoms". We used programmable M13 hyperphage display to preserve critical disulfide-bonded structures for highly parallelized single-round biopanning with quantitation via high-throughput DNA sequencing. Our approach led to the discovery of Kunitz-type domain containing proteins that target the human itch receptor Mas-related G-protein coupled receptor member X4, which plays a crucial role in itch perception. Deep learning-based structural homology mining identified two endogenous human homologs, tissue factor pathway inhibitor (TFPI), and serine peptidase inhibitor, Kunitz type 2 (SPINT2), which exhibit agonist-dependent potentiation of Mas-related G-protein coupled receptor member X4. Highly multiplexed screening of animal venoms and metavenoms is therefore a promising approach to uncover new drug candidates.

Oxidative stress (OS) and inflammation play essential roles in the development of diabetic nephropathy (DN). Tirzepatide (TZP) has a protective effect in diabetes. However, its underlying mechanism in DN remains unclear. DN model mice were induced by intraperitoneal injection of streptozotocin (STZ; 60 mg/kg), followed by administration of different doses of TZP (3 and 10 nmol/kg) via intraperitoneal injection for 8 weeks. The effects of TZP on DN were evaluated by detecting DN-related biochemical indicators, kidney histopathology, apoptosis, OS, and inflammation levels. Additionally, to further reveal the potential mechanism, we investigated the role of TZP in modulating the IL-17 pathway. TZP reduced serum creatinine (sCR), blood urea nitrogen (BUN), and advanced glycosylation end products (AGEs) levels, while simultaneously promoting insulin secretion in diabetic mice. Additionally, TZP attenuated tubular and glomerular injury and reduced renal apoptosis levels. Further studies found that TZP increased the levels of SOD and CAT, and decreased MDA. Meanwhile, TZP also reduced the expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in both mouse serum and kidney homogenates. TZP effectively inhibited the IL-17 pathway, and subsequent intervention with an IL-17 pathway agonist (IL-17A) reversed the suppressive effects of TZP on OS and inflammation. TZP can improve DN by inhibiting OS and inflammation through the suppression of the IL-17 pathway.

High-fat diet (HFD) currently is reported that in connection with cognitive impairment. Tirzepatide is a novel dual receptor agonist for glycemic control. But whether Tirzepatide exerts a protective effect in HFD-related cognitive impairment remains to be explore.

During the study, the cognitive dysfunction mice model induced by HFD were established. The expressions synapse-associated protein and other target proteins were detected. The oxidative stress parameters, levels of inflammatory cytokine were also detected.

Our findings proved that Tirzepatide administration attenuates high fat diet-related cognitive impairment. Tirzepatide administration suppresses microglia activation, alleviates oxidative stress as well as suppressed the expression of NLRP3 in HFD mice by up-regulating SIRT3 expression. In conclusion, Tirzepatide attenuates HFD-induced cognitive impairment through reducing oxidative stress and neuroinflammation via SIRT3-NLRP3 signaling.

This study suggest that Tirzepatide has neuroprotective effects in HFD-related cognitive dysfunction mice model, which provides a promising treatment of HFD-related cognitive impairment.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-Like peptide-1 receptor agonists (GLP-1 RA) are recommended in people with type 2 diabetes (T2D) for glycaemic control and for people with high cardiovascular risk. However, current guidelines do not specifically address the role of initial early combination therapy with SGLT2i and GLP-1 RA or dual gastric inhibitory polypeptide (GIP)/GLP-1 RA, but rather sequential initiation with either in T2D. This review synthesizes the available evidence on the use of SGLT2i and GLP-1-based therapies for T2D and provides a rationale for their combination. The combination of SGLT2i with GLP-1-based therapies addresses complementary pathophysiological mechanisms and enhances efficacy in achieving target haemoglobin A1C (HbA1c) levels. SGLT2i and GLP-1 RA also have been shown to prevent complications of T2D. While both classes reduce adverse cardiorenal events, SGLT2i has a predominant effect on prevention of kidney dysfunction and heart failure, whereas GLP-1 RA has a more marked effect on the risk of atherosclerotic cardiovascular disease. Both drug classes have favourable safety profiles. Finally, weight loss with combination therapy may have disease-modifying effects that may reverse T2D progression. We propose that the combination of SGLT2i with GLP-1 RA or dual GIP/GLP-1 RA should be considered for most patients with T2D who do not have contraindications.

The study aimed to verify the effect of Tirzepatide (Tzp, a dual agonist GIP/GLP-1) on intestinal health and microbiota balance in an obese diabetic ovariectomized (Ovx) mice model. Female C57BL/6 mice with Ovx and diet-induced obesity with diabetes were treated with Tzp (10 nmol/kg) for four weeks. Control (C) and obese-diabetic subgroups (Od) were formed (group abbreviations: O, Ovx; T, Tzp; n = 30/group): C, CT, CO, COT, Od, OdT, OdO, OdOT. The ileum was structurally and molecularly studied, and cecal feces had microbial DNA determined. Tzp improved the intestinal barrier structure and protection. Cldn12 (Claudin 12) increased, and Muc2 (Mucin 2) decreased. JamA (junctional adhesion molecules) and Ocln (Occludin) increased. Tzp mitigated macrophage activation and inflammation, altered composition, and the contribution to microbiota: Firmicutes decreased, and Bacteroidetes increased, changing the Firmicutes / Bacteroidetes ratio. Proteobacteria, Actinobacteria, Bifidobacterium, and Clostridium increased. In addition, Bacteroides, Prevotella, and Akkermansia increased. PCA indicated a significant action of Cd14, Muc2, and Tlr4 on CO and Il17 on OdO; Il10, Cd206, Cd12, Ocln, and JamA in Od. Bacteroides, Bifidobacterium, Clostridium, Actinobacteria, and Bacteroides were enhanced in CT and COT, Provotella, Proteobacteria, and Firmicutes in CO, Od, OdT, OdO, and Akkermansia in OdOT. In conclusion, the intestinal barrier function in our model is compromised by alterations in phylogenetic diversity and intestinal microbiota, which characterize dysbiosis and potentially enable the influx of toxins into other tissues. Treatment with Tzp demonstrated the ability to reverse intestinal dysbiosis, help repair intestinal barrier integrity, and mitigate possible endotoxemia through anti-inflammatory signaling pathways.