Effect of Semaglutide on Cardiac Structure and Function in Patients With Obesity-Related Heart Failure.

BACKGROUND: Obesity is associated with adverse cardiac remodeling and is a key driver for the development and progression of heart failure (HF). Once-weekly semaglutide (2.4 mg) has been shown to improve HF-related symptoms and physical limitations, body weight, and exercise function in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), but the effects of semaglutide on cardiac structure and function in this population remain unknown. OBJECTIVES: In this echocardiography substudy of the STEP-HFpEF Program, we evaluated treatment effects of once-weekly semaglutide (2.4 mg) vs placebo on cardiac structure and function. METHODS: Echocardiography at randomization and 52 weeks was performed in 491 of 1,145 participants (43%) in the STEP-HFpEF Program (pooled STEP-HFpEF [Semaglutide Treatment Effect in People with Obesity and HFpEF] and STEP-HFpEF DM [Semaglutide Treatment Effect in People with Obesity, HFpEF, and Type 2 Diabetes] trials). The prespecified primary outcome was change in left atrial (LA) volume, with changes in other echocardiography parameters evaluated as secondary outcomes. Treatment effects of semaglutide vs placebo were assessed using analysis of covariance stratified by trial and body mass index, with adjustment for baseline parameter values. RESULTS: Overall, baseline clinical and echocardiographic characteristics were balanced among those receiving semaglutide (n = 253) and placebo (n = 238). Between baseline and 52 weeks, semaglutide attenuated progression of LA remodeling (estimated mean difference [EMD] in LA volume, -6.13 mL; 95% CI: -9.85 to -2.41 mL; P = 0.0013) and right ventricular (RV) enlargement (EMD in RV end-diastolic area: -1.99 cm2; 95% CI: -3.60 to -0.38 cm2; P = 0.016; EMD in RV end-systolic area: -1.41 cm2; 95% CI: -2.42 to -0.40] cm2; P = 0.0064) compared with placebo. Semaglutide additionally improved E-wave velocity (EMD: -5.63 cm/s; 95% CI: -9.42 to -1.84 cm/s; P = 0.0037), E/A (early/late mitral inflow velocity) ratio (EMD: -0.14; 95% CI: -0.24 to -0.04; P = 0.0075), and E/e' (early mitral inflow velocity/early diastolic mitral annular velocity) average (EMD: -0.79; 95% CI: -1.60 to 0.01; P = 0.05). These associations were not modified by diabetes or atrial fibrillation status. Semaglutide did not significantly affect left ventricular dimensions, mass, or systolic function. Greater weight loss with semaglutide was associated with greater reduction in LA volume (Pinteraction = 0.033) but not with changes in E-wave velocity, E/e' average, or RV end-diastolic area. CONCLUSIONS: In the STEP-HFpEF Program echocardiography substudy, semaglutide appeared to improve adverse cardiac remodeling compared with placebo, further suggesting that treatment with semaglutide may be disease modifying among patients with obesity-related HFpEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM]; NCT04916470).

Clinical Effects of Glucagon-Like Peptide-1 Agonist Use for Weight Loss in Women With Polycystic Ovary Syndrome: A Scoping Review.

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal regulatory hormone that stimulates insulin release from the pancreas. While GLP-1 receptor agonists (GLP-1 RAs) have traditionally been utilized to address insulin resistance, their potential application in treating polycystic ovary syndrome (PCOS) has recently garnered attention. This study aimed to investigate the therapeutic efficacy of GLP-1 RAs use for weight loss in women diagnosed with PCOS. We conducted a scoping review following the Joanna Briggs Institute (JBI) methodology and adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our investigation delved into the clinical effects experienced by women of diverse racial and ethnic backgrounds with PCOS who were prescribed GLP-1 RAs for weight loss. Peer-reviewed articles from Ovid Medline, Web of Science, CINAHL, Cochrane CENTRAL, SCOPUS, and ClinicalTrials.gov spanning from 2012 to 2023 were scrutinized. After eliminating duplicates, 811 articles were identified, and ultimately, eight met the eligibility criteria for inclusion. All studies were published in English and exhibited wide geographic diversity. The included studies uniformly reported reductions in weight and body mass index (BMI) among patients who were prescribed GLP-1 RAs, specifically liraglutide or exenatide. Additionally, evidence pointed towards improvements in anthropometric parameters (MF1) (including total body weight, BMI, reduction in waist circumference, and total fat percentage), glucose homeostasis, cardiovascular inflammatory markers (midregional pro-atrial natriuretic peptide (MR-proANP) and mid-regional pro-adrenomedullin (MR-proADM)), rates of pregnancy, and menstrual regulation. However, findings regarding the impact of GLP-1 RAs on lipid profiles were inconsistent. Although some short-term adverse effects were noted, long-term effects of GLP-1 RAs use remain undetermined. GLP-1 RA use demonstrated promising clinical outcomes for women with PCOS, including reduced BMI, improved metabolic parameters, menstrual regularity, and increased rates of natural pregnancy. While the current evidence is encouraging, further research is warranted to elucidate both short- and long-term adverse effects of GLP-1 RA therapy for PCOS.

Evaluating Cardiovascular Benefits of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) in Type 2 Diabetes Mellitus: A Systematic Review.

Cardiovascular risks and complications remain elevated in patients with type 2 diabetes even after appropriate control of contributing factors like glycemic control, hypertension, and lipid profile. More efficient methods are needed to address this issue in type 2 diabetics. Newer drugs like glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown a cardioprotective effect in addition to glycemic control. This systematic review aims to study the latest literature findings on the cardiovascular effects of GLP-1 RAs in patients with type 2 diabetes. We used PubMed, Google Scholar, Science Direct, and Biomed Central databases for our data collection. Our review adheres to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The outcomes evaluated in the review include major adverse cardiovascular events (MACE), heart failure, stroke, all-cause mortality, and effects on cardiovascular risk factors. After careful inspection and quality check, we included 14 articles in the systematic review. GLP-1 RAs were associated with a significant reduction in cardiovascular mortality, all-cause mortality, nonfatal myocardial infarction (MI), and nonfatal stroke, especially in patients with existing cardiovascular risk factors. However, more evidence is required to determine if these benefits extend to those without such risk factors. Limited data suggest that GLP-1 RAs might have a protective effect on arrhythmias, but this area needs further investigation. Despite their potential, several barriers hinder the widespread use of GLP-1 RAs. In conclusion, GLP-1 RAs significantly reduce cardiovascular mortality, all-cause mortality, nonfatal MI, and stroke, with minor effects on hospitalization due to heart failure. Benefits are greater in patients with cardiovascular risk factors. A comprehensive, multilevel approach to policy development and implementation is necessary to optimize the use of these medications in eligible populations.

Too good to be true: Are GLP-1 receptor agonists the new metformin?

Recently, a health-care database study showed that persons with type 2 diabetes taking GLP-1 receptor agonists (GLP-1 RA) had a significantly lower risk of 10 out of 13 obesity-related cancers than patients taking insulin (Wang L, et al. JAMA Netw Open. 2024 7: e2421305). For some cancers, hazard ratios <0.5 were reported. This is reminiscent of studies published >10 years ago showing that people with type 2 diabetes taking metformin had a lower risk of many types of cancer than those not taking metformin. In some studies, also risk reductions of >50 % were reported. The strong effects observed in the metformin studies were explained by time-related biases, in particular, immortal time bias. In the current GLP-1 RA study, it was striking that the curves for the cumulative incidence of several cancers in GLP-1 RA and insulin users diverged immediately after therapy onset. This indicates that there is most likely a time-related bias: insulin is given at much later stages of type 2 diabetes than GLP-1 RA. The current study suggests that one should be sceptical about database results when spectacular risk reductions are reported. Time-related bias should always be considered as an alternative explanation.

A Controversy Regarding the Identity of the Enzyme That Mediates Glucagon-Like Peptide 1 Synthesis in Human Alpha Cells.

Processing of proglucagon into glucagon-like peptide-1 (GLP-1) and GLP-2 in intestinal L cells is mediated by the prohormone convertase 1/3 (PC1/3) while PC2 is responsible for the synthesis of glucagon in pancreatic alpha cells. While GLP-1 is also produced by alpha cells, the identity of the convertase involved in its synthesis is still unsettled. It also remains to be determined whether all alpha cells produce the incretin. The aims of this study were first, to elucidate the identity of the proconvertase responsible for GLP-1 production in human alpha cells, and second, to ascertain whether the number of glucagon cells expressing GLP-1 increase during diabetes. To answer these questions, sections of pancreas from donors' non-diabetic controls, type 1 and type 2 diabetes were processed for double-labelled immunostaining of glucagon and GLP-1 and of each hormone and either PC1 or PC2. Stained sections were examined by confocal microscopy. It was found that all alpha cells of islets from those three groups expressed GLP-1 and PC2 but not PC1/3. This observation supports the view that PC2 is the convertase involved in GLP-1 synthesis in all human glucagon cells and suggests that the regulation of its activity may have important clinical application in diabetes.

Frequently asked questions to the 2023 obesity medicine association position statement on compounded peptides: A call for action.

Background: In 2023, the Obesity Medicine Association (OMA) published "Compounded peptides: An Obesity Medicine Association Position Statement." Since this publication, the use of compounded peptides for the treatment of obesity has continued to evolve, leading to additional confusion and questions from obesity medicine clinicians and their patients. Methods: This frequently asked questions (FAQ) document and "Call for Action" commentary is based upon the existing evidence and practical clinical experiences of the authors. Results: This FAQ is intended to provide insights beyond the original 2023 OMA Position Statement regarding the use of "compounded peptides" for treating obesity. Three obstacles impair patient access to highly effective peptide anti-obesity medications: insufficient production especially during times of high demand, high costs, and lack of clarity surrounding the role of compounded peptides. Solutions to enhance patient access to these medications lie within the existing legal and regulatory framework and Food and Drug Administration policies. Implementing these solutions necessitates dispelling misinformation and providing clear guidance on the appropriate prescribing and administration of compounded peptides, particularly during times of acknowledged shortage. Conclusion: Among stakeholders with aligned priorities, challenges can often be overcome by collaboration and communication. Towards the goal of providing patient-centered care, the OMA calls on applicable stakeholders (e.g., pharmaceutical companies, compounding pharmacy organizations, health insurance companies, and the Food and Drug Administration) to work collaboratively to achieve a consensus that improves patient access to safe anti-obesity medications. The purpose of this "Call to Action" is to ask stakeholders to provide clinicians and their patients clarity regarding the role of compounded peptide anti-obesity medications during times of FDA-acknowledged shortages. Finally, this FAQ review provides clinicians with a simple and practical checklist respective to the potential use of compounded peptides.

Association between Glucagon-Like Peptide 1 (GLP-1) Receptor Agonists Exposure and Intraocular Pressure Change: GLP-1 Receptor Agonists and Intraocular Pressure Change.

OBJECTIVE: This study aims to provide data on the effects of glucagon-like peptide 1 receptor (GLP-1R) agonists on intraocular pressure (IOP). DESIGN: Retrospective clinical cohort study. SETTING: Multicenter. STUDY POPULATION: 1247 glaucoma surgery and treatment naïve eyes of 626 patients who were initiated on GLP-1R agonists compared to 1083 glaucoma surgery and treatment naïve eyes of 547 patients who were initiated on other oral antidiabetics. OBSERVATION PROCEDURES: The University of California Health Data Warehouse was queried for patients exposed to GLP-1R agonists or other oral antidiabetics. Index date was defined as the date of first exposure to the medication. Eyes with at least one pre-exposure and one post-exposure tonometry record within 365 days of the index date were included in the analysis. Clinical and laboratory data elements were extracted from the database. Eyes were censored from the analysis upon exposure to glaucoma hypotensive medication or glaucoma surgery. ∆IOP was analyzed using a paired t-test. Regression analysis was conducted using generalized estimating equations (GEE) accounting for inter-eye correlation. Sensitivity analyses were performed to assess the robustness of the findings. MAIN OUTCOME MEASURES: Primary outcome measure was ∆IOP after exposure to the medication. RESULTS: The median age of all included subjects was 66.2 years [IQR=18.3]; 607 (51.7%) were female, and 667 (56.9%) were Caucasian. Median pre-exposure IOP, HbA1c, and BMI were 15.2 mmHg [IQR=3.8], 7.5 [IQR=2.4], and 29.8 [IQR=9.4], respectively. 776 individuals (66.1%) had diabetes, with the median number of active oral antidiabetics being 1.0 [IQR=1.0], and 441 (37.5%) being insulin users. Several pre-exposure characteristics significantly differed between the GLP-1R agonist and the control group. The mean ∆IOP was -0.4±2.8 mmHg (paired t-test p<0.001) and -0.2±3.3 mmHg (paired t-test p = 0.297) in the GLP-1R agonist and other antidiabetics groups, respectively. Pre-exposure IOP was the only independent predictor of ΔIOP in multivariable GEE. Sensitivity analyses yielded similar results. CONCLUSIONS: Although GLP-1R agonists were significantly associated with a decrease in IOP in the paired analysis, they were not associated with ΔIOP in multivariable GEE. Moreover, the difference between the ΔIOP in the two groups was small. Future prospective studies following a standardized dose and delivery method may provide further insights.

The Antiobesity Effect and Safety of GLP-1 Receptor Agonist in Overweight/Obese Adolescents Without Diabetes Mellitus: A Systematic Review and Meta-Analysis.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly semaglutide, have become the leading anti-obesity drugs for adults, and a similar trend may follow in adolescents with its recent approval for this age group. However, there is a lack of comparative analysis on the weight loss effects and safety of GLP-1 RAs in obese or overweight pediatric and adolescent populations, especially those who are non-diabetic. This systematic review and meta-analysis aim to provide current evidence on the efficacy and safety of GLP-1 RAs as an anti-obesity treatment in obese or overweight non-diabetic pediatric and adolescent populations. METHOD:  We searched electronic databases from inception until January 2024 for randomized controlled trials (RCTs) that analyzed the weight loss effect of GLP-1 receptor agonists in adolescents with obesity or overweight without diabetes mellitus. Search results were screened, and eligible studies were included to perform a systematic review and meta-analysis using the Review Manager (RevMan) computer program Version 5.4.1 (The Cochrane Collaboration, 2020) with a random-effects model. The primary efficacy outcomes were changes in body weight, BMI, and BMI Z-score, while the secondary outcomes were the incidence of gastrointestinal adverse events, treatment discontinuation rate due to adverse events, and incidence of serious adverse events. The mean difference, odds ratio, and 95% confidence interval (CI) were used to present the meta-analysis results. Publication bias was visualized using a funnel plot. The quality of the studies was analyzed using Cochrane's Risk of Bias tool (RoB2). RESULTS: A total of seven RCTs with 576 adolescent participants were included in the analysis. GLP-1 RAs significantly achieved greater weight loss than placebo, with a mean difference of -4.98 kg (-8.49, -1.46), I² = 99%, p = 0.006. Subgroup analysis showed that semaglutide had the most pronounced anti-obesity effect (mean difference of -17.70 kg (-18.89, -16.51), p < 0.00001), compared to liraglutide (mean difference of -2.26 kg (-5.17, 0.65), I² = 99%, p = 0.13) and exenatide (mean difference of -3.17 kg (-4.45, -1.90), I² = 0%, p < 0.0001). Similar results were obtained for other efficacy parameters such as BMI and BMI z-score. However, GLP-1 RA was associated with more gastrointestinal adverse events (such as nausea and vomiting) than placebo (3.06 (2.12, 4.42), I² = 0%, p < 0.00001), with incidence comparable among all GLP-1 RAs in the subgroup analysis. The overall risk of bias among included studies was either of 'some concern' or 'high risk.' CONCLUSIONS: Our meta-analysis demonstrated that GLP-1 RAs had a superior anti-obesity effect compared to placebo or lifestyle modification in obese or overweight non-diabetic adolescents, particularly semaglutide, which had a more pronounced anti-obesity effect than liraglutide and exenatide, with tolerable gastrointestinal adverse effects.

Pharmacokinetics and safety profiles of beinaglutide injection, a recombinant human GLP-1, in adults with overweight/obesity: results from a phase I clinical trial.

Background: Beinaglutide, whose active ingredient is rhGLP-1, has been widely used as a pharmacological therapy for T2DM. We explored the safety and pharmacokinetics of beinaglutide in Chinese overweight/obese volunteers to lay a foundation for clinical applications of beinaglutide as an anti-obesity drug. Methods: An open-label, single center, multiple ascending dose phase I clinical trial was conducted in 16 overweight/obese Chinese volunteers. The plasma concentrations of beinaglutide were determined by a validated ELISA method and the pharmacokinetic parameters were estimated via non-compartmental analysis methods. Adverse events were also recorded. Results: Beinaglutide sequentially multiple dosing (three times daily) at different doses were generally well tolerated, without serious AEs leading to discontinuation of the trial. After multiple subcutaneous injections of different doses (0.1, 0.14 and 0.2 mg), the average blood concentration of beinaglutide with or without baseline correction showed a similar trend among different dose groups on different study days. After reaching the peak concentration around 15 min, it began to decrease, and the median of Tmax and Tmax,adj was 10-15 min. The exposure in vivo increased in proportion to the dosage increment, demonstrating linear pharmacokinetic characteristics. There were no statistically significant differences in the main PK parameters and no accumulation of beinaglutide after multiple dosing. After multiple subcutaneous injections, a gender difference was observed, while no differences in BMI were found under the grouping conditions. Conclusion: The safety profile and pharmacokinetic properties support further development and clinical applications of beinaglutide as an anti-obesity drug. Systematic Review Registration: [https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000BPEI&selectaction=Edit&uid=U00050YQ&ts=2&cx=wy0ioj].

GLP-1-based therapies for the treatment of resistant hypertension in individuals with overweight or obesity: a review.

Despite the availability of a wide range of antihypertensive agents, a significant proportion of individuals with resistant hypertension (RHTN) struggle to achieve blood pressure (BP) control. Obesity ranks among the most significant modifiable risk factors for RHTN, with 56-91% of patients with RHTN classified as overweight or obese. Glucagon-like peptide-1 receptor agonist (GLP-1 RAs) are a class of anti-obesity medications that have recently demonstrated efficacy in reducing BP and improving cardiovascular (CV) outcomes in individuals with overweight or obesity. Among the available GLP-1-based therapies, liraglutide, semaglutide, and tirzepatide have been approved for chronic weight management in this population. Tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist, has the greatest effect on weight loss and BP reduction compared to GLP-1 RAs alone. To our knowledge, no trials have directly evaluated the effect of GLP-1 RAs or dual GLP-1/GIP receptor agonists on RHTN management. In this review article, we propose that targeting weight loss through GLP-1-based therapies should be explored as a treatment option for individuals with RHTN who are overweight or obese.

Options for patients with out-of-control blood pressure: after all avenues have been exhausted.

INTRODUCTION: Uncontrolled hypertension is the leading risk factor for global mortality. Most hypertensive patients can be controlled with standard medication combinations, but some may not respond adequately to ≥3 or even to ≥5 antihypertensive agents. AREAS COVERED: In this review, we summarize the recent literature on difficult-to-treat hypertension identified by a Medline search, and we discuss the options for fourth line and subsequent therapy. EXPERT OPINION: It is essential to confirm resistant hypertension with out-of-office blood pressure measurements and to consider lifestyle factors, adherence to medication and secondary causes of hypertension. When true resistant hypertension is confirmed and blood pressure is not controlled with an optimal triple combination, preferably as a fixed dose combination tablet, spironolactone is usually recommended as the fourth medication. Comorbid conditions should be treated as appropriate with sodium-glucose-cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, sacubitril-valsartan or finerenone. Renal denervation appears to be a useful addition to overcome some of the problems of medication adherence. The endothelin antagonist aprocitentan may be a final option in some countries. Of the drugs in development, the RNA based therapeutics that inhibit angiotensinogen synthesis appear to be some of the most promising.

The Role of Obesity as a Cardiac Disease Risk Factor in Patients with Type 2 Diabetes.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is the leading cause of death globally and is closely associated with obesity and type 2 diabetes mellitus (T2DM). This review examines the interplay between obesity, T2DM, and CVD, highlighting the increasing prevalence and economic burden of these conditions. RECENT FINDINGS: Pharmacologic therapies, particularly glucagon-like peptide-1 receptor agonists, show promise in substantial weight loss and subsequent reduction of adverse cardiovascular events in obese individuals with and without diabetes. Obesity significantly contributes to the development of insulin resistance and T2DM, further escalating CVD risk. The common co-occurrence of these three conditions may involve several other pathophysiological mechanisms, such as chronic inflammation, increased visceral adiposity, and endothelial dysfunction. Until recently, lifestyle modifications and bariatric surgery had been the primary methods for weight loss and mitigating obesity-associated cardiovascular risk. Newer pharmacological options have led to a paradigm shift in our approach to obesity management as they provide substantial benefits in weight loss, glycemic control, and cardiovascular risk reduction.

Glucagon-like peptide-1 receptor agonists and risk of gastrointestinal cancers: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly used for glucose lowering and weight-loss. However, their association with gastrointestinal cancer remains uncertain. This meta-analysis assesses the risk of gastrointestinal cancer in patients treated with GLP-1 RAs. METHODS: We searched Medline/PubMed, Embase, and Scopus databases from inception to November 15, 2023, for randomized controlled trials (RCTs) with at least 24 weeks of safety follow-up. Pooled risk ratios (RRs) were calculated using fixed- and random-effect models. Risk of bias was assessed using the revised Cochrane risk-of-bias tool, and certainty of evidence was determined using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. RESULTS: We included 90 RCTs with 124,791 participants, with an average follow-up of 3.1 years per participant. No significant association was found between GLP-1 RAs and the risk of any gastrointestinal cancer (RRrandom=0.99, 95 % CI: 0.86-1.13), or site-specific gastrointestinal cancers including biliary tract (RR=0.98, 0.54-1.78), colorectal (RR=1.13, 0.92-1.39), gallbladder (RR=1.32, 0.43-4.00), gastric (RR=0.88, 0.58-1.33), hepatic (RR=0.79, 0.51-1.21), oesophageal (RR=0.70, 0.38-1.28), pancreatic (RR=1.05, 0.77-1.43), and small intestine cancer (RR=0.78, 0.20-3.04). The corresponding absolute risk differences excluded important impacts on risk. Additional analyses, limited to placebo-controlled trials, high-dose studies, or those with a follow-up duration of ≥5 years, confirmed these findings. Risk of bias was generally low and the certainty of evidence was high for all outcomes. CONCLUSIONS: This meta-analysis found no significant impact of GLP-1 RAs on gastrointestinal cancer risk. Long-term safety monitoring of these agents remains important. SYSTEMATIC REVIEW REGISTRATION: CRD42023476762.

Team players in the pathogenesis of metabolic dysfunctions-associated steatotic liver disease: The basis of development of pharmacotherapy.

Nutrient metabolism is regulated by several factors. Social determinants of health with or without genetics are the primary regulator of metabolism, and an unhealthy lifestyle affects all modulators and mediators, leading to the adaptation and finally to the exhaustion of cellular functions. Hepatic steatosis is defined by presence of fat in more than 5% of hepatocytes. In hepatocytes, fat is stored as triglycerides in lipid droplet. Hepatic steatosis results from a combination of multiple intracellular processes. In a healthy individual nutrient metabolism is regulated at several steps. It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component. Several hormones, peptides, and genes have been described that participate in nutrient metabolism. Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP. As of now several publications have revealed very intricate regulation of nutrient metabolism, where most of the regulatory factors are tied to each other bidirectionally, making it difficult to comprehend chronological sequence of events. Insulin hormone is the primary regulator of all nutrients' metabolism both in prandial and fasting states. Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes; metabolic, inflammation and repair, and cell growth and regeneration. Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands, adiponectin, leptin, and adiponutrin. Insulin hormone has direct effect on these final modulators. Whereas blood glucose level, serum lipids, incretin hormones, bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle. The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) that help us understand the disease natural course, risk stratification, role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine. PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states; MASLD, cardiovascular disease and cancer. More than 1000 publications including original research and review papers were reviewed.

Hesperidin activates the GLP-1R/cAMP-CREB/IRS2/PDX1 pathway to promote transdifferentiation of islet α cells into ß cells Across the spectrum.

Background and aims: In all age, FoShou as a Chinese medicinal herb has been active in various kinds of Traditional Chinese medicine formula to treating diabetes. Hesperidin (HES), the main monomeric component of FoShou, has been extensively investigated for interventions with pathogenic mechanism of diabetes as well as subsequent treatment of associated complications. Islet ß-cells have an essential effect on dynamically regulating blood sugar. Functional abnormalities in these cells and their death are strongly associated with the onset of diabetes. Therefore, induction of islet endocrine cell lineage re-editing for damaged ßcell replenishment would be a promising therapeutic tool. Previously, it has been found that HES can protect islet ß-cells in vivo, But, the regenerative function of HES in islet ß cells and its role in promoting differential non-ß cells transdifferentiation into ß cells and cell fate rewriting associated mechanisms remain unclear.This work focused on investigating whether HES can induce islet α cells transdifferentiation into ß cells for achieving damaged ß cell regeneration and the causes and possible mechanisms involved in the process. Materials and methods: In brief, 60 mg/kg/d streptozotocin (STZ) was administered intraperitoneally in each male C57bL/6J mouse raised by the high-sugar and high-fat diet (HFD) to create a diabetic mouse model with severe ß-cell damage. After 28 consecutive days of HES treatment (160 mg/kg; 320 mg/kg; once daily, as appropriate). Tracing the dynamics of α as well as ß cell transformation, together with ß cells growth and apoptosis levels during treatment by cell lineage tracing. The self-enforcing transcriptional network on which the cell lineage is based is used as a clue to explore the underlying mechanisms. Guangdong Pharmaceutical University's Animal Experiment Ethics Committee (GDPulac2019180) approved all animal experiments. Results: Localization by cell lineage we find that transdifferentiated newborn ß-cells derived from α cells appeared in the islet endocrine cell mass of DM mice under HES'action. Compared to the model group, expressed by Tunel staining and CXCL10 levels the overall apoptosis rate of ß-cells of the pancreas were reduced,the inflammatory infiltration feedback from HE staining were lower.Ki-67 positive cells showed enhanced ß-cell proliferation. Decreased HbA1c and blood glucose contents, elevated C-Peptide and insulin contents which respond to ability of nascent beta cells. Also upregulated the mRNA levels of MafA, Ngn3, PDX-1, Pax4 and Arx. Moreover, increased the expression of TGR5/cAMP-CREB/GLP-1 in mouse intestinal tissues and GLP-1/GLP-1R and cAMP-CREB/IRS2/PDX-1 in pancreatic tissues. Conclusions: HES directly affects ß-cells, apart from being anti-apoptotic and reducing inflammatory infiltration. HES promotes GLP-1 release by intestinal L cells by activating the TGR5 receptor in DM mouse and regulating its response element CREB signaling. GLP-1 then uses the GLP-1/GLP-1R system to act on IRS2, IRS2 as a port to influence α precursor cells to express PDX-1, with the mobilization of Pax4 strong expression than Arx so that α cell lineage is finally reversed for achieving ß cell endogenous proliferation.

The signalling association of glucagon-like peptide-1 and its receptors in the gastrointestinal tract and GPR40 and insulin receptor in the pancreas of sheep.

The present study was aimed at gaining insight into the signalling relationship between glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) in the regulation of glucose metabolism. Further, to assess the role of G-protein-coupled receptor 40 (GPR40) and insulin receptor (INSR) in the pancreas of sheep that were supplemented with calcium salts of long-chain fatty acids (CSFAs). An experiment was carried out over a period of 60 days with eighteen sheep, and they were fed with a standard basal diet. The sheep were divided into three groups: CSFA0 (without CSFAs), while CSFA3 and CSFA5 were supplemented with 3 % and 5 % of CSFAs, respectively. Plasma concentrations of GLP-1, insulin, glucagon, and glucose were assessed every two weeks. At the end of the experiment, sheep were slaughtered, and samples of gastrointestinal tract (GIT) epithelial tissues and pancreas were collected to assess the relative expression of mRNA of GPR40, GLP-1R, and INSR. Postprandial GLP-1 and insulin were increased by 3.7-4.1 and 1.45-1.5 times, respectively, in the CSFAs-supplemented groups compared to CSFA0. Post-feeding, glucagon and glucose levels decreased in CSFA3 and CSFA5 compared to CSFA0. The results indicated that the supplementation of LCFAs increased the expression of GLP-1R in the GIT and pancreas, as well as the mRNA of GPR40 and INSR in the pancreas. Chemosensing of LCFAs by GPR40 in the pancreas triggers signalling transduction, and enhanced GLP-1 and GLP-1R resulted in moderately increased insulin secretion and reduced glucagon levels. These combined effects, along with the glucose-lowering effect of GLP-1, effectively lowered glucose levels in normoglycemic sheep.

Association between glucagon-like peptide-1 receptor agonists and risk of suicidality: A comprehensive analysis of the global pharmacovigilance database.

AIM: To evaluate the potential association between suicidality and glucagon-like peptide-1 receptor agonists (GLP-1RAs), as well as other medications used for obesity and diabetes, using comprehensive global data. MATERIALS AND METHODS: This study utilized the World Health Organization's pharmacovigilance database, encompassing adverse drug reaction reports from 1967 to 2023, from 170 countries (total reports, N = 131 255 418). We present the reported odds ratios (RORs) with 95% confidence intervals (CIs) and information component (IC) with IC025 regarding the association between GLP-1RA use and suicidality. RESULTS: Although reports of GLP-1RA-associated suicidality increased gradually from 2005 to 2023 (n = 332), no evidence of an association was observed (ROR 0.15 [95% CI 0.13 to 0.16]; IC -2.77 [IC025 -2.95]). The lack of evidence of an association persisted regardless of whether GLP-1RAs were used for diabetes treatment (ROR 0.13 [95% CI 0.11 to 0.14]; IC -2.95 [IC025 -3.14]) or obesity treatment (ROR 0.44 [95% CI 0.34 to 0.58]; IC -1.16 [IC025 -1.62]). However, an association was found between suicidality and other diabetes medications excluding GLP-1RAs (ROR 1.13 [95% CI 1.10 to 1.15]; IC 0.17 [IC025 0.13]). Similarly, the potential association with suicidality was observed in medications used to treat obesity excluding GLP-1RAs (ROR 1.08 [95% CI 1.01 to 1.14]; IC 0.10 [IC025 0.01]). CONCLUSIONS: The suspected association between GLP-1RA use and suicidality, as raised by the European Medicines Agency, was not found in our global analysis. This indicates that the sporadic reports of GLP-1RA-associated suicidality are likely influenced by factors such as comorbidities present in the GLP-1RA user population.

[Drug therapy of type-2-diabetes-is metformin dispensable now?] / Arzneitherapie des Diabetes mellitus Typ 2 ­ ist Metformin neuerdings verzichtbar?

Metformin has been recommended as first-line pharmacological therapy in type­2 diabetes (T2D) since 1998. It was the first medication that demonstrated cardiovascular benefits in obese subjects with T2D. Efficacy and safety of metformin have since been demonstrated in further studies and in real-world data on its use in practice. The recommendation of metformin as baseline therapy has reached wide acceptance internationally. During the period 2015-2021, large cardiovascular safety trials showed superiority for cardiovascular morbidity and partly also mortality outcomes for most substances of the novel antidiabetic substance classes of GLP­1 receptor agonists and SGLT­2 inhibitors in people with T2D and very high cardiovascular risk or preexisting cardiovascular disease. The evidence for these two substance classes is now broader than for metformin. Therefore, the question arises as to whether it is still justified to recommend metformin generally as first-line therapy in T2D. This article provides an overview of the study data as well as an overview of the evidence-based guidelines. The status and position of metformin in the treatment of T2D are discussed.

The influence of insulin and incretin-based therapies on renal tubular transport.

The tubular function of the kidney is very complex and is finely regulated by many factors. These include a variety of hormonal signaling pathways which are involved in the expression, activation and regulation of renal transporters responsible for the handling of electrolytes. Glucose-lowering drugs such as insulin and incretin-based therapies, exert a well-known renal protective role in diabetic kidney disease, mainly acting at the glomerular level. In the literature, several studies have described the effect of insulin and the incretin hormones on tubular transport. Most of these studies focused on the variations in excretion and clearance of sodium but did not extensively and systematically investigate the possible variations that these hormones may induce in the tubular regulation of all the other electrolytes, urea metabolism, acid-base balance and urinary pH. While insulin action on the kidney is very well-described, the renal tubular impact of incretin-based therapies is less consistent and the results available are scarce. To our knowledge, this is the first review summarizing the effects induced on renal tubules by insulin, glucagon-like peptide-1 (GLP-1) receptor agonists and serine protease dipeptidyl peptidase-4 (DPP4) inhibitors in both healthy and diabetic human subjects. This is significant because it highlights the existence of a renal-gut and pancreas axis which also has a direct tubular effect and enables a deeper understanding of renal physiology.