Glucagon-like Peptide-1 Receptor Research Articles

The emerging role of GLP-1 receptor agonists in treating or preventing cancer

With the growing incidence of obesity-related malignancies, glucagon-like peptide-1 (GLP-1) receptor agonists represent an intriguing potential clinical avenue for cancer prevention and treatment. Population-based data suggest that individuals who have taken GLP-1 receptor agonists have a decreased incidence of obesity-related cancers. Moreover, in vivo and in vitro studies have demonstrated the antitumor activity of these agents independent of other antineoplastic therapeutics. Additionally, other pre-clinical studies have shown that GLP-1 receptor agonists may help overcome resistance to chemotherapy-refractory cancer cells, thus demonstrating a plausible role in cancer treatment. Randomized controlled trials utilizing GLP-1 receptor agonists in both cancer prevention and treatment may allow for a better understanding of the role of these agents in modern oncology.

Cardiovascular Disease in Patients with Chronic Kidney Disease: Current Understanding, Preventative Strategies, and Future Directions.

Chronic kidney disease (CKD) presents a significant burden on global health, with cardiovascular disease (CVD) being a leading cause of mortality in this population. Despite advancements in pharmacotherapies, preventing CVD in CKD patients remains challenging due to the intricate interplay of traditional risk factors and novel pathophysiological processes. This review aims to elucidate the current understanding of CVD prevention in CKD, encompassing epidemiology, risk factors, diagnostic considerations, and pharmacological therapeutic strategies. CKD patients exhibit a unique cardiovascular risk profile characterized by traditional risk factors such as hypertension and dyslipidemia, as well as CKD-specific factors including albuminuria, vascular calcification, and valvulopathies. The utility of coronary artery calcium scoring in risk stratification and the efficacy of aspirin, lipid-lowering agents, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, and nonsteroidal mineralocorticoid receptor antagonists in CVD prevention are discussed. Despite promising findings, challenges such as lack of specific guidelines and data gaps persist, highlighting the need for multidisciplinary efforts to address the CVD burden in the CKD population effectively. Further research is warranted to optimize preventative strategies and improve outcomes in this high-risk population.

Glp1r-Lepr coexpressing neurons modulate the suppression of food intake and body weight by a GLP-1/leptin dual agonist.

Glucagon-like peptide-1 (GLP-1) and leptin signal recent feeding and long-term energy stores, respectively, and play complementary roles in the modulation of energy balance. Previous work using single-cell techniques in mice revealed the existence of a population of leptin receptor (Lepr)-containing dorsomedial hypothalamus (DMH) neurons marked by the expression of GLP-1 receptor (Glp1r; LepRGlp1r neurons) that play important roles in the control of feeding and body weight by leptin. Here, we demonstrate the existence of a population of LepRGlp1r neurons in the DMHs of nonhuman primates (NHPs), suggesting the potential translational relevance of these neurons. Consequently, we developed a GLP-1R/LepR dual agonist and demonstrated the physiological activity of both components in vivo using leptin-deficient and Lepr-deficient murine models. We further found roles for LepRGlp1r neurons in mediating the dual agonist's efficacy on food intake and body weight loss. Ablating Lepr in Glp1r-expressing neurons (LeprGlp1rKO mice) abrogated the suppression of food intake by the dual agonist. Furthermore, reactivation of Glp1r expression in Lepr neurons on an otherwise Glp1r-null background (Glp1rLeprRe mice) was sufficient to permit the suppression of food intake and body weight by the dual agonist. Hence, LepRGlp1r neurons represent targets for a GLP-1R/LepR dual agonist that potently reduces food intake and body weight.

GLP-1 Receptor Agonists Alleviate Diabetic Kidney Injury via β-Klotho-Mediated Ferroptosis Inhibition.

Semaglutide (Smg), a GLP-1 receptor agonist (GLP-1RA), shows renal protective effects in patients with diabetic kidney disease (DKD). However, the exact underlying mechanism remains elusive. This study employs transcriptome sequencing and identifies β-Klotho (KLB) as the critical target responsible for the role of Smg in kidney protection. Smg treatment alleviates diabetic kidney injury by inhibiting ferroptosis in patients, animal models, and HK-2 cells. Notably, Smg treatment significantly increases the mRNA expression of KLB through the activation of the cyclic adenosine monophosphate (cAMP) signaling pathway, specifically through the phosphorylation of protein kinase A (PKA) and cAMP-response element-binding protein (CREB). Subsequently, the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway is activated, reprograming the key metabolic processes of ferroptosis such as iron metabolism, fatty acid synthesis, and the antioxidant response against lipid peroxidation. Suppression of ferroptosis by Smg further attenuates renal inflammation and fibrosis. This work highlights the potential of GLP-1RAs and KLB targeting as promising therapeutic approaches for DKD management.

Molecular connectomics reveals a glucagon-like peptide 1-sensitive neural circuit for satiety.

Liraglutide and other glucagon-like peptide 1 receptor agonists (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons that inhibit the hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc). To identify these afferents, we developed a method combining rabies-based connectomics with single-nucleus transcriptomics. Here, we identify at least 21 afferent subtypes of AgRP neurons in the mouse mediobasal and paraventricular hypothalamus, which are predicted by our method. Among these are thyrotropin-releasing hormone (TRH)+ Arc (TRHArc) neurons, inhibitory neurons that express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TRHArc neurons inhibits AgRP neurons and feeding, probably in an AgRP neuron-dependent manner. Silencing TRHArc neurons causes overeating and weight gain and attenuates liraglutide's effect on body weight. Our results demonstrate a widely applicable method for molecular connectomics, comprehensively identify local inputs to AgRP neurons and reveal a circuit through which GLP-1RAs suppress appetite.

Glucagon-like peptide-1 receptor agonists in peri-operative care: Dispelling myths and unveiling insights with essential considerations for anaesthesiologists.

With the growing use of glucagon-like-peptide-1 (GLP-1) receptor (GLP-1R) agonists as anti-obesity medication it is becoming increasingly important to examine its consequences in the peri-operative period. GLP-1R agonists are known for their glucose-lowering and gastroparetic effects of which the latter causes some safety concerns regarding induction of anaesthesia, more specifically the risk of pulmonary aspiration. This article gathers the available evidence on this subject in addition to the already established guidelines. Current evidence makes us assume there is indeed an increased level of gastroparesis, but there are no studies to date with evidence of a presumed elevated risk of pulmonary aspiration. Future perspectives should focus on the actual risk of pulmonary aspiration and the possible implementation of ultrasound in the preoperative assessment.

GLP-1RA improves diabetic renal injury by alleviating glomerular endothelial cells pyrotosis via RXRα/circ8411/miR-23a-5p/ABCA1 pathway.

Lipotoxicity has been implicated in diabetic kidney disease (DKD). However, the role of high glucose levels in DKD and the underlying renal protective mechanisms of GLP-1 receptor agonists (GLP-1RAs) remain unclear. To investigate cholesterol accumulation, pyroptosis in glomerular endothelial cells (GEnCs), and the renal protective mechanisms of GLP-1RAs, we used various techniques, including RT-qPCR, Oil Red O staining, Western blotting, lactate dehydrogenase (LDH) activity assays, circRNA microarrays, bioinformatics analysis, gain and loss-of-function experiments, rescue experiments, and luciferase assays. Additionally, in vivo experiments were conducted using C57BL/6J and ApoE-deficient (ApoE-/-) mice. GEnCs exposed to high glucose exhibited reduced cholesterol efflux, which was accompanied by downregulation of ATP-binding cassette transporter A1 (ABCA1) expression, cholesterol accumulation, and pyroptosis. Circ8411 was identified as a regulator of ABCA1, inhibiting miR-23a-5p through its binding to the 3'UTR. Additionally, higher glucose levels decreased circ8411 expression by inhibiting RXRα. GLP-1RAs effectively reduced cholesterol accumulation and cell pyroptosis by targeting the RXRα/circ8411/miR-23a-5p/ABCA1 pathway. In diabetic ApoE-/- mice, renal structure and function were impaired, with resulted in increased cholesterol accumulation and pyroptosis; however, GLP-1RAs treatment reversed these detrimental changes. These findings suggest that the RXRα/circ8411/miR-23a-5p/ABCA1 pathway mediates the contribution of high glucose to lipotoxic renal injury. Targeting this pathway may represent a potential therapeutic strategy for patients with DKD and hypercholesterolemia. Moreover, GLP-1RAs may provide renal protective effects by activating this pathway.

Impact of DPP-4 Inhibitors in Patients with Diabetes Mellitus and Heart Failure: An In-Depth Review

The increasing prevalence of both type 2 diabetes mellitus and heart failure has underscored the urgent need for optimized therapeutic strategies that address the complex interplay between these conditions. Dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as a popular class of glucose-lowering agents due to their favorable glycemic effects, safety profile, and potential cardiovascular benefits. However, the impact of DPP-4 inhibitors on heart failure outcomes in patients with diabetes remains contentious, with conflicting evidence from clinical trials and observational studies. This review critically examines current evidence on the use of DPP-4 inhibitors in patients with coexisting diabetes and heart failure, focusing on pharmacodynamics, safety, and efficacy outcomes. We explore the physiological mechanisms by which DPP-4 inhibitors may influence heart failure risk, including modulation of inflammation, oxidative stress, and myocardial fibrosis. Clinical trials such as SAVOR-TIMI 53, EXAMINE, and TECOS are evaluated to provide a comprehensive analysis of DPP-4 inhibitors’ effects on hospitalization for heart failure, mortality, and cardiovascular events in diabetic patients. While some trials suggest an increased risk of HF hospitalizations with specific DPP-4 inhibitors (e.g., saxagliptin), others report neutral effects, raising questions about the class effects versus individual drug characteristics within this group. Additionally, we address discrepancies in outcomes related to patient demographics, HF phenotype, and comorbid conditions that may influence DPP-4 inhibitors’ risk–benefit profile. Comparative insights into alternative glucose-lowering therapies such as SGLT2 inhibitors and GLP-1 receptor agonists are also provided, highlighting potential implications for treatment selection in this high-risk population. In summary, this review synthesizes available evidence on DPP-4 inhibitors’ impact in diabetic patients with heart failure, aiming to guide clinicians in making informed therapeutic decisions. While DPP-4 inhibitors remain a viable option in diabetes management, caution is warranted in patients with advanced heart failure, and future research is essential to refine patient-specific guidelines.

GLP-1 receptor signaling restores aquaporin 4 subcellular polarization in reactive astrocytes and promotes amyloid β clearance in a mouse model of Alzheimer's disease.

The physiological actions of a gut hormone, glucagon-like peptide-1 (GLP-1), in Alzheimer's disease (AD) brain remain poorly understood, although GLP-1 receptor (GLP-1R) expression in this organ has been shown in several experimental studies. Therefore, we explored whether the GLP-1R signaling promotes the clearance of amyloid β (Aβ) (1-42) which is a core pathological hallmark of AD, focusing on the water channel protein aquaporin 4 (AQP4) localized to astrocyte endfeet perivascular membranes in intact brain. First, we confirmed that Glp1r mRNA is predominantly expressed at perivascular site of astrocytes in normal mouse cerebral cortex through in situ hybridization analysis. Next, we observed that 20-week subcutaneous administration of a GLP-1R agonist (GLP-1RA) liraglutide significantly reduced Aβ (1-42) accumulation in the cerebral cortex and improved spatial working memory in an AD mouse model, AppNL-G-F/NL-G-F mice. Furthermore, our current data revealed that the 4-week liraglutide treatment relocalized subcellular AQP4 in morphologically injured reactive astrocytes of AppNL-G-F/NL-G-F mice to the cell surface perivascular site through PKA-mediated AQP4 phosphorylation. Such translocation of phosphorylated AQP4 to astrocyte cell surface following incubation with liraglutide was observed also in the present in vitro study using the cell line in which AQP4 cDNA was introduced into immortalized human astrocyte. These results suggest that enhanced intracerebral GLP-1R signaling following peripheral administration of GLP-1RA restores AQP4 subcellular polarization in reactive astrocytes and would promote Aβ excretion possibly through increasing AQP4-mediated intracerebral water flux in the brain in AD.

Adequate sleep duration accentuates the effect of glucagon-like peptide-1 receptor variant on HbA1c: A gene-environment interaction study

BackgroundBoth glucagon-like peptide-1 receptor (GLP1R) agonists and lifestyle modifications are widely adopted in managing glycemia. However, the joint effects of GLP1R agonists with lifestyle on glycemic traits have not been evaluated. MethodsThis gene-environment study tested the interaction between GLP1R-rs10305492 variant, consistent with the effect of GLP1R agonist therapies, and four lifestyle factors (diet, physical activity, sleep duration, and chronotype) for glucose and glycated hemoglobin (HbA1c) levels among 263,846 UK Biobank participants. Linear regression models were conducted to evaluate the effects of the rs10305492 and lifestyle factors on glucose and HbA1c levels. ResultsGLP1R-rs10305492-AA/AG genotype combined a healthy diet, regular physical activity, adequate sleep duration, or morning chronotype were associated with lower glucose and HbA1c levels (all P for trend < 0.001). A synergistic effect was found between rs10305492 and sleep duration on HbA1c, suggesting a recommended adequate sleep duration (7–8 h/day) may amplify the HbA1c lowering effect of GLP1R agonists. Joint effects of the rs10305492 and adequate sleep were associated with a 26 % reduced risk of hyperglycemia (>7.8 mmol/L) risk and a 22 % lower of high HbA1c (>39 mmol/mol or 5.7 %). ConclusionsCombining GLP1R agonists with adequate sleep may provide additional benefits for glycemic control in clinical practice.

The role of glucagon-like peptides in osteosarcopenia.

Various metabolic abnormalities including obesity, insulin resistance, hypertension, dyslipidemia, hyperthyroidism, and low vitamin D levels have been linked to both osteopenia and sarcopenia. Osteo-sarcopenia is also commonly observed due to aging that notably include postmenopausal women. GLP-1, a labile incretin secreted from the intestinal L-cells stimulates insulin secretion and sensitivity, making it an effective anti-diabetic medication. GLP-1 binds to its receptor, the GLP-1 receptor, a G-protein-coupled receptor, and leads to the stimulation of adenylate cyclase, increasing the levels of cyclic AMP (cAMP). Elevated cAMP then activates protein kinase A and other downstream signaling pathways. These signaling cascades result in various cellular responses, such as enhanced insulin secretion from pancreatic beta cells, improved insulin sensitivity, and modulation of appetite and gastric emptying. Additionally, GLP-1 signaling can promote cell growth and survival, contributing to its effects on muscle and bone health. Its role as an anti-diabetic medication has been enhanced through various modifications to extend its half-life, thereby improving its effectiveness and druggability. GLP-1 analogs, initially developed for diabetes management, have also been harnessed for obesity treatment due to the effect of GLP-1 to induce satiety and slow gastric emptying. Beyond their well-known anti-diabetic and anti-obesity effects, GLP-1 agonists can enhance muscle mass and bone density, making them valuable in addressing conditions like sarcopenia and osteoporosis. This review focuses on the effects of GLP-1 analogs on musculoskeletal health, by critically assessing the underlying signaling mechanisms in order to understand their translational potential for the treatment of osteo-sarcopenia.

Kidney effects of Glucagon-Like Peptide 1 (GLP1): from molecular foundations to a pharmacophysiological perspective.

GLP1 receptor agonists (GLP1-RAs) are drugs that mimic the effects of the incretin hormone GLP1 and were initially introduced in medicine for the treatment of diabetes in 2005 and for obesity in 2014. Over time, data from secondary and exploratory objectives of large randomized controlled-trials suggested that GLP1-RAs could also exert renal action by slowing the progression of kidney disease in patients with and without diabetes. Based on this rationale, the Flow study (1 mg semaglutide vs placebo) was designed and recruitment began in 2019 until May 2021. The recently published results confirmed the effect of semaglutide in reducing the composite renal outcome. However, similar to SGLT2 inhibitors, the potential mechanisms behind the renal effects of GLP1-RAs still need to be elucidated. The aim of this review is to address the different physiological mechanisms of GLP1-RAs at the renal level, using evidence from experimental studies and current scientific literature.

Exendin-4, a glucagon-like peptide-1 receptor agonist, regulates ductus arteriosus by vasodilation and anti-remodeling through the PKA pathway

The mechanisms of ductus arteriosus (DA) closure involve vasoconstriction and vascular remodeling. Previous findings indicate that the glucagon-like peptide-1 receptor agonist (GLP-1RA) exhibits antihypertensive and anti-remodeling effects in the pulmonary circulation. However, its role in the DA remains unknown. This study aimed to investigate whether exendin-4 (Ex-4), a GLP-1RA, can regulate DA patency and elucidate its mechanisms. After confirming the presence of GLP-1R in neonatal rat DA tissue in vivo, the effects of Ex-4 on DA patency in neonatal rats were sequentially examined. Two hours after birth, we observed spontaneous closure of the DA in control rats. In contrast, Ex-4 prevented the closure of DA, accompanied by reduced intimal thickening. Ex-4 attenuated oxygen-induced vasoconstriction in isolated DA rings ex vivo. This effect was diminished in the presence of H89, a PKA inhibitor. In vitro, Ex-4 inhibited platelet-derived growth factor (PDGF)-BB-induced proliferation and migration of DA smooth muscle cells. Additionally, Ex-4 inhibited PDGF-BB-induced reactive oxygen species (ROS) production, calcium mobilization, and signal transduction of MAPK and Akt pathways. Furthermore, Ex-4 preserved the nuclear expression of Nrf2 attenuated by PDGF-BB. Similarly, all these in vitro effects of Ex-4 were blunted by H89. In conclusion, Ex-4 maintains postnatal DA patency through vasodilatation and anti-remodeling via the PKA pathway. The GLP-1R/PKA pathway emerges as a promising target of DA patency in clinical management.

GLP-1 receptor agonists in patients with chronic kidney disease and either overweight or obesity.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as game-changers across the cardiovascular-kidney-metabolic (CKM) spectrum: overweight/obesity, type 2 diabetes mellitus (T2DM) and associated chronic kidney disease (CKD) and cardiovascular disease (CVD). Liraglutide, semaglutide and tirzepatide are European Medicines Agency approved to improve metabolic control in T2DM and to decrease weight in persons with obesity [body mass index (BMI) ≥30kg/m2] or with overweight (BMI ≥27kg/m2) associated with weight-related comorbidities such as hypertension, dyslipidaemia, CVD and others. Additionally, liraglutide and semaglutide are approved to reduce CVD risk in patients with CVD and T2DM. Semaglutide is also approved to reduce CVD risk in patients with CVD and either obesity or overweight and in phase 3 clinical trials showed kidney and cardiovascular protection in patients with T2DM and albuminuric CKD (FLOW trial) as well as in persons without diabetes that had CVD and overweight/obesity (SELECT trial). Thus, nephrologists should consider prescribing GLP-1 RAs to improve metabolic control, reduce CVD risk or improve kidney outcomes in three scenarios: patients with overweight and a related comorbid condition such as hypertension, dyslipidaemia or CVD, patients with obesity and patients with T2DM. This review addresses the promising landscape of GLP-1 RAs to treat persons with overweight or obesity, with or without T2DM, within the context of CKD, assessing their safety and impact on weight, metabolic control, blood pressure and kidney and cardiovascular outcomes, as part of a holistic patient-centred approach to preserve CKM health.

Safety, pharmacokinetics and pharmacodynamics of multiple-dose noiiglutide (SHR20004), a novel GLP-1 receptor agonist, in Chinese obese subjects without diabetes mellitus.

This study aimed to assess the safety, pharmacokinetics and pharmacodynamics of noiiglutide (SHR20004), a novel glucagon-like peptide-1 receptor agonist, in Chinese obese participants without diabetes mellitus (DM). This phase 1, randomised, double-blind, placebo-controlled study enrolled adult participants with body mass index (BMI) ≥28 kg/m2. The study used a titration method, each subject received daily noiiglutide injection for 3-6 weeks, until reaching the final dose of 0.18, 0.24, 0.30 or 0.36 mg per day. Each dose group consisted of 10 participants, with eight receiving noiiglutide and two receiving placebos. Safety assessments were conducted throughout the study, and pharmacokinetics and pharmacodynamics were evaluated. Most treatment-emergent adverse events were of mild to moderate in severity, with no serious adverse event or adverse event led to withdraw. Blood concentration of noiiglutide reached a steady state after daily administration for 4 days, with no significant accumulation. Mean elimination half-life (t1/2) was between 9.90 and 11.8 h at steady state. At the end of treatment, the mean weight loss compared to baseline for the placebo group and each treatment group was -1.89, -3.26, -5.45, -4.35 and -7.46 kg respectively. The weight and BMI reductions observed in each noiiglutide treatment group were greater than those in the placebo group and exhibited an increasing trend with extended administration duration. Daily administration of noiiglutide using a titration method was well tolerated by Chinese obese participants without DM and showed potential therapeutic effect for weight loss.

ANMCO Statement: semaglutide in cardio-nephro-metabolic disorders

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

Relationship between residual gastric content and peri-operative semaglutide use assessed by gastric ultrasound: a prospective observational study.

Semaglutide is a long-acting glucagon-like peptide-1 receptor agonist known to delay gastric emptying. Despite a growing body of evidence, its peri-operative safety profile remains uncertain, particularly with regard to the risk of increased residual gastric content and aspiration of gastric contents during anaesthesia. We hypothesised that semaglutide interruption of ≤ 10 days before elective surgical procedures is insufficient to reduce or normalise the residual gastric content, despite fasting intervals that comply with current guidelines. In this prospective observational study, we recruited patients who received pre-operative once-weekly subcutaneous semaglutide within 10 days of the procedure (semaglutide group) and control patients who had not been exposed to semaglutide (non-semaglutide group). On the day of surgery, all patients underwent pre-operative point-of-care gastric ultrasound to evaluate their residual gastric content. Increased residual gastric content was defined as any solid content or > 1.5 ml.kg-1 of clear fluids as assessed by gastric ultrasound. We recruited 220 patients, 107 in the semaglutide group and 113 in the non-semaglutide group. Increased residual gastric content was found in 43/107 patients (40%) in the semaglutide group and 3/113 (3%) in the non-semaglutide group (p < 0.001). In propensity-weighted analysis, semaglutide use (OR 36.97, 95%CI 16.54-99.32), age (OR 0.95, 95%CI 0.93-0.98) and male sex (OR 2.28, 95%CI 1.29-4.06) were significantly associated with increased residual gastric content. There were no cases of pulmonary aspiration of gastric contents. Pre-operative semaglutide use within 10 days of elective surgical procedures was independently associated with increased risk of residual gastric content on pre-operative gastric ultrasound assessment.

Glucagon-like peptide-1 receptor

Michael Krashes discusses glucagon-like peptide-1 receptors, their physiological role in glucose metabolism and the mode of action of their agonists that are used to treat obesity and were later shown to promote weight loss.

Cycling alpha cells in regenerative drug-treated human pancreatic islets may serve as key beta cell progenitors.

Diabetes results from an inadequate number of insulin-producing human beta cells. There is currently no clinically available effective means to restore beta cell mass in millions of people with diabetes. Although the DYRK1A inhibitors, either alone or in combination with GLP-1 receptor agonists (GLP-1) or transforming growth factor β (TGF-β) superfamily inhibitors (LY), induce beta cell replication and increase beta cell mass, the precise mechanisms of action remain elusive. Here we perform single-cell RNA sequencing on human pancreatic islets treated with a DYRK1A inhibitor, either alone or with GLP-1 or LY. We identify cycling alpha cells as the most responsive cells to DYRK1A inhibition. Lineage trajectory analyses suggest that cycling alpha cells may serve as precursor cells that transdifferentiate into beta cells. Collectively, in addition to enhancing expression of beta cell phenotypic genes in beta cells, our findings suggest that regenerative drugs may be targeting cycling alpha cells in human islets.

Role of Incretin Mimetics in Cardiovascular Outcomes and Other Classical Cardiovascular Risk Factors beyond Obesity and Diabetes Mellitus in Nondiabetic Adults with Obesity: a Meta-analysis of Randomized Controlled Trials.

Emerging data on cardiovascular outcomes, specifically major adverse cardiovascular events (MACE), are being reported from various trials involving incretin mimetics, such as glucagon-like peptide-1 receptor agonists (GLP-1 RA) and glucose-dependent insulinotropic polypeptide (GIP), especially among patients with obesity and diabetes. Our aim was to evaluate this matter, while also involving various traditional cardiovascular risk factors [e.g., several body weight (BW) parameters, blood pressure (BP), lipid profile]. A search of PubMed, Europe PMC, ScienceDirect, Cochrane, and ClinicalTrials.gov up to September 2024 was performed to identify GLP-1 RA and GIP trials in MACE risk reduction as a primary endpoint. Our secondary endpoints included a reduction in BW, waist circumference (WC), body mass index (BMI), BP changes, and lipid modifying effects, while also yielding safety concerns surrounding the use of these pharmaceutical agents. Mean differences (MD) and risk ratios (RR) were summarized using random-effects model. A total of 11 eligible randomized controlled trials (RCTs) comprising 8 GLP-1 RA trials and 3 dual GLP-1 RA/GIP (tirzepatide) trials were included. Compared with control groups, GLP-1 RA significantly reduced the MACE risk by 32% [RR 0.68 (95% CI 0.53-0.87); P = 0.002; I2 = 73%, P-heterogeneity < 0.001] and 59% for tirzepatide [RR 0.41 (95% CI 0.18-0.92); P = 0.03; I2 = 0%, P-heterogeneity = 0.96]. Incretin mimetics also substantially reduced BW, BP, and improved lipid panel measures. However, there was an increased risk of adverse events, specifically gastrointestinal disorders within the incretin mimetics subset. Incretin mimetics have shown promise in reducing MACE risk while also enhancing cardiovascular risk factors, including blood pressure and lipid profile, in adults with obesity without diabetes.