Incretin Mimetics Research Articles

Risk of Esophageal and Gastric Cancer in Patients with Type 2 Diabetes Receiving Glucagon-like Peptide-1 Receptor Agonists (GLP-1 RAs): A National Analysis.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are becoming more popular in managing type 2 diabetes mellitus (T2DM). Concerns linger over potential links to malignancies like pancreatic and thyroid cancers, requiring more research to clarify their safety profiles. Additionally, evidence suggests GLP-1 RAs may lower colorectal and pancreatic cancer risk, especially in obese and overweight individuals, indicating a protective effect beyond weight loss. Current studies leave a gap in comprehensively understanding cancer risks associated with GLP-1 RAs, which prompts further research to enhance our understanding of their overall safety. We queried the US Collaborative Network (63 health care organizations) of the TriNetX research database. Patients with T2DM were identified and divided into two cohorts: patients on GLP-1 RAs and patients not on GLP-1 RAs. We excluded tobacco use and alcohol use disorders, obese patients with a body mass index (BMI) of >25 kg/m2, and those with a family history of gastrointestinal malignancy, infectious mononucleosis, chronic gastritis, pernicious anemia, helicobacter pylori infection, or gastroesophageal reflux disease (GERD). We used a 1:1 propensity score matching (PSM) model using patients' baseline characteristics, medications, labs, and genetics. We compared the rate of gastric cancer and esophageal cancer at the seven-year mark. A total of 2,748,431 patients with T2DM were identified. Of those, 6% (n = 167,077) were on a GLP-1 RA and 94% (n = 2,581,354) were not on a GLP-1 RA. After PSM, both cohorts included 146,277 patients. Patients with T2DM who were on a GLP-1 RA, compared to those who were not, had a statistically significant lower risk of both gastric cancer (0.05% vs. 0.13%, p < 0.0001) and esophageal cancer (0.04% vs. 0.13%, p < 0.0001) at the seven-year mark. The use of GLP-1 RAs in patients with T2DM does not significantly increase the risk of gastric or esophageal cancer. This finding supports the continued use of GLP-1 analogues as a therapeutic option in managing T2DM, considering their well-established benefits and low risk of complications. Based on the study results, these medications may even have a protective effect against these malignancies.

Liraglutide prevents body and fat mass gain in ovariectomized Wistar rats

Estrogens exert beneficial metabolic effects by reducing food intake and enhancing energy expenditure through both central and peripheral mechanisms. The decrease of estrogen, as occurs in ovariectomy (OVX), leads to metabolic disturbances, such as increased body weight, adipose tissue mass, basal blood glucose, and impaired glucose tolerance. These effects can be reversed by reintroducing estrogen. GLP-1 and its receptor agonists, known for their antihyperglycemic properties, also exhibit anorexigenic effects. Besides that, research indicates that GLP-1 analogs can induce metabolic changes peripherally, such as increased fatty acid oxidation and inhibited lipogenesis. Given the shared metabolic actions of GLP-1 and estrogens, we explored whether liraglutide, a GLP-1 agonist, could mitigate the metabolic effects of estrogen deficiency. We tested this hypothesis using ovariectomized rats, a model that simulates menopausal estrogen deficiency, and treated them with either liraglutide or 17β-Estradiol benzoate for 21 days. Ovariectomy resulted in elevated DPP-IV activity in both plasma and inguinal white adipose tissue (iWAT). While estrogen replacement effectively countered the DPP-IV increase in both plasma and iWAT, liraglutide only prevented the rise in iWAT DPP-IV activity. Liraglutide prevented body weight and fat mass gain after ovariectomy to the same extent as estradiol treatment. This can be explained by the lower food intake and food efficiency caused by estradiol and liraglutide. However, liraglutide was associated with increased pro-inflammatory cytokines and inflammatory cells in white adipose tissue. Further research is crucial to fully understand the potential benefits and risks of using GLP-1 receptor agonists in the context of menopause.

Chemistry Matters—From a Putative Peptide to Effective Treatments for Diabetes and Obesity

In this Viewpoint, 2024 Lasker-DeBakey Clinical Medical Research Award winner Svetlana Mojsov describes her discovery of GLP-1 (7-37), the biologically active incretin that led to development of effective GLP-1 analogues for treating diabetes and obesity.

The crucial role of beta-catenin in the osteoprotective effect of semaglutide in an ovariectomized rat model of osteoporosis.

Postmenopausal osteoporosis is a common chronic medical illness resulting from an imbalance between bone resorption and bone formation along with microarchitecture degeneration attributed to estrogen deficiency and often accompanied by other medical conditions such as weight gain, depression, and insomnia. Semaglutide (SEM) is a recently introduced GLP-1 receptor agonist (GLP-1RA) for the treatment of obesity and type 2 diabetes mellitus by mitigating insulin resistance. It has been discovered that the beneficial effects of GLP-1 are associated with alterations in lipolysis, adipogenesis, and anti-inflammatory processes. GLP-1 analogs transmit signals directly to adipose tissue. Mesenchymal stem cells (MSCs) are multidisciplinary cells that originate from bone marrow, migrate to injury sites, and promote bone regeneration. MSCs can differentiate into osteoblasts, adipose cells, and cartilage cells. Our aim is to investigate the role of semaglutide on bone formation and the Wnt signaling pathway. Osteoporosis was induced in female rats by ovariectomy, and the ovariectomized rats were treated with alendronate as standard treatment with a dose of 3mg/kg orally and semaglutide with two doses (150 mcg/kg and 300 mcg/kg) S.C. for 10 successive weeks. Semaglutide ameliorates bone detrimental changes induced by ovariectomy. It improves bone microarchitecture and preserves bone mineral content. Semaglutide ameliorates ovariectomy-induced osteoporosis and increases the expression of β-catenin, leading to increased bone formation and halted receptor activator of nuclear factor kappa-Β ligand (RANKL's) activation. Semaglutide can be used as a potential prophylactic and therapeutic drug against osteoporosis, possibly by activating Wnt signaling and decreasing bone resorption.

Preparation and characterization of BSA-loaded liraglutide and platelet fragment nanoparticle delivery system for the treatment of diabetic atherosclerosis

BackgroundDiabetic atherosclerosis is one of the main causes of morbidity and mortality worldwide, but its therapeutic options are limited. Liraglutide (LIR), a synthetic analog of GLP-1 approved as an anti-obesity drug by the FDA, has been reported as a promising drug for diabetic atherosclerosis. However, the main problem with LIR is its use that requires regular parenteral injections, which necessitates the improvement of drug delivery for increased efficiency and minimization of injection numbers.ResultsThe objective of our present study was to prepare and characterize nanoparticles (BSA@LIR-PMF) for targeted drug delivery using LIR-encapsulated platelet membrane fragments (PMF) coated bovine serum albumin (BSA). We used various methods to characterize the prepared nanoparticles and evaluated their efficiency on diabetes-induced atherosclerosis in vitro and in vivo. The results showed that the nanoparticles were spherical and had good stability and uniform size with intact membrane protein structure. The loading and encapsulation rates (LR and ER) of BSA@LIR-PMF were respectively 7.96% and 85.56%, while the cumulative release rate was around 77.06% after 24 h. Besides, we also examined the impact of BSA@LIR-PMF on the proliferation, migration, phagocytosis, reactive oxygen species (ROS) levels, oxidative phosphorylation, glycolysis, lactate and ATP levels, and lipid deposition in the aortas. The results indicated that BSA@LIR-PMF could effectively inhibit ox-LDL-stimulated abnormal cell proliferation and migration, reduce the level of ROS and lactate concentration, and enhance the level of ATP, thereby improving oxidative phosphorylation in ox-LDL-treated cells.ConclusionBSA@LIR-PMF significantly inhibited diabetes-induced atherosclerosis. It was anticipated that the BSA@LIR-PMF nanoparticles might be used for treating diabetes-associated cardiovascular complications.

Movement disorders related to antidiabetic medications: a real-world pharmacovigilance study

BackgroundDiabetic Mellitus (DM) has progressively emerged as a worldwide health problem, leading to the widespread deployment of antidiabetic drugs as the primary therapy in the global population. The incidence of diabetes medications-related movement disorders (drMD) is noteworthy but underestimated by clinical practitioners. Research design and MethodsIn order to address the incidence of drMD in DM patients and realize the serious outcomes associated with drMD, we conducted a real-world pharmacovigilance study of 612,043 DM patients using the FDA Adverse Event Reporting System (FAERS) database from January 2004 to September 2023. Reporting Odd Ratio (ROR) was calculated to reflect the risk of drMD. A multivariable logistic regression analysis was employed to adjust crude ROR with the mixed factors including age, sex and various antidiabetic treatments. Afterward, a Mendelian Randomization (MR) study was performed to elucidate the underlying genetic correlation between the genetically proxied targets of antidiabetic drugs and motor disorders. ResultsAmong 11,729 cases of motor adverse events in DM patients, six categories of drMD were significantly associated with DM medications. Noticeably, metformin was revealed to drastically increase the incidence of parkinsonism (adjusted ROR:3.97; 95 %CI (3.03, 5.19), p = 5.68e-24), bradykinesia (adjusted ROR:1.69; 95 %CI (1.07,2.59), p = 0.02) and irregular hyperkinesia, including chorea, choreoathetosis and athetosis. Insulin/insulin analogues and GLP-1 analogues presented notably higher odds of tremor: the adjusted ROR (aROR) of insulin and GLP-1 analogue is respectively 1.24 (95 %CI (1.15,1.34), p = 2.51e-08) and 1.78 (95 %CI (1.65,1.91), p = 5.64e-54). The combined therapeutic effects of multiple genetic variants of metformin, especially AMP-activated protein kinase (AMPK) were markedly linked to a greater likelihood of developing secondary parkinsonism (OR:10.816, p = 0.049) according to MR analyses. ConclusionThe use of antidiabetic medications was significantly related to an increased incidence of movement disorders in DM patients. Moreover, MR analyses provided further genetic evidence for the pharmacovigilance study. This comprehensive investigation might help physicians recognize neurological adverse events associated with antidiabetic treatments and administer effective interventions.

FRAP analysis of peptide diffusion in extracellular matrix mimetic hydrogels as an in vitro model for subcutaneous injection

Subcutaneous (SC) injection is a common route of administration for drug compounds with poor oral bioavailability. However, bioavailability is often variable and incomplete, and there is as yet no standard accepted medium for simulation of the human SC environment. In this work we evaluate a FRAP based method for quantitative determination of local self-diffusion coefficients within extracellular matrix (ECM) mimetic hydrogels, potentially useful as in vitro models for drug transport in the ECM after SC injection. Gels were made consisting of either agarose, cross-linked collagen (COL) and hyaluronic acid (HA) or cross-linked HA. The diffusivities of uncharged FITC-dextran (FD4), the highly charged poly-lysine (PLK20) and poly-glutamic acid (PLE20) as well as the GLP-1 analogue exenatide were determined within the gels using FRAP. The diffusion coefficients in uncharged agarose gels were in the range of free diffusion in PBS. The diffusivity of cationic PLK20 in gels containing anionic HA was substantially decreased due to strong electrostatic interactions. Peptide aggregation could be observed as immobile fractions in experiments with exenatide. We conclude that the FRAP method provides useful information of peptides’ interactions and transport properties in hydrogel networks, giving insight into the mechanisms affecting absorption of drug compounds after subcutaneous injection.

A comprehensive study on the identification and characterization of major degradation products of synthetic liraglutide using liquid chromatography-high resolution mass spectrometry.

Liraglutide (LGT) is a synthetic glucagon-like peptide-1 analogue mainly used for the treatment of type-2 diabetes or obesity. Comprehensive stability testing is essential in the development and routine quality control of synthetic therapeutic peptide pharmaceuticals. The GLP-1 peptide drugs are usually formulated in aqueous-base solution, which can generate stability issues during manufacturing, storage or shipment. The current study endeavors to observe the chemical stability behavior of LGT by exposing the drug substance to oxidative and hydrolytic stress conditions. A simple liquid chromatography (LC) method was developed where sufficient resolution between LGT and the generated degradation products was achieved. In total, 19 degradation products (DPs) were separated under acidic, basic and oxidative stress conditions. Using LC-HRMS, MS/MS studies, the generated degradation products were identified and characterized. The mechanistic fragmentation pathway for all generated DPs were established and the plausible chemical structure for the identified DPs was predicted based on MS/MS data. The results strongly suggest that LGT is highly susceptible to degrade under oxidative and hydrolytic conditions. Furthermore, this study provides insights into the hydrolytic and oxidative stability of LGT, which can be implied during generic and novel formulation drug development and discovery in synthesizing relatively stable GLP-1 analogues.

Oral Semaglutide in Type 2 Diabetes: Clinical-Metabolic Outcomes and Quality of Life in Real-World Practice.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a novel class of incretin mimetics for treating type 2 diabetes (T2D). This study evaluated the impact of semaglutide, the first oral GLP-1RA, on glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body composition and anthropometric parameters. Additionally, the effects on cardiovascular risk factors and quality of life (QoL) in T2D patients were assessed. Methods: A prospective observational study with a six-month follow-up was conducted. Clinical parameters, including HbA1c, FPG, anthropometric measurements, blood pressure, cardiovascular risk factors, Diabetes Treatment Satisfaction Questionnaire (DTSQ) responses, and Short Form (36) Health Survey (SF-36) responses, were collected at baseline (T0) and at six months (T1). Results: Sixty-one subjects were enrolled, with there being an average T2D duration of 4.67 ± 3.93 years. Significant decreases were observed in HbA1c (µ = -1.24; SD = 1.33; p < 0.05), FPG (µ = -31.01 mg/dL; SD = 41.71; p < 0.05), body composition and anthropometric parameters (p < 0.05), and cardiovascular risk factors (p < 0.05), with an increase in DTSQ scores (p < 0.05). Conclusions: The administration of 14 mg/day oral semaglutide improved several clinical parameters after six months of treatment. These findings suggest semaglutide is effective in improving glycemic control, weight management, and some cardiovascular risk factors in T2D patients.

Current and experimental pharmacotherapy for the management of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, with its incidence increasing in parallel with the global prevalence of obesity and type 2 diabetes mellitus. Despite our steadily increasing knowledge of its pathogenesis, there is as yet no available pharmacotherapy specifically tailored for NAFLD. To define the appropriate management, it is important to clarify the context in which the disease appears. In the case of concurrent metabolic comorbidities, NAFLD patients are treated by targeting these comorbidities, such as diabetes and obesity. Thus, GLP-1 analogs, PPAR, and SGLT2 inhibitors have recently become central to the treatment of NAFLD. In parallel, randomized trials are being conducted to explore new agents targeting known pathways involved in NAFLD progression. However, there is an imperative need to intensify the effort to design new, safe drugs with biopsy-proven efficacy. Of note, the main target of the pharmacotherapy should be directed to the regression of fibrotic NASH, as this histologic stage has been correlated with increased overall as well as liver-related morbidity and mortality. Herein we discuss the drugs currently at the forefront of NAFLD treatment.

Size-exclusion LC-UV/HRMS based method for the analysis of aggregates in synthetic GLP-1 analog liraglutide and evaluation of excipient impact on aggregation.

Peptide aggregation is one of the key challenges associated with the development of therapeutic peptides. Peptide and protein aggregates are considered as one of the most important critical quality attributes (CQA). Therapeutic liraglutide (LGT) is proteinaceous in nature, and aggregation can be triggered by various environmental stress condition. Therefore, it is essential to separate and identify aggregation states of such drugs. In this study, we have established size exclusion chromatography-liquid chromatography-ultraviolet/high resolution mass spectrometry (SEC-LC-UV/HRMS) method to separate and identify the stress induced LGT aggregates. LGT samples were subjected to photolytic, thermal, freeze thaw and shaking stress conditions. Additionally, LGT solution was incubated with surfactant and excipient that are commonly used in peptide formulation, to evaluate their impact on aggregation level and physicochemical stability over time. The developed SEC method was also validated for specificity, accuracy, precision and linearity. The results of this study will be useful for investigators to monitor LGT aggregates during product development.

Changes in glomerular filtration rate in patients with body mass index≥35kg/m2 treated with metabolic and bariatric surgery versus GLP-1 agonist at 1-year follow-up.

Metabolic and bariatric surgery (MBS) reduces glomerular hyperfiltration. The renoprotective effects of GLP-1 analogs were derived from clinical studies in type 2 diabetes (T2D). The objective of this study was to evaluate the changes in glomerular filtration rate (GFR) over time associated with weight loss in patients with a BMI ≥ 35kg/m2 treated with liraglutide compared with patients treated with MBS. A longitudinal study derived from a retrospective cohort of patients with BMI≥35kg/m2 treated with either MBS or liraglutide 3mg/day, with follow-up ≥1year. Clinical variables, baseline GFR, and 1-year GFR were analyzed. A generalized estimating equation (GEE) model was used to compare changes in GFR between both groups while controlling for confounding variables. A total of 159 patients were included in the analysis. Of these, 129 patients underwent MBS (median age 60.5years [IQR 51.8-66.6], body mass index (BMI) 40.9kg/m2 [IQR 0.68-0.89]), and 30 patients were treated with liraglutide (median age 56years [IQR 46-62], BMI 37.4kg/m2 [IQR 0.69-0.93]). No difference in baseline GFR or at 12months of follow-up was found between the two interventions. GEE analysis revealed an increase of 0.32mL/min/1.73m2 per month of follow-up. Factors associated with a greater increase in GFR were the percentage total weight loss (%TWL) (0.12mL/min/1.73m2, p=0.023) and baseline GFR (0.69mL/min/1.73m2, p>0.001) for both interventions, independent of a history of T2D. In patients with BMI≥35kg/m2, changes in GFR are related to %TWL and baseline GFR, regardless of the presence of diabetes or the type of intervention used.

Effect of New Antidiabetics on Steatosis in Nerve Tissues and Nerve Conduction Velocity: Possible Role of Nerve Growth Factor (NGF)/Synaptophysin and Nrf2/HO-1 Pathways.

The current study aims to investigate the impact of the GLP1 analog (semaglutide) and SGLT2 inhibitor (dapagliflozin) on nerve functions, morphology, and the underlying mechanisms involving nerve growth factor (NGF)/synaptophysin and Nrf2/HO-1 pathways in obese rats. Forty male Sprague Dawley rats, aged six to eight weeks, were classified into five groups; normal group (high-fat diet {HFD} for 12 weeks, metformin group (HFD for 12 weeks + metformin in last four weeks), dapagliflozin group (HFD for 12 weeks +dapagliflozin in last four weeks, semaglutide group (HFD for 12 weeks + semaglutide in last four weeks). At the end of the experiment, the sciatic nerve was collected for nerve conduction study, oxidative stress marker (malondialdehyde, i.e., MDA), real-time polymerase chain reaction (PCR) study (for HO-1 and Nrf2), oil red O staining, electron microscopic examination and immunohistochemistry for NGF and synaptophysin. The HFD group showed a significant rise in blood glucose, serum lipids, homeostatic model assessment (HOMA) index, lipid deposition in nerve tissues, and lipid peroxidation (MDA) in nerve tissues with significant attenuation in nerve conduction velocity (NCV), the expression of Nrf2 and HO-1 genes and significant attenuation in area stained with NGF and synaptophysin. On the other hand, pretreatment with either dapagliflozin or semaglutide led to considerable enhancement in the deteriorated serum and nerve tissue parameters and reversed the pathological changes. New antidiabetic drugs like SGLT2 inhibitors (more powerful) and GLP1 analog might have neuroprotective beneficial effects besides controlling the glycemic state in obese rats. This effect may result from reduced oxidative stress and increased Nrf2 levels, HO-1, synaptophysin, and NGF in the nerve tissues of obese rats.

Strategic approaches to enhance the adoption of GLP-1 analogs for diabetes and obesity treatment in India

Strategic approaches to enhance the adoption of GLP-1 analogs for diabetes and obesity treatment in India

Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain's satiety center. They also stimulate insulin secretion in pancreatic β-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.

Incretin mimetics and acute pancreatitis: enemy or innocent bystander?

The incretin enhancers and mimetics, including dipeptidyl peptidase-4 (DPP-4) inhibitors, GLP-1 receptor agonists (GLP-1RA) and GLP-1/GIP co-agonists, have become mainstays in the treatment of type 2 diabetes (T2D). Recently, the approval of certain GLP-1RA and GLP-1/GIP co-agonists for the treatment of obesity has broadened their popularity and use. In this review, we summarize the evidence for an association of these drugs with acute pancreatitis and other adverse events of special interest to gastroenterologists. In addition to pancreatic islets, GLP-1 receptors are expressed in the exocrine cells of the pancreas. There is inconsistent evidence for an association of DPP-4 inhibitors, GLP-1RA and co-agonists with risk for acute pancreatitis in individual trials. Meta-analyses of long-term randomized controlled trials indicate a small risk of acute pancreatitis associated with DPP-4 inhibitors but not GLP-1RA or co-agonists. Cholecystitis and cholelithiasis may be more common among those treated with GLP-1RA and GLP-1/GIP co-agonists. There is no evidence that any of these drugs are associated with an increased risk of pancreatic cancer. While drugs that leverage the incretin system are increasingly being used for patients with T2D and obesity, caution in warranted in those with a history of pancreatitis and gallbladder disease.

GLP-1/GIP Agonist as an Intriguing and Ultimate Remedy for Combating Alzheimer's Disease through its Supporting DPP4 Inhibitors: A Review.

Alzheimer's disease (AD) is a widespread neurological illness in the elderly, which impacted about 50 million people globally in 2020. Type 2 diabetes has been identified as a risk factor. Insulin and incretins are substances that have various impacts on neurodegenerative processes. Preclinical research has shown that GLP-1 receptor agonists decrease neuroinflammation, tau phosphorylation, amyloid deposition, synaptic function, and memory formation. Phase 2 and 3 studies are now occurring in Alzheimer's disease populations. In this article, we present a detailed assessment of the therapeutic potential of GLP-1 analogues and DPP4 inhibitors in Alzheimer's disease. This study aimed to gain insight into how GLP-1 analogues and associated antagonists of DPP4 safeguard against AD. This study uses terms from search engines, such as Scopus, PubMed, and Google Scholar, to explore the role, function, and treatment options of the GLP-1 analogue for AD. The review suggested that GLP-1 analogues may be useful for treating AD because they have been linked to anti-inflammatory, neurotrophic, and neuroprotective characteristics. Throughout this review, we discuss the underlying causes of AD and how GLP signaling functions. With a focus on AD, the molecular and pharmacological effects of a few GLP-1/GIP analogs, both synthetic and natural, as well as DPP4 inhibitors, have been mentioned, which are in the preclinical and clinical studies. This has been demonstrated to improve cognitive function in Alzheimer's patients.

Obesity and Asthma: Implementing a Treatable Trait Care Model.

Recognition of obesity as a treatable trait of asthma, impacting its development, clinical presentation and management, is gaining widespread acceptance. Obesity is a significant risk factor and disease modifier for asthma, complicating treatment. Epidemiological evidence highlights that obese asthma correlates with poorer disease control, increased severity and persistence, compromised lung function and reduced quality of life. Various mechanisms contribute to the physiological and clinical complexities observed in individuals with obesity and asthma. These encompass different immune responses, including Type IVb, where T helper 2 cells are pivotal and driven by cytokines like interleukins 4, 5, 9 and 13, and Type IVc, characterised by T helper 17 cells and Type 3 innate lymphoid cells producing interleukin 17, which recruits neutrophils. Additionally, Type V involves immune response dysregulation with significant activation of T helper 1, 2 and 17 responses. Finally, Type VI is recognised as metabolic-induced immune dysregulation associated with obesity. Body mass index (BMI) stands out as a biomarker of a treatable trait in asthma, readily identifiable and targetable, with significant implications for disease management. There exists a notable gap in treatment options for individuals with obese asthma, where asthma management guidelines lack specificity. For example, there is currently no evidence supporting the use of incretin mimetics to improve asthma outcomes in asthmatic individuals without Type 2 diabetes mellitus (T2DM). In this review, we advocate for integrating BMI into asthma care models by establishing clear target BMI goals, promoting sustainable weight loss via healthy dietary choices and physical activity and implementing regular reassessment and referral as necessary.

1858-LB: A Novel GLP-1 Analog, GZR18, Induced an 18.6% Weight Reduction in Subjects with Obesity in a Phase Ib/IIa Trial

1858-LB: A Novel GLP-1 Analog, GZR18, Induced an 18.6% Weight Reduction in Subjects with Obesity in a Phase Ib/IIa Trial

Insulin resistance and neurodegenerative diseases

Insulin resistance is a condition where normal or elevated insulin levels fail to elicit the expected biological response, with significant implications for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Despite extensive research, the precise cellular mechanisms driving insulin resistance and its role in neurodegeneration remain elusive. Insights into insulin signaling dysregulation, amyloid-beta accumulation, neuroinflammation, and impaired mitochondrial function shed light on the complex interplay between insulin resistance and neurodegeneration. Various therapeutic strategies targeting insulin resistance, including insulin interventions, GLP-1 analogs, intranasal insulin, and lifestyle interventions, offer promising avenues for mitigating disease progression. This review provides a comprehensive overview of insulin resistance and its association with neurodegenerative disorders, highlighting key molecular and cellular insights, therapeutic approaches, and future directions.