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peptide science.

Screening for HFpEF in pacemaker patients: Study design and protocol of the PM-HFpEF study.

PLoS One

Elisabeth Santos, Rafael Teixeira, João Almeida +11 more

Heart failure with preserved ejection fraction (HFpEF) is common in older multimorbid patients and is associated with substantial morbidity and mortality. Pacemaker (PM) patients may be particularly vulnerable given the clustering of conventional HFpEF risk factors and the hemodynamic effects of long-term right ventricular pacing. Nevertheless, HFpEF is rarely systematically assessed in device clinics.

sweelin®, a novel sweet protein, does not affect blood glucose and insulin levels - a double-blind, crossover, randomized study.

Food Chem

Yael Lifshitz, Rotem Saban, Shira Paz +5 more

A novel hyper-sweet protein, sweelin®, enables sugar reduction without compromising taste. This double-blind, randomized, crossover study evaluated the effect of sweelin® on blood glucose, insulin and GLP-1 levels compared to stevia and dextrose in healthy adults. In this study, subjects consumed sweelin® (0.051 g), stevia Reb-M (0.225 g) or dextrose (75 g) in beverages matched for sweetness levels. Blood samples were collected at baseline and during 120-min post consumption. Each participant (n = 19) consumed each of the three beverages in a randomized order. At every time point after consumption, as well as iAUC, glucose and insulin levels were significantly lower following sweelin® consumption compared to dextrose (p < 0.0001), and not different from stevia. Overall, the findings indicate that sweelin®, is well tolerated and does not increase blood glucose, insulin or GLP-1 levels in healthy individuals, and suggest that sweelin® may serve as a metabolically neutral alternative for individuals seeking to reduce sugar intake. This trial was registered at clinicaltrials.gov (identifier code: NCT06520293).

Structural insights into histone mimicry by the small hepatitis delta antigen.

J Biol Chem

Haiyun Hu, Mengjiao Lv, Xiaohui Wang +11 more

Hepatitis delta virus (HDV) is a satellite RNA virus that requires hepatitis B virus (HBV) for propagation but replicates its genome independently in the nucleus. The small form of the hepatitis delta antigen (S-HDAg) is essential for replication and is regulated by post-translational modifications. Acetylation at lysine 72 (K72ac) enables S-HDAg to interact with the bromodomain (BRD) of the host chromatin remodeler bromodomain adjacent to zinc finger domain protein 2B (BAZ2B) to promote viral replication. However, the structural basis for this interaction has remained elusive. Here, we provide structural and biophysical insights into this interaction through quantitative binding assays and X-ray crystallography. Isothermal titration calorimetry revealed that BRDs of BAZ2B and its close homolog BAZ2A bind to the viral peptide weakly, with BAZ2A-BRD exhibiting a modestly higher affinity. The crystal structure of BAZ2A-BRD in complex with the S-HDAg-K72ac peptide demonstrates an inverted binding orientation relative to canonical histone ligands, rationalizing the weak interaction. Mutagenesis studies confirmed the critical binding interface both in vitro and in cells. These findings elucidate the molecular mechanism by which HDV co-opts host BAZ2 bromodomains via a unique, weak-affinity interaction, providing a structural framework for understanding viral replication.

LRBA regulates actin cytoskeleton dynamics through NMIIA during B cell immune responses.

EMBO Rep

Elena Sindram, Juan Eduardo Montero-Hernández, Quentin Frenger +16 more

Patients with lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency typically suffer from severe B cell dysfunction. However, the underlying mechanisms remain incompletely understood. In this study, we identify non-muscle myosin IIA (NMIIA) as an interaction partner of LRBA in B cells, and uncover a role for LRBA in regulating actin cytoskeleton dynamics during B cell activation. LRBA-deficient B cells exhibit abnormal migration, impaired F-actin polymerization, and reduced B cell receptor signalling and polarization upon activation. In addition, LRBA deficiency severely disrupts immune synapse formation as evidenced by diminished central SMAC formation, reduced microtubule organizing center translocation and disrupted BCR and lysosome polarization. Consistent with these defects, internalization of the BCR-antigen complex is also impaired. Mechanistically, NMIIA activation, assessed by myosin light chain (MLC) phosphorylation, is reduced in LRBA-deficient cells. In addition, LRBA co-localizes with active NMIIA during both migration and immune synapse formation. Collectively, our findings establish LRBA as an important regulator of cytoskeleton dynamics during B cell activation, which may contribute to the defective humoral immunity observed in LRBA-deficient patients.

GLP-1 agonist and neuroprotection in Stroke and Parkinson's disease: A systematic review.

Dis Mon

Drashti S Parekh, Dastan Kudaiarov, Pugazhendi Inban +3 more

Glucagon-like peptide-1 receptor agonists have been shown to have neuroprotective effects in metabolic diseases, but their application in neurodegenerative diseases (stroke and Parkinson's disease) has not been adequately studied.

Author Correction: Exercise alleviates cognitive dysfunction in Alzheimer's disease mice via skeletal muscle-derived extracellular vesicles that enhance plaque clearance by microglia.

Nat Aging

Jiaquan Lin, Xiaoyan Shao, Tianshu Shi +21 more

Cost-effectiveness of iGlarLixi vs. IDegAsp in individuals with type 2 diabetes: a BRAVO model-based evaluation.

Front Public Health

Jiali Qin, Man Tang, Xiaomei Wang +5 more

This study aimed to evaluate the long-term cost-effectiveness of insulin glargine/lixisenatide injection (iGlarLixi) vs. insulin degludec/insulin aspart (IDegAsp) in individuals with poorly controlled type 2 diabetes in China.

Restoring Satiety After GLP-1/GIP Pharmacotherapy: Metabolic Stability, Diet Quality, and the Gut Microbiota.

Int J Mol Sci

Lidia Lasik, Natalia Ukleja-Sokołowska

GLP-1 receptor agonists and dual GLP-1/GIP agonists have significantly transformed the treatment of obesity, enabling clinically meaningful weight reduction and improvements in cardiometabolic parameters. However, clinical trial data indicate that cessation of therapy is associated with biologically driven weight regain and a partial loss of metabolic benefits. This phenomenon underscores the chronic nature of obesity and the limited durability of effects achieved through pharmacotherapy alone. Nevertheless, structured clinical frameworks describing how to maintain satiety and metabolic stability after GLP-1/GIP dose reduction or discontinuation remain limited. The aim of this narrative review is to discuss the mechanisms underlying weight regain following dose reduction or discontinuation of GLP-1/GIP pharmacotherapy and to present strategies supporting long-term metabolic stabilisation. Weight regain is driven in part by persistent metabolic adaptations, including a reduction in resting energy expenditure (adaptive thermogenesis), alterations in the hunger-satiety axis (increased ghrelin, reduced leptin signalling), and potentially incomplete restoration of adipose tissue and liver-related metabolic function, although direct evidence in this specific setting remains limited. Weight loss is often accompanied by a reduction in fat-free mass, which further lowers energy expenditure and increases susceptibility to a positive energy balance after treatment cessation. It remains unclear whether pharmacological suppression of appetite results in sustained normalisation of endogenous satiety regulation after treatment cessation, and its effects on gut microbiota function remain uncertain. In clinical practice, key priorities include preserving muscle mass (adequate protein intake, resistance training), maintaining dietary nutrient density, stabilising postprandial glycaemia, and ensuring sufficient intake of fermentable fibre to support short-chain fatty acid production and gut-brain signalling. GLP-1/GIP pharmacotherapy should be viewed as a component of an integrated model of obesity treatment. We propose that long-term weight stabilisation may require a transition from pharmacologically induced satiety to satiety supported by diet quality, preserved fat-free mass, and metabolic stability. Further research is needed to define optimal post-treatment strategies and to identify patients in whom therapy can be safely reduced or discontinued. This transition should be regarded as a conceptual framework and forward-looking hypothesis requiring validation in prospective studies.

Mice lacking β-arrestin-2 in melanocortin 4 receptor-expressing neurons show marked metabolic deficits.

JCI Insight

Misbah Rashid, Lei Wang, Zhenzhong Cui +7 more

Hypothalamic melanocortin 4 receptors (MC4Rs) play a central role in regulating food intake and energy homeostasis. In fact, inactivating mutations in the MC4R gene are the most common form of monogenic obesity. Agonist activation of MC4Rs reduces food intake by modulating hypothalamic signaling circuits. Thus, a detailed understanding of the signaling pathways that regulate MC4R activity is of considerable translational relevance. Ligand-activated MC4Rs not only interact with heterotrimeric G proteins but also can recruit β-arrestin-2 (barr2) to the receptor. The potential functional role of barr2 in regulating the anorectic effects of MC4R signaling remains unexplored. In the present study, we used mutant mouse models to demonstrate MC4R-mediated activation of barr2/ERK signaling in MC4R neurons of the paraventricular nucleus leads to reduced food intake. We also found the appetite-suppressing effect of setmelanotide, an MC4R agonist FDA approved for the treatment of certain types of obesity, requires the presence of barr2 in MC4R-containing neurons. These data suggest that MC4R agonists able to promote MC4R/barr2 interactions with high efficacy may become useful as appetite-suppressing drugs.

Nucleobindin-derived peptides and stress regulation in vertebrates.

Gen Comp Endocrinol

Paalki Sethi, Atefeh Nasri, Suraj Unniappan

Stress response entails a complex array of interactions between the neuroendocrine system and physiological and behavioral effects. When a sensory stimulus is perceived as stressful, the brain triggers a response controlled by two key neuroendocrine systems: the sympathetic pathways for the "fight or flight" response, and the hypothalamus-pituitary-adrenal (HPA) axis, for a long-term stress response. Growing evidence suggests that nucleobindin (Nucb)-derived peptides nesfatin-1 and nesfatin-1-like peptide (NLP), two anorexigens and metabolic regulators, are also involved in stress regulation. Nesfatin-1 stimulates corticotropin-releasing hormone (CRH) in the hypothalamus to induce stress and satiety. Nesfatin-1 and NLP activate the stress axis, stimulating adrenocorticotropic hormone (ACTH) synthesis and modulating cortisol synthesis. Nesfatin-1 elicits stress behavior, such as anxiety and depression. Nesfatin-1 and NLP regulate both stress and metabolism, suggesting their role in interlinking these processes. This review discusses the involvement of nesfatin-1 and NLP in stress-related pathways in vertebrates, their mechanism of action, as well as existing knowledge gaps that warrant further research.

BPC-157 and Its Novel Hybrid Analogs as Inhibitors of Acetylcholinesterase.

Int J Mol Sci

Juliana Jelińska, Michalina Józwiak, Łukasz Szeleszczuk +5 more

Acetylcholinesterase (AChE) inhibition remains a key therapeutic strategy in the management of neurodegenerative disorders such as Alzheimer's disease. In this study, the inhibitory potential of the gastric pentadecapeptide BPC-157 and two newly designed hybrid analogs, CIARA-1 and CIARA-2, was investigated for the first time. The hybrid peptides were rationally designed by combining a BPC-157-derived fragment with an arginine-containing C-terminal sequence to enhance interactions with the enzyme's active and peripheral binding sites. Enzyme kinetics were evaluated using a modified Ellman assay, and inhibition parameters were determined through Lineweaver-Burk analysis. All tested compounds exhibited a competitive mechanism of inhibition, as evidenced by increased Michaelis-Menten constant (Km) values with unchanged maximum velocity (Vmax), indicating competition with the substrate at the catalytic site of AChE. Among the tested compounds, CIARA-1 demonstrated the highest inhibitory potency, reflected by the lowest inhibition constant (Ki = 0.24 mM) and IC50 value (2.52 mM), followed by CIARA-2 (Ki = 0.29 mM; IC50 = 2.73 mM) and BPC-157 (Ki = 0.48 mM; IC50 = 2.80 mM). These findings were consistent with molecular modeling predictions, supporting stronger binding interactions for CIARA-1. Despite significantly lower potency compared to clinically used AChE inhibitors, the studied peptides represent a promising scaffold for further optimization. Overall, this work demonstrates that BPC-157 and its hybrid analogs act as reversible competitive AChE inhibitors, with enhanced activity observed for structurally modified derivatives. The results highlight the potential of peptide-based hybrid molecules as multifunctional candidates in the development of novel therapeutics targeting cholinergic dysfunction.

Reparative Outcomes in Corneal Infection: Linking Adjunctive Tβ4 Treatment to Nerve Regeneration and Visual Function.

Invest Ophthalmol Vis Sci

Abdul Shukkur Ebrahim, Li Liu, Thomas W Carion +7 more

Previous studies have shown that adjunctive thymosin beta-4 (Tβ4) with ciprofloxacin reduces bacterial keratitis severity, enhances wound repair, and promotes a return to homeostasis. However, its impact on corneal nerves and visual function, two critical but often overlooked determinants of long-term outcomes, remains unexplored. The present study addresses this gap by evaluating whether adjunctive Tβ4 supports nerve regeneration and restores visual function after infection.

Inhibition of IGF1R in Early MMTV-Wnt1 Mammary Tumors: A Transcriptomic Analysis.

Cancers (Basel)

Joseph J Bulatowicz, Alexander Lemenze, Elvan Dogan +4 more

Background: The insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase whose both overexpression and underexpression have been implicated in the initiation and progression of breast tumorigenesis. The mechanism through which underexpression of the receptor contributes to a more aggressive phenotype is currently less understood. Methods: Through the expression of a dominant-negative IGF1R, we studied the phenotypic effects of receptor inhibition on early MMTV-Wnt1 mouse mammary tumors. Utilizing histopathological techniques and single-cell RNA-sequencing, we explored cellular heterogeneity and transcriptional alterations that occur as a result of IGF1R inhibition. Results: Examination of primary tumors failed to reveal obvious differences in tissue architecture or expression of differentiation markers with IGF1R inhibition. Both cohorts of tumors produced metastatic lesions in the lung. Single-cell RNA-sequencing identified previously unknown epithelial subpopulations that were present in both tumor types. In tumors with inhibited IGF1R, a previously undescribed epithelial population marked by expression of both Krt14 and Krt6a was identified, transcriptionally distinct from its MMTV-Wnt1 counterpart, and present in the smallest lung metastases. In human breast cancer patients, expression levels of KRT14 and KRT6A negatively correlated with expression of IGF1R. Conclusions: Inhibition of the IGF1R in a mouse model of basal-like breast cancer produces transcriptionally distinct Krt6a+/Krt14+ epithelial cells, which are present in the smallest metastatic lesions identified in the lung. Expression of genes associated with this population may potentially be effective biomarkers of metastatic capacity in basal-like breast tumors with low levels of IGF1R expression.

Genetic Variability in the IGF-1 Axis Modulates Cancer-Associated Cachexia and Prognosis.

Cancers (Basel)

Mariana Moreira Pires, Inês Guerra de Melo, Ana Carolina Leão Silva +7 more

Background: Cancer-associated cachexia (CAC) is a multifactorial syndrome driven by a profound metabolic and inflammatory dysregulation. Due to the central role of the insulin-like growth factor 1 (IGF-1) pathway in regulating muscle mass, energy metabolism, and inflammation, this study evaluated the relevance of five IGF-1 axis-related single-nucleotide polymorphisms (SNPs), namely IGF1 rs6220, insulin-like growth factor 1 receptor (IGF1R) rs2016347 and rs2684788, growth hormone receptor (GHR) rs6873545, and insulin receptor substrate 1 (IRS1) rs1801278. Methods: The impact of these variants on CAC onset and overall survival (OS) was assessed in a cohort of 140 cancer patients. Results: While overall-cohort analyses did not reach statistical significance, exploratory analyses suggested potential associations between the IGF1 rs6220 GG and GHR rs6873545 CC genotypes and increased CAC risk in male patients. A trend for higher CAC prevalence was also noted in younger patients (<63 years) with the rs6873545 CC genotype. For pre-CAC and CAC patients, exploratory subgroup analyses on patients' OS were conducted following no significant results in the overall cohort. Among older patients and those with high prognostic nutritional index (PNI; >44.2), the IGF1 rs6220 G allele was associated with longer OS. Conversely, the IGF1R rs2016347 G allele and rs2684788 T allele were linked to poorer OS across multiple pre-CAC and CAC subgroups. The effects of GHR rs6873545 varied across subgroups, suggesting context-dependent activity. Conclusions: This study highlights the functional heterogeneity of IGF-1 axis-related genetic variants, indicating potential to serve as predictors of CAC. Given the exploratory nature of these findings, validation in larger cohorts is required to confirm the associations found.

Primary culture and characterization of human upper limb muscle satellite cells: an experimental study.

J Yeungnam Med Sci

Young-Ju Lim, Min-Jung Ma, Wansuk Son +5 more

Human muscle satellite (stem) cells (MuSCs) are essential for investigating muscle physiology, regeneration, and disease mechanisms. Primary cultures derived directly from human tissues offer a more physiologically relevant model than immortalized cell lines. However, the isolation and characterization of MuSCs from human upper limb tissues are limited. Therefore, this study aimed to establish and characterize a primary culture system for MuSCs obtained from human upper limb muscle tissue.

Regenerative Medicine: Advanced Therapy for Muscle Tissue Restoration.

Int J Mol Sci

Roman Deev, Evgeniy Kopylov, Iurii Slepov +3 more

Skeletal muscle loss resulting from traumatic injury, sarcopenia, and myopathies remains a major clinical challenge due to the limited regenerative capacity of adult muscle tissue. This review systematically examines advanced biomedical therapeutic approaches to restoring muscle mass and function, including gene therapy, microRNA, cell-based strategies, and tissue engineering. Key mechanisms of muscle histogenesis and regeneration are discussed, with emphasis on the roles of satellite cells, growth factors (IGF-1, VEGF), and transcriptional regulators. Preclinical studies demonstrate that viral and non-viral delivery of myogenic factors can enhance muscle repair, reduce fibrosis, and improve functional outcomes. However, translation to clinical practice is hindered by challenges such as immune responses, inadequate reinnervation, and the complexity of replicating native tissue architecture. Emerging strategies combining gene delivery with rehabilitation, immunomodulation, or exosome therapy show synergistic effects. Although clinical trials targeting sarcopenia and muscle defects using anti-myostatin antibodies, stem cell-derived products, and acellular scaffolds have reported modest gains in strength and lean mass, no definitive regenerative therapy has been approved. While significant progress has been made, achieving full structural and functional muscle regeneration will require combinatorial approaches that address vascularization, innervation, and the inflammatory microenvironment.

Fibro-Adipogenic Progenitor Cell Alterations in Skeletal Muscle: Pathological Dysfunction or Adaptive Reprogramming?

Int J Mol Sci

Margarita Y Sorokina, Oksana A Ivanova, Anna A Kostareva +1 more

In skeletal muscle, there are two main progenitor populations crucial for growth, maintenance, and repair: satellite cells (SCs) and interstitial cells, of which fibro-adipogenic progenitor cells (FAPs) are the best characterized fraction. However, data on how specific diseases or physiological conditions affect the biological properties of FAPs are limited. In this review we analyze data obtained with FAPs purified from skeletal muscle tissue from Duchenne muscular dystrophy (both human patients and mdx mice models), hindlimb functional unloading (rats), and type 2 diabetes (T2DM, human patients). Here we discuss how disuse/disease affect FAP's properties: the adaptive metabolic remodeling; the alterations in adipogenic differentiation in vitro; the possible role of particular subpopulations of FAPs in disease development; the role of FAPs in cell-to-cell interactions during skeletal muscle degeneration and regeneration. Current research has outlined how different physiological and pathological conditions alter FAPs' behavior, highlighting FAPs as a potential target for clinical protocols aimed at treating or mitigating skeletal muscle disorders. Future studies should clarify how FAPs govern cell-to-cell interactions during skeletal muscle degeneration and regeneration, offering critical insights for therapies targeting diverse neuromuscular diseases.

n-3 Polyunsaturated Fatty Acids and Sarcopenia: Recent Advances and Mechanistic Research.

Nutrients

Haoran Li, Wenlong Xu, Yingjia Hu +3 more

Sarcopenia is an age-related syndrome characterized by the progressive loss of skeletal muscle mass, strength, and function, significantly impairing older adults' independence and quality of life. Given their anti-inflammatory, antioxidant, and metabolic regulatory properties, n-3 polyunsaturated fatty acids (n-3 PUFAs) have emerged as a promising nutritional strategy to mitigate this muscle degeneration. This review systematically synthesizes existing evidence regarding the association between n-3 PUFAs and sarcopenia. To capture the relevant literature, we searched PubMed, Web of Science, CNKI, and Wanfang Data using a combination of subject headings and free-text terms. We supplemented primary search terms-such as "n-3 polyunsaturated fatty acids," "omega-3 fatty acids," "sarcopenia," and "muscle mass"-with mechanism-related keywords like "inflammation," "muscle satellite cells," and "oxidative stress." We also manually screened the reference lists of the included literature. Our inclusion criteria encompassed interventional studies, observational studies, and high-quality reviews, while excluding conference abstracts, duplicate publications, and studies with incomplete data. This review first outlines the established biological mechanisms linking n-3 PUFAs to the pathological progression of sarcopenia, specifically detailing how these fatty acids improve muscle satellite cell function, suppress inflammation and oxidative stress, and ameliorate metabolic disorders. Next, we critically evaluate recent clinical studies and reviews, analyzing sources of study heterogeneity such as variations in sample size, intervention dose and duration, outcome measures, and baseline participant characteristics. We also highlight current research hotspots-including specialized pro-resolving mediators (SPMs), the gut-organ axis, combined interventions, and precision nutrition strategies-while emphasizing the functional differences between EPA and DHA to guide future intervention designs. Current evidence indicates that while n-3 PUFA supplementation can improve muscle strength and physical performance in older adults, its effects on muscle mass remain inconsistent. Addressing key research gaps, particularly the lack of standardized core outcome measures and unclear dose-response relationships, is critical. Ultimately, future research must prioritize developing high-bioavailability formulations, conducting personalized trials based on baseline n-3 PUFA status, and deepening investigations into inter-organ networks to translate these nutritional insights into effective sarcopenia prevention and management strategies.

Retrospective Comparative Study of Oral Versus Subcutaneous Semaglutide in Patients with Type 2 Diabetes Mellitus.

Int J Mol Sci

Barbara Toffoli, Matteo Michieletto, Stella Bernardi +1 more

Semaglutide represents a unique therapeutic option for patients with type 2 diabetes mellitus (T2DM), being the first and currently only glucagon-like peptide-1 receptor agonist (GLP-1RA) available in both subcutaneous and oral formulations. This study aimed to compare the effectiveness of oral versus subcutaneous (sc) semaglutide on metabolic parameters and cardiovascular risk factors in T2DM patients. This is a retrospective real-world study including adult patients with T2DM taking oral or sc semaglutide followed at the ASUGI Diabetes Center. We analyzed data from 434 patients (median age 70 years, diabetes duration 13 years), treated with oral (n = 232) or sc (n = 202) semaglutide. The oral formulation had a higher discontinuation rate. Among these patients, 130 patients in the oral group and 145 in the sc group had an 18-month follow-up. When comparing these groups, patients taking sc semaglutide had a significantly higher baseline BMI. However, multivariate linear regression models suggested that both formulations were comparably effective in reducing HbA1c and BMI, with baseline values being the primary predictors of response. To address BMI imbalances, propensity score matching was performed, identifying 55 matched pairs. Both oral and sc semaglutide reduced HbA1c and BMI and there were no significant differences in the median change in HbA1c and BMI between groups. Interestingly, oral semaglutide was associated with a significantly greater reduction in diastolic blood pressure compared to the sc formulation. Furthermore, concomitant therapy with SGLT2 inhibitors significantly enhanced the reduction in total and LDL cholesterol. Oral and subcutaneous semaglutide show comparable effectiveness in lowering HbA1c and BMI in a real-world setting.

Evaluation of the Efficacy of Semaglutide Dose Escalation in Reducing HbA1c Levels and Insulin Dose in Type 2 Diabetes Patients: Real-World Semaglutide Data from Türkiye, SEMA-TR Study.

J Clin Med

Hilmi Erdem Sumbul, Bektas Isik, Ahmet Gazi Mustan +16 more

Background: Several studies have demonstrated that adding semaglutide to the treatment of patients with type 2 diabetes mellitus (T2DM) reduces insulin requirements and glycated hemoglobin (HbA1c) levels. This study aimed to investigate real-world evidence for the effects of semaglutide dose escalation on HbA1c, body weight, dyslipidemia, and insulin dose reduction in patients with T2DM in the Cukurova region of Türkiye. Methods: This retrospective cohort study enrolled 500 patients (255 male, 245 female; mean age 56.1 ± 10.8 years) who initiated semaglutide therapy for T2DM between 2024 and 2025. Patients were grouped according to their maximum semaglutide dose: 0.25 mg (Group I), 0.50 mg (Group II), and 1.00 mg (Group III). The primary endpoint was the change in HbA1c from baseline to end of study (30 weeks) across semaglutide dose escalation groups. Secondary endpoints included changes in body weight, frequency of insulin dose reduction, and effects on lipid parameters. Results: A total of 117 patients (23.4%) discontinued semaglutide therapy, while 383 patients (76.6%) completed the study. The primary endpoint revealed a mean HbA1c reduction of -1.03 ± 0.35% from baseline to end of study (95% CI 0.99-1.07; t = 58.644; p < 0.001). Reductions in HbA1c increased progressively from Group I to Group III (HbA1c: -0.72 ± 0.28, -1.02 ± 0.26, -1.27 ± 0.34%). Insulin dose reduction frequency increased significantly from Group I to Group III (40%, 41%, and 51%, respectively; p = 0.010), with a statistically significant difference only between Group I and Group III. At the end of follow-up, rates of hypoglycemic episodes and gastrointestinal (GI) adverse events were similar across groups. Conclusions: In a real-world population from the Cukurova region of Türkiye, semaglutide dose escalation in T2DM patients achieved clinically meaningful glycemic control, body weight reduction, LDL-cholesterol lowering, and a significant increase in insulin dose reduction frequency, without a significant increase in GI adverse events.