Adiponectin may play a crucial role in the metabolic effects of GLP-1RAs treatment in patients with Type 2 Diabetes Mellitus: a preliminary longitudinal study

Adiponectin may play a crucial role in the metabolic effects of GLP-1RAs treatment in patients with Type 2 Diabetes Mellitus: a preliminary longitudinal study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Adiponectin may play a crucial role in the metabolic effects of GLP-1RAs treatment in patients with Type 2 Diabetes Mellitus: a preliminary longitudinal study Antonella Al Refaie, Leonardo Baldassini, Caterina Mondillo, Elena Ceccarelli, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4584263/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Nov, 2024 Read the published version in Endocrine → Version 1 posted 8 You are reading this latest preprint version Abstract Purpose Type 2 diabetes mellitus (T2DM) stands as the most prevalent metabolic disorder globally. T2DM entails numerous cardiovascular complications, which contribute significantly to morbidity, mortality, and increased public spending worldwide. The real challenge for new diabetes drugs lies not only in reducing blood glucose levels and glycated hemoglobin but also in preventing cardiovascular risk. Emerging receptor agonists for glucagon-like peptide-1 (GLP-1RAs) have demonstrated a pivotal role in diabetes management and mitigating cardiovascular risk. Methods We conducted a 12-month longitudinal investigation evaluating the cardio-metabolic effects of GLP-1RAs on a cohort 65 Caucasian patients diagnosed with T2DM who were scheduled for treatment with GLP-1RAs. Fifty-four T2DM patients successfully completed the 12-month study period, with 30 receiving dulaglutide and 24 receiving semaglutide. Results In our study population, GLP-1RAs resulted in several positive changes beyond the observed weight loss: a shift in fat distribution, indicated by a reduction in the percentage of visceral fat (1.21 vs 1.17, p < 0.05); a significant decrease in LDL cholesterol levels (p < 0.05) and triglycerides (p < 0.01); and a significant increase in serum adiponectin levels (p < 0.05), potentially indicating a reduction in insulin resistance and inflammation. Additionally, we observed a significant decrease in microalbuminuria and media-intimal thickness at the carotid vessel level (p < 0.05). Conclusions In patients with T2DM 1-year therapy with GLP-1RAs has a positive effect on the main determinants of cardiovascular risk including body weight, visceral fat, dyslipidemia and atherosclerosis. Moreover, the increase in adiponectin may play a pivotal role in controlling the inflammatory state and the mechanisms of vascular damage. Type 2 Diabetes Mellitus (T2DM) atherosclerosis GLP1-RAs (Dulaglutide Semaglutide) Adiponectin Lipids Body Composition Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Diabetes mellitus stands as the most prevalent metabolic disorder globally, contributing to what is now recognized as a true 'diabetes pandemic' due to its significant increase in prevalence. Type 2 diabetes mellitus (T2DM) ranks as the 8th leading cause of mortality worldwide [ 1 ], and is characterized by high rates of mortality, morbidity, and healthcare expenditure. A considerable portion of healthcare costs stems from the microvascular and macrovascular complications associated with T2DM, including coronary heart disease, stroke, peripheral arterial disease, heart failure, diabetic retinopathy, nephropathy, and neuropathy. Additionally, over two-thirds of deaths among T2DM patients result from cardiovascular complications (CVD), which often manifest at least 15 years earlier in diabetics due to accelerated atherosclerosis associated with T2DM [ 2 – 4 ] These data emphasize the fundamental significance of cardiovascular prevention; in fact, he optimal treatment for T2DM should not solely focus on lowering blood glucose levels, but also address cardiovascular risk factors.. Among the new antidiabetic drugs currently available for diabetes, receptor agonists for glucagon-like peptide-1 (GLP-1RAs) appear to be able to both reduce glycated hemoglobin levels and positively act on cardiovascular risk. GLP-1RAs, similarly to incretin hormones, stimulate insulin secretion after an oral glucose load through the incretin effect. The ability of these drugs to reduce cardiovascular risk is independent from their hypoglycemic action [ 5 ]. Many pleiotropic effects of GLP-1RAs have been recognized in vitro and in vivo [ 6 ]. In fact, there is substantial evidence supporting their involvement in arterial vasodilatation, promotion of angiogenesis and exertion of anti-inflammatory and anti-atherosclerotic effects [ 7 , 8 ]. Recent studies have reported that GLP-1RAs drugs are able to determine a reduction in body weight, waist circumference and, probably, also visceral fat [ 9 ]. Furthermore, some studies, though not all, have found that diabetic patients treated with GLP-1RAs exhibit increased levels of adiponectin, a hormone secreted by adipose tissue that has antiatherogenic and anti-inflammatory properties [ 10 ]. However, the molecular mechanism underlying the elevation in circulating adiponectin are yet to be elucidated [ 10 , 11 ]. Instead, the effects of GLP-1RAs on the levels of myostatin, the most important cytokine produced by muscle tissue, have not yet been defined [ 12 ]. The aim of this longitudinal study carried out in a cohort of T2DM patients was to evaluate the effects of 1-year treatment with GLP-1RAs on some of the major determinants of CVD risk and on adiponectin and myostatin serum levels. Materials and Methods Patients For this research, we recruited both male and female patients diagnosed with T2DM who were referred to the Diabetology and Metabolic Diseases Unit of the Department of Internal Medicine at the University Hospital of Siena (Italy) for whom the diabetologist had planned to start treatment with GLP-1RAs. Between May 2022 and December 2022, a total of 80 consecutive T2DM patients commenced therapy with GLP-1RAs (either dulaglutide or semaglutide) and were evaluated for the study. Following the inclusion/exclusion criteria, 65 T2DM patients (30 men and 35 women) were enrolled in this 12-month study, with 36 receiving a prescription for dulaglutide and 29 for semaglutide. The inclusion criteria were as follows: patients initiating therapy with GLP-1RAs for the first time, aged between 50 and 80 years, with HbA1c levels greater than 6.5% and less than 10%. Patients with T2DM who had previously received GLP-1RA therapy or were currently receiving insulin, thiazolidinediones, SGLT2 inhibitors, or acarbose were excluded. All patients underwent comprehensive clinical, laboratory, and instrumental assessments prior to initiating therapy and again after 12 months. Specifically, a thorough medical history was obtained, and all patients underwent measurements of weight and height. Furthermore, body mass index (BMI), calculated as the ratio of weight in kilograms to the square of height in meters, was determined for each patient. Vital parameters, such as systolic (SBP) and diastolic (DBP) blood pressure and heart rate, were also evaluated. The maintenance doses for dulaglutide (1.5-3.0 mg weekly) and semaglutide (1.0–2.0 mg weekly) were achieved after an 8–12 week dose escalation period as per the instructions provided in the leaflet. The flow chart of the T2DM patients involved in the study is shown in Fig. 1 . An informed written consent was obtained from all participants, and the research protocol received approval from the Institutional Review Board of Siena University Hospital (ID-21211/21). Prior to statistical analysis, all collected data underwent anonymization procedure. Biochemical parameter After fasting for at least 12 hours, patients underwent blood sampling for the evaluation of plasma glucose (FPG), glycated hemoglobin (HbA1c), creatinine, microalbuminuria, transaminases, total cholesterol (TOT-C), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein cholesterol-cholesterol (LDL-C), triglycerides (TG), adiponectin and myostatin. All samples were stored at -80°C while awaiting analysis, and then they were batched and measured in one assay. HbA1c was measured by a turbidimetric inhibition immunoassay (Siemens Healthcare Diagnostics, Newark, USA). All lipid parameters (TOT-C, HDL-C, LDL-C and TG) and FPG were measured using a colorimetric method (Autoanalyzer Menarini, Florence, Italy). In our institution the intra- and inter-assay coefficients of variation were, respectively, 1.8 and 3.8% for TOT-C, 2.0 and 3.0% for HDL-C, 1.5% and 2.3% for LDL-C assessment and 1.7 and 2.9% for TG. Adiponectin was measured by a commercially available radioimmunoassay (Adiponectin Human RIA kit; DRG International, Mountainside, NJ), which measures multiple forms of adiponectin (trimer, hexamer, and high–molecular weight forms). The results were expressed in micrograms per milliliter; the intra- and interassay coefficients of variation were 3.8% and 8.4%, respectively, at concentrations between 3 and 15 microg/mL. Serum myostatin was determined by an ELISA method (Human Myostatin, Elisa Kit, My BioSource, San Diego, CA,). In our institution the intra- and inter-assay coefficients of variation were 5% and 8%, respectively. Body Composition Assessment Body composition parameters were determined using a dual-energy X-ray absorptiometry device (Lunar Prodigy; GE Healthcare, Waukesah, WI) in conjunction with Encore 2002 software. All scans were performed by the same operator while the subjects were wearing light indoor clothing and no removable metal objects. Among the body composition parameters we considered total fat mass (absolute value and percentage) and total lean mass (absolute value and percentage). We also obtained information about the distribution of fat, so the percentage of android fat, gynoid fat and the ratio between android and gynoid fat. The “android region” has a lower boundary at the pelvis cut and the upper boundary above the pelvis cut by 20% of the distance between the pelvis and the neck cuts. The lateral boundaries are the arm cuts. The “gynoid region” has an upper boundary Body Fat between the upper part of the greater trochanters and a lower boundary defined at a distance equal to twice the height of the android region. The lateral boundaries are outer leg cuts. Carotid atherosclerosis evaluation All subjects underwent ultrasonographic examination of the epiaortic vessels, carried out by a single operator unaware of the study protocol by using a MEGAS device (Esaote) with a 7.5 MHz B-mode linear probe. All examinations were carried out in a quiet, dark, and temperature-controlled room. The participants lay in the supine position on a scan bed with their necks slightly extended, and heads rotated contralaterally to the side evaluated. From the ultrasonographic examination we obtained the media-intimal thickness (IMT), obtained from the distance between the hyperechogenic line due to the blood-intima interface, and the hyperechogenic line due to the media-adventitia interface. Using the dilation of the bulb and the flow divider as anatomical references, the IMT was evaluated in an area free of plaque in the three standardized carotid segments: the distal 1-cm of the common carotid artery, the carotid bifurcation, and the proximal 1-cm of the internal carotid artery [ 13 ]. A statistical evaluation was performed on the calculated average of the left and right carotid artery IMT measurements. A plaque was defined as the presence of focal wall thickening that is at least 50% greater than the surrounding or as a focal region with carotid IMT greater than 1.5 mm that protrudes into the lumen. Atherosclerosis was defined as IMT value greater than 1 mm or the presence of plaque [ 13 ]. Statistical analysis All values were expressed as mean ± SD. The Kolmogorov–Smirnov test was used to verify the normality of the distribution of the outcome variables. For all parameters the absolute changes over time for each patient were expressed as a percentage of the baseline values. Paired t-test and Wilcoxon matched-pairs signed-ranks test were used, where appropriate, to compare the changes with baseline values. Student's t-test and Mann–Whitney U-test were used to compare the differences between patient groups. All tests were done two-sided, and p < 0.05 was considered statistically significant. All tests were performed using the SPSS statistical package for Windows version 16.0 (SPSS Inc., Chicago) . Results The demographic, clinical, and laboratory characteristics of the study population at baseline and after 12 months of therapy with GLP-1RAs receptor agonists are reported in Table 1 . Twenty-six males and twenty-eight females, totaling fifty-four T2DM patients, concluded the 12-month study duration. Among them, thirty had received treatment with dulaglutide, while twenty-four had been administered semaglutide. As expected, after 12 months of therapy with GLP-1RAs, we observed a significant reduction in fasting plasma glucose values (p < 0.01), glycated hemoglobin (p < 0.05) and also in microalbuminuria values (p < 0.05). Furthermore, a significant (p < 0.01) decrease in body weight (from 84.4 to 80.2 Kg) and BMI (from 30.2 to 28.6 Kg/m2) was observed. The percentage of patients with BMI values indicative of obesity and overweight was significantly higher at baseline compared to the control after 12 months (43.3% vs 37.1% and 46.7% vs 35.2%, respectively, p < 0.05) (data not shown). In Table 1 we also reported the values of total fat mass and total lean mass at baseline and after 12 months; both total fat mass and total lean mass showed a clear reduction at the end of the study period without however reaching statistical significance. The IMT at the end of the treatment period with GLP-1RAs also presented a reduction which reached the statistical significance (p < 0.05). Table 1 Demographic, clinical and laboratory characteristics of the study population at baseline and after 12 months of therapy with GLP-1RAs Baseline 12 Months p M/F 65 (30/35) 54 (26/28) Age (years) 66.4 ± 8.45 67.3 ± 8.5 n.s. Weight (Kg) 84.38 ± 12.82 80.19 ± 11.89 0.01 Height (cm) 167.87 ± 8.35 167.03 ± 7.95 n.s. BMI (Kg/m 2 ) 30.24 ± 4.52 28.68 ± 3.73 0.01 Duration of T2DM (years) 13.72 ± 9.73 Fasting plasma glucose (mg/dl) 152.4 ± 52.2 122.3 ± 21.5 0.01 Glycated hemoglobin (%) 60.67 ± 21.00 50.92 ± 8.99 0.05 Microalbuminuria (mg/L) 104.2 ± 433.6 88.6 ± 330.2 0.05 Total Fat Mass (kg) 33.72 ± 8.03 32.85 ± 7.35 n.s. Total Lean Mass (kg) 49.81 ± 11.63 48.47 ± 10.80 n.s. Android /Ginoid Fat Mass ratio 1.21 ± 0.26 1.17 ± 0.22 0.05 Media-intimal thickness (mm) 1.56 ± 0.39 1.38 ± 0.33 0.05 GLP-1RAs receptor agonists for glucagon-like peptide-1, M male, F Female, BMI body mass index, T2DM type 2 diabetes mellitus Furthermore, upon analyzing the change in the ratio between android fat and gynoid fat at baseline and after 12 months of treatment with GLP-1RAs, we observed a significant reduction (1.21 vs. 1.17, p < 0.05) [Figure 2 ]. Figure 3 shows the trend of lipid parameters in T2DM patients at baseline and after 12 months of therapy with GLP-1RAs; a reduction in all parameters is evident, though statistical significance was reached only for LDL cholesterol (p < 0.05) and triglycerides.(p < 0.01). Serum levels of adiponectin and myostatin at baseline and after 12 months of therapy with GLP-1RAs are reported in Fig. 4 . Serum adiponectin levels showed a significant increase from 9.6 ± 5.8 mcg/ml at baseline to 11.6 ± 7.0 mcg/ml at the end of treatment (p < 0.01). On the contrary, the serum levels of myostatin values showed a reduction going from 12.5 ± 2.4 ng/ml at baseline to 11.4 ± 2.1 ng/ml at month 12 without however reaching statistical significance [Figure 4 ]. Furthermore, upon dividing the study population based on weight loss (less than and more than 5%), we noted that the increase in adiponectin was more pronounced in the group of patients who lost more than 5% of their weight (with a rise of 19.8% in subjects who lost less than 5% and 25% in those who lost more than 5%, respectively) [Figure 5 ]. In both the initial assessment and upon completion of the study, there were no significant differences in the values of anthropometric, laboratory and instrumental data between T2DM patients undergoing treatment with dulaglutide and those receiving semaglutide. (Supplementary materials) Discussion The findings from our research affirm the significant contribution of GLP-1RAs in the treatment approach for patients with T2DM, especially among individuals grappling with overweight and obesity, which are closely linked to heightened cardiovascular risks [ 14 ]. In our population study we observed, as expected, a significant weight loss. It is well-established that weight loss alone can enhance various metabolic functions and contribute to a decrease in cardiovascular risk [ 15 ]. However, in this study the weight loss was not associated with a significant change in the percentages of fat mass and lean mass. To our knowledge, this is the first study to have observed a reduction in the ratio of android fat to gynoid fat in patients treated with GLP-1RAs. This finding suggests a reduction in the percentage of adipose tissue with a visceral distribution, which it is known to be strongly linked to increased cardiovascular risk [ 16 ]. The reduction of visceral fat could potentially be a mechanism to account for the observed cardiovascular benefits in past trials involving liraglutide among individuals diagnosed with type 2 diabetes [ 9 ]. Therefore, GLP-1RAs, being able to induce both weight loss and a reduction in visceral fat, would seem to play a dual role in cardiovascular prevention. Another favorable result which underlines the contribute of GLP-1RAs in the improvement of cardio metabolic risk is represented by the significant reduction in serum values of both LDL-cholesterol and triglycerides ​​ after one year of therapy with GLP-1RAs despite the absence of changes in lipid-lowering treatment compared to baseline. These results regarding the impact of GLP-1RAs on lipid parameters appear to be in agreement with several previous studies [ 17 , 18 ]. The important effect of GLP-1RAs on lipid metabolism could open a new perspective for their use in hepatic steatosis which is a frequent complication of T2DM and represents an important cardiovascular risk factor in both diabetic and non-diabetic populations [ 19 ]. A statistically significant reduction in microalbuminuria levels was also observed in our study population; this data is also of considerable importance: microalbuminuria is considered a marker of vascular dysfunction and atherogenesis and it is an independent risk factor for all cardiovascular diseases [ 20 , 21 ]. Therefore, the reduction of microalbuminuria observed in our patients after one year treatment with GLP-1RAs would be the mirror of a reduction of vascular inflammation and atherosclerosis. Another result which would confirm this reduction of vascular inflammation and the proinflammatory state is the increase in adiponectin levels after 12 months of GLP-1RAs therapy [ 22 ]. Furthermore, in our study population the increase in adiponectin was greater in the group of patients who presented a weight loss > 5%. Adiponectin is a secretory product of adipocytes of white adipose tissue, which, unlike other adipokines, is produced and secreted at higher rates in the presence of a low white (in particular, visceral) adipose tissue mass [ 23 ]. Its role involves directing triglyceride storage toward subcutaneous adipose tissue, thereby reducing lipid overload and the associated lipotoxicity and dysfunction in muscle, liver, and the pancreas [ 23 ]. The elevation of adiponectin levels plays a positive role in reducing cardiovascular risk. In fact, low levels of adiponectin are linked to an increased cardiovascular risk and greater insulin resistance [ 24 , 25 ]. Patients affected by T2DM who are overweight or obese have reduced serum adiponectin values which however present a significant increase in the presence of adequate weight loss [ 10 ]. Literature data indicate that GLP-1RAs increase adiponectin levels presumably through a direct effect on adipocytes [ 26 , 27 ]. A recent meta-analysis has highlighted that the increase in adiponectin induced by GLP-1RAs depends on the potency and dose of the drugs, being modest and inconsistent with exenatide and much more marked with liraglutide and semaglutide [ 10 , 22 ]. The role of adiponectine on insulin resistance in our study could be also perfectly pointed out by the statistically significant inverse correlation between adiponectin and blood fasting glucose values and glycated hemoglobin [ 19 , 21 , 22 ]. This is the first "in vivo" study that has analyzed the changes in serum myostatin induced by GLP-1RAs therapies, reporting a reduction in myostatin at the end of 12 months of therapy, although it did not reach statistical significance. However, this data may represent a stimulus for further studies aimed at evaluating the effect of GLP-1RAs on myostatin and diabetic muscular atrophy [ 12 ]. At baseline, our patients with type 2 diabetes and an average disease duration of over 13 years exhibited average IMT values elevated and indicative of carotid atherosclerosis. In agreement with some previous reports our study highlighted that one-year treatment with GLP-1RAs determined a statistically significant reduction in carotid IMT, a surrogate marker of atherosclerosis [ 28 , 29 ]. Although the mechanisms by which GLP-1RAs drugs determine an antiatherosclerotic effect have not yet been well defined, it is conceivable that the improvement of the lipid profile, the reduction of inflammation and the modifications of the cytokine profile play an important role [ 30 , 31 ]. This data, contributes to underlining the favorable role of GLP-1RAs in reducing the risk of major cardiovascular events. Our study presents some limitations. Firstly, the number of patients enrolled in the present study is relatively small. Secondly, the absence of a control group undergoing weight loss solely through lifestyle modifications prevents us from determining whether the alterations in both IMT and biochemical parameters are due to the direct effects of GLP-1RAs or to weight loss. However, this study also has several strengths, including its longitudinal design, a prolonged duration of follow-up, and the assessment of intima-media thickness at a single center by a skilled operator who was external to the study. Conclusion The ability to reduce cardiovascular risk is one of the most important characteristics currently required for antidiabetic drugs. The results of this study indicate that in patients with T2DM a one-year therapy with GLP-1RAs exerts a positive influence on several key determinants of cardiovascular risk, including body weight, visceral fat, dyslipidemia, and atherosclerosis.. The significant increase in adiponectin levels may also play a pivotal role in controlling the inflammatory state and the mechanisms of vascular damage in diabetic patients. Future randomized controlled studies on larger patient cohorts are needed to confirm and develop the findings of this study. Declarations Author contributions AA: Conceptualization, Methodology, Resources, Writing – review & editing; LB: Resources, Methodology, Writing. CM: Resources, Writing; EC: Resources; LG: review & editing; RT: review & editing; SG: Conceptualization, Supervision, Writing – review. CC: Conceptualization, Methodology, Statistical analysis, Writing – review & editing; All authors approved the final version to be published. Funding. No funds, grants or other support was received Compliance with ethical standards Conflict of interest The authors declare no competing interests Ethics approval and consent to participate The study was performed in line with the principles of the 1964 Helsinki Declaration and its later amendments. Institutional Review Board approval was obtained for the study protocol (ID 14783/19). All the study patients gave their written informed consent to participate in the study. Data availability The data that support the findings of this study are available from the corresponding author, [CC], upon reasonable request. References American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 37 Suppl 1:S81-90 (2014) H. Sun, P. Saeedi, S. Karuranga, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res. Clin. 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Abate, Liraglutide decreases carotid intima-media thickness in patients with type 2 diabetes: 8-month prospective pilot study. Cardiovasc. Diabetol. 13:49 (2014) https://doi:10.1186/1475-2840-13-49 M. Rizzo, A.A. Rizvi, A.M. Patti, et al. Liraglutide improves metabolic parameters and carotid intima-media thickness in diabetic patients with the metabolic syndrome: an 18-month prospective study. Cardiovasc. Diabetol. 15:162. https://doi:10.1186/s12933-016-0480-8 R. Menghini, V. Casagrande, S. Rizza, M. Federici, GLP-1RAs and cardiovascular disease: is the endothelium a relevant platform? Acta. Diabetol. 60:1441–1448 (2023) https:// doi: 10.1007/s00592-023-02124-w B. Park, E. Bakbak, H. Teoh, et al. GLP-1 receptor agonists and atherosclerosis protection: the vascular endothelium takes center stage. Am. J. Physiol. Heart. Circ. Physiol. 326:H1159-H1176 (2024) https://doi:10.1152/ajpheart.00574.2023 Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterial.docx Cite Share Download PDF Status: Published Journal Publication published 09 Nov, 2024 Read the published version in Endocrine → Version 1 posted Editorial decision: Revision requested 28 Aug, 2024 Reviews received at journal 28 Aug, 2024 Reviewers agreed at journal 27 Aug, 2024 Reviewers agreed at journal 02 Jul, 2024 Reviewers invited by journal 15 Jun, 2024 Editor assigned by journal 15 Jun, 2024 Submission checks completed at journal 15 Jun, 2024 First submitted to journal 14 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4584263","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":320845497,"identity":"2cb550ec-d64b-4993-84d7-bd49ca900101","order_by":0,"name":"Antonella Al Refaie","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Antonella","middleName":"Al","lastName":"Refaie","suffix":""},{"id":320845498,"identity":"fed12f44-4bd0-48ef-ac01-70e1f0b8d047","order_by":1,"name":"Leonardo Baldassini","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Leonardo","middleName":"","lastName":"Baldassini","suffix":""},{"id":320845500,"identity":"b1c36576-698f-46c4-b350-cf3fdfb2311e","order_by":2,"name":"Caterina Mondillo","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Caterina","middleName":"","lastName":"Mondillo","suffix":""},{"id":320845501,"identity":"98c49bda-d42b-43b3-bbcd-6b8286ef4b03","order_by":3,"name":"Elena Ceccarelli","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Elena","middleName":"","lastName":"Ceccarelli","suffix":""},{"id":320845502,"identity":"1446a082-f51c-48d8-be48-c0c2c9cf40b4","order_by":4,"name":"Roberto Tarquini","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Roberto","middleName":"","lastName":"Tarquini","suffix":""},{"id":320845503,"identity":"944370ab-b162-4e73-9bff-c9a1f1b00107","order_by":5,"name":"Luigi Gennari","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Luigi","middleName":"","lastName":"Gennari","suffix":""},{"id":320845504,"identity":"17ac04a9-671d-49aa-adfb-8348d27997f4","order_by":6,"name":"Stefano Gonnelli","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Stefano","middleName":"","lastName":"Gonnelli","suffix":""},{"id":320845506,"identity":"761e4ea2-a170-4256-8426-ff36191c6064","order_by":7,"name":"Carla Caffarelli","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBUlEQVRIie2QsWrDMBCGzxjk5cCrAoa8whVB6ZDEr5JgcBe3BLpkNHTIIuiaPEceoBKCTsnusV08ZUjposFD5eClFKtrB33DHQh93H8HEAj8TyLV1+S5b+s7TF1TQIA+56rg29JV4jipB8Xn/FCA1PA8pqTb07uysJgii9vLhXgmmget7RqyfEThx3vSEoobyZjY71yw2+ZxadATjKAEhaCi12ktYrwqFRnfLpS2oDtQuWTJV9w5Rewq0tan8BKMm7KSDEXcX4x4RcoXjDctmIyKwilPkXQKP57J9AlRjVzspYw+zpvF3AU7gN3M8nRbiU/bzfKkHhkzHOH3eN//QCAQCPzBN6l0THkach2zAAAAAElFTkSuQmCC","orcid":"","institution":"University of Siena","correspondingAuthor":true,"prefix":"","firstName":"Carla","middleName":"","lastName":"Caffarelli","suffix":""}],"badges":[],"createdAt":"2024-06-14 23:08:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4584263/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4584263/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12020-024-04085-8","type":"published","date":"2024-11-09T15:58:15+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60337679,"identity":"ff65b5d2-721b-4804-8bd7-d6379a450dd8","added_by":"auto","created_at":"2024-07-15 17:40:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":35184,"visible":true,"origin":"","legend":"\u003cp\u003eThe study flow-chart\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4584263/v1/ad874ecf278fad3603cafee4.png"},{"id":60337684,"identity":"0da7bf00-c98c-40d3-b31f-470af5dc7ff6","added_by":"auto","created_at":"2024-07-15 17:40:45","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":15899,"visible":true,"origin":"","legend":"\u003cp\u003eAndroid/Gynoid Fat Mass ratio in T2DM patients at baseline and after 12 months of therapy with GLP-1RAs\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4584263/v1/b6a25e8ce219a787890aad8e.png"},{"id":60338752,"identity":"bb266fae-0af4-4130-ac37-24e09ff754f2","added_by":"auto","created_at":"2024-07-15 17:48:44","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":19735,"visible":true,"origin":"","legend":"\u003cp\u003eValues of lipids parameters in T2DM patients at baseline and after 12 months of therapy with GLP-1RAs\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4584263/v1/ae5eced0d28cc3db1a483d43.png"},{"id":60337681,"identity":"df04a9e2-95b4-4dde-9197-f27b11cf3b15","added_by":"auto","created_at":"2024-07-15 17:40:44","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":15259,"visible":true,"origin":"","legend":"\u003cp\u003eSerum levels of adiponectin (A) and myostatin serum levels (B) in T2DM patients at baseline and after 12 months of therapy with GLP-1RAs\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4584263/v1/a635dd314d327cae8ec8c70d.png"},{"id":60339341,"identity":"ed250239-9f04-4345-854b-3685c5b86dc2","added_by":"auto","created_at":"2024-07-15 17:56:44","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":13111,"visible":true,"origin":"","legend":"\u003cp\u003eSerum levels of adiponectin at baseline and after 12 months treatment with GLP-1RAs in T2DM patients who had body weight reduction less or more than 5%\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-4584263/v1/65a4bac8d0fc0f1ed342fdb9.png"},{"id":68750027,"identity":"d9693d5e-2916-4f08-9738-a731e22a4af8","added_by":"auto","created_at":"2024-11-11 16:08:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":527787,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4584263/v1/35ff410c-0441-43d6-9ea2-fd0fb5a49109.pdf"},{"id":60337683,"identity":"dade8ad8-a8c7-4362-a0f1-0846b61c3d9b","added_by":"auto","created_at":"2024-07-15 17:40:44","extension":"docx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":21439,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4584263/v1/79cf2a4fbbd00dcc1a9c1e73.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Adiponectin may play a crucial role in the metabolic effects of GLP-1RAs treatment in patients with Type 2 Diabetes Mellitus: a preliminary longitudinal study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDiabetes mellitus stands as the most prevalent metabolic disorder globally, contributing to what is now recognized as a true 'diabetes pandemic' due to its significant increase in prevalence. Type 2 diabetes mellitus (T2DM) ranks as the 8th leading cause of mortality worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], and is characterized by high rates of mortality, morbidity, and healthcare expenditure. A considerable portion of healthcare costs stems from the microvascular and macrovascular complications associated with T2DM, including coronary heart disease, stroke, peripheral arterial disease, heart failure, diabetic retinopathy, nephropathy, and neuropathy. Additionally, over two-thirds of deaths among T2DM patients result from cardiovascular complications (CVD), which often manifest at least 15 years earlier in diabetics due to accelerated atherosclerosis associated with T2DM [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] These data emphasize the fundamental significance of cardiovascular prevention; in fact, he optimal treatment for T2DM should not solely focus on lowering blood glucose levels, but also address cardiovascular risk factors.. Among the new antidiabetic drugs currently available for diabetes, receptor agonists for glucagon-like peptide-1 (GLP-1RAs) appear to be able to both reduce glycated hemoglobin levels and positively act on cardiovascular risk. GLP-1RAs, similarly to incretin hormones, stimulate insulin secretion after an oral glucose load through the incretin effect. The ability of these drugs to reduce cardiovascular risk is independent from their hypoglycemic action [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Many pleiotropic effects of GLP-1RAs have been recognized in vitro and in vivo [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In fact, there is substantial evidence supporting their involvement in arterial vasodilatation, promotion of angiogenesis and exertion of anti-inflammatory and anti-atherosclerotic effects [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Recent studies have reported that GLP-1RAs drugs are able to determine a reduction in body weight, waist circumference and, probably, also visceral fat [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Furthermore, some studies, though not all, have found that diabetic patients treated with GLP-1RAs exhibit increased levels of adiponectin, a hormone secreted by adipose tissue that has antiatherogenic and anti-inflammatory properties [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, the molecular mechanism underlying the elevation in circulating adiponectin are yet to be elucidated [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Instead, the effects of GLP-1RAs on the levels of myostatin, the most important cytokine produced by muscle tissue, have not yet been defined [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe aim of this longitudinal study carried out in a cohort of T2DM patients was to evaluate the effects of 1-year treatment with GLP-1RAs on some of the major determinants of CVD risk and on adiponectin and myostatin serum levels.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eFor this research, we recruited both male and female patients diagnosed with T2DM who were referred to the Diabetology and Metabolic Diseases Unit of the Department of Internal Medicine at the University Hospital of Siena (Italy) for whom the diabetologist had planned to start treatment with GLP-1RAs. Between May 2022 and December 2022, a total of 80 consecutive T2DM patients commenced therapy with GLP-1RAs (either dulaglutide or semaglutide) and were evaluated for the study. Following the inclusion/exclusion criteria, 65 T2DM patients (30 men and 35 women) were enrolled in this 12-month study, with 36 receiving a prescription for dulaglutide and 29 for semaglutide. The inclusion criteria were as follows: patients initiating therapy with GLP-1RAs for the first time, aged between 50 and 80 years, with HbA1c levels greater than 6.5% and less than 10%. Patients with T2DM who had previously received GLP-1RA therapy or were currently receiving insulin, thiazolidinediones, SGLT2 inhibitors, or acarbose were excluded. All patients underwent comprehensive clinical, laboratory, and instrumental assessments prior to initiating therapy and again after 12 months. Specifically, a thorough medical history was obtained, and all patients underwent measurements of weight and height. Furthermore, body mass index (BMI), calculated as the ratio of weight in kilograms to the square of height in meters, was determined for each patient. Vital parameters, such as systolic (SBP) and diastolic (DBP) blood pressure and heart rate, were also evaluated. The maintenance doses for dulaglutide (1.5-3.0 mg weekly) and semaglutide (1.0\u0026ndash;2.0 mg weekly) were achieved after an 8\u0026ndash;12 week dose escalation period as per the instructions provided in the leaflet. The flow chart of the T2DM patients involved in the study is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. An informed written consent was obtained from all participants, and the research protocol received approval from the Institutional Review Board of Siena University Hospital (ID-21211/21). Prior to statistical analysis, all collected data underwent anonymization procedure.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eBiochemical parameter\u003c/h2\u003e \u003cp\u003eAfter fasting for at least 12 hours, patients underwent blood sampling for the evaluation of plasma glucose (FPG), glycated hemoglobin (HbA1c), creatinine, microalbuminuria, transaminases, total cholesterol (TOT-C), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein cholesterol-cholesterol (LDL-C), triglycerides (TG), adiponectin and myostatin.\u003c/p\u003e \u003cp\u003eAll samples were stored at -80\u0026deg;C while awaiting analysis, and then they were batched and measured in one assay. HbA1c was measured by a turbidimetric inhibition immunoassay (Siemens Healthcare Diagnostics, Newark, USA). All lipid parameters (TOT-C, HDL-C, LDL-C and TG) and FPG were measured using a colorimetric method (Autoanalyzer Menarini, Florence, Italy). In our institution the intra- and inter-assay coefficients of variation were, respectively, 1.8 and 3.8% for TOT-C, 2.0 and 3.0% for HDL-C, 1.5% and 2.3% for LDL-C assessment and 1.7 and 2.9% for TG.\u003c/p\u003e \u003cp\u003eAdiponectin was measured by a commercially available radioimmunoassay (Adiponectin Human RIA kit; DRG International, Mountainside, NJ), which measures multiple forms of adiponectin (trimer, hexamer, and high\u0026ndash;molecular weight forms). The results were expressed in micrograms per milliliter; the intra- and interassay coefficients of variation were 3.8% and 8.4%, respectively, at concentrations between 3 and 15 microg/mL. Serum myostatin was determined by an ELISA method (Human Myostatin, Elisa Kit, My BioSource, San Diego, CA,). In our institution the intra- and inter-assay coefficients of variation were 5% and 8%, respectively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eBody Composition Assessment\u003c/h2\u003e \u003cp\u003eBody composition parameters were determined using a dual-energy X-ray absorptiometry device (Lunar Prodigy; GE Healthcare, Waukesah, WI) in conjunction with Encore 2002 software. All scans were performed by the same operator while the subjects were wearing light indoor clothing and no removable metal objects. Among the body composition parameters we considered total fat mass (absolute value and percentage) and total lean mass (absolute value and percentage). We also obtained information about the distribution of fat, so the percentage of android fat, gynoid fat and the ratio between android and gynoid fat. The \u0026ldquo;android region\u0026rdquo; has a lower boundary at the pelvis cut and the upper boundary above the pelvis cut by 20% of the distance between the pelvis and the neck cuts. The lateral boundaries are the arm cuts. The \u0026ldquo;gynoid region\u0026rdquo; has an upper boundary Body Fat between the upper part of the greater trochanters and a lower boundary defined at a distance equal to twice the height of the android region. The lateral boundaries are outer leg cuts.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eCarotid atherosclerosis evaluation\u003c/h2\u003e \u003cp\u003eAll subjects underwent ultrasonographic examination of the epiaortic vessels, carried out by a single operator unaware of the study protocol by using a MEGAS device (Esaote) with a 7.5 MHz B-mode linear probe. All examinations were carried out in a quiet, dark, and temperature-controlled room. The participants lay in the supine position on a scan bed with their necks slightly extended, and heads rotated contralaterally to the side evaluated. From the ultrasonographic examination we obtained the media-intimal thickness (IMT), obtained from the distance between the hyperechogenic line due to the blood-intima interface, and the hyperechogenic line due to the media-adventitia interface. Using the dilation of the bulb and the flow divider as anatomical references, the IMT was evaluated in an area free of plaque in the three standardized carotid segments: the distal 1-cm of the common carotid artery, the carotid bifurcation, and the proximal 1-cm of the internal carotid artery [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. A statistical evaluation was performed on the calculated average of the left and right carotid artery IMT measurements. A plaque was defined as the presence of focal wall thickening that is at least 50% greater than the surrounding or as a focal region with carotid IMT greater than 1.5 mm that protrudes into the lumen. Atherosclerosis was defined as IMT value greater than 1 mm or the presence of plaque [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll values were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. The Kolmogorov\u0026ndash;Smirnov test was used to verify the normality of the distribution of the outcome variables. For all parameters the absolute changes over time for each patient were expressed as a percentage of the baseline values. Paired t-test and Wilcoxon matched-pairs signed-ranks test were used, where appropriate, to compare the changes with baseline values. Student's t-test and Mann\u0026ndash;Whitney U-test were used to compare the differences between patient groups. All tests were done two-sided, and p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. All tests were performed using the SPSS statistical package for Windows version 16.0 (SPSS Inc., Chicago) .\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe demographic, clinical, and laboratory characteristics of the study population at baseline and after 12 months of therapy with GLP-1RAs receptor agonists are reported in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Twenty-six males and twenty-eight females, totaling fifty-four T2DM patients, concluded the 12-month study duration. Among them, thirty had received treatment with dulaglutide, while twenty-four had been administered semaglutide. As expected, after 12 months of therapy with GLP-1RAs, we observed a significant reduction in fasting plasma glucose values (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), glycated hemoglobin (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and also in microalbuminuria values (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Furthermore, a significant (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) decrease in body weight (from 84.4 to 80.2 Kg) and BMI (from 30.2 to 28.6 Kg/m2) was observed. The percentage of patients with BMI values indicative of obesity and overweight was significantly higher at baseline compared to the control after 12 months (43.3% vs 37.1% and 46.7% vs 35.2%, respectively, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (data not shown). In Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e we also reported the values of total fat mass and total lean mass at baseline and after 12 months; both total fat mass and total lean mass showed a clear reduction at the end of the study period without however reaching statistical significance. The IMT at the end of the treatment period with GLP-1RAs also presented a reduction which reached the statistical significance (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic, clinical and laboratory characteristics of the study population at baseline and after 12 months of therapy with GLP-1RAs\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 Months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65 (30/35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (26/28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66.4\u0026thinsp;\u0026plusmn;\u0026thinsp;8.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67.3\u0026thinsp;\u0026plusmn;\u0026thinsp;8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (Kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84.38\u0026thinsp;\u0026plusmn;\u0026thinsp;12.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80.19\u0026thinsp;\u0026plusmn;\u0026thinsp;11.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e167.87\u0026thinsp;\u0026plusmn;\u0026thinsp;8.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e167.03\u0026thinsp;\u0026plusmn;\u0026thinsp;7.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (Kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30.24\u0026thinsp;\u0026plusmn;\u0026thinsp;4.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.68\u0026thinsp;\u0026plusmn;\u0026thinsp;3.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of T2DM (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.72\u0026thinsp;\u0026plusmn;\u0026thinsp;9.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFasting plasma glucose (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e152.4\u0026thinsp;\u0026plusmn;\u0026thinsp;52.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e122.3\u0026thinsp;\u0026plusmn;\u0026thinsp;21.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlycated hemoglobin (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.67\u0026thinsp;\u0026plusmn;\u0026thinsp;21.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50.92\u0026thinsp;\u0026plusmn;\u0026thinsp;8.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicroalbuminuria (mg/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e104.2\u0026thinsp;\u0026plusmn;\u0026thinsp;433.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88.6\u0026thinsp;\u0026plusmn;\u0026thinsp;330.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Fat Mass (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33.72\u0026thinsp;\u0026plusmn;\u0026thinsp;8.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.85\u0026thinsp;\u0026plusmn;\u0026thinsp;7.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Lean Mass (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49.81\u0026thinsp;\u0026plusmn;\u0026thinsp;11.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48.47\u0026thinsp;\u0026plusmn;\u0026thinsp;10.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAndroid /Ginoid Fat Mass ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedia-intimal thickness (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eGLP-1RAs\u003c/em\u003e receptor agonists for glucagon-like peptide-1, \u003cem\u003eM\u003c/em\u003e male, \u003cem\u003eF\u003c/em\u003e Female, \u003cem\u003eBMI\u003c/em\u003e body mass index, \u003cem\u003eT2DM\u003c/em\u003e type 2 diabetes mellitus\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFurthermore, upon analyzing the change in the ratio between android fat and gynoid fat at baseline and after 12 months of treatment with GLP-1RAs, we observed a significant reduction (1.21 vs. 1.17, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) [Figure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the trend of lipid parameters in T2DM patients at baseline and after 12 months of therapy with GLP-1RAs; a reduction in all parameters is evident, though statistical significance was reached only for LDL cholesterol (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and triglycerides.(p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSerum levels of adiponectin and myostatin at baseline and after 12 months of therapy with GLP-1RAs are reported in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Serum adiponectin levels showed a significant increase from 9.6\u0026thinsp;\u0026plusmn;\u0026thinsp;5.8 mcg/ml at baseline to 11.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.0 mcg/ml at the end of treatment (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). On the contrary, the serum levels of myostatin values showed a reduction going from 12.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4 ng/ml at baseline to 11.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1 ng/ml at month 12 without however reaching statistical significance [Figure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e]. Furthermore, upon dividing the study population based on weight loss (less than and more than 5%), we noted that the increase in adiponectin was more pronounced in the group of patients who lost more than 5% of their weight (with a rise of 19.8% in subjects who lost less than 5% and 25% in those who lost more than 5%, respectively) [Figure \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e]. In both the initial assessment and upon completion of the study, there were no significant differences in the values of anthropometric, laboratory and instrumental data between T2DM patients undergoing treatment with dulaglutide and those receiving semaglutide. (Supplementary materials)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe findings from our research affirm the significant contribution of GLP-1RAs in the treatment approach for patients with T2DM, especially among individuals grappling with overweight and obesity, which are closely linked to heightened cardiovascular risks [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In our population study we observed, as expected, a significant weight loss. It is well-established that weight loss alone can enhance various metabolic functions and contribute to a decrease in cardiovascular risk [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, in this study the weight loss was not associated with a significant change in the percentages of fat mass and lean mass.\u003c/p\u003e \u003cp\u003eTo our knowledge, this is the first study to have observed a reduction in the ratio of android fat to gynoid fat in patients treated with GLP-1RAs. This finding suggests a reduction in the percentage of adipose tissue with a visceral distribution, which it is known to be strongly linked to increased cardiovascular risk [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The reduction of visceral fat could potentially be a mechanism to account for the observed cardiovascular benefits in past trials involving liraglutide among individuals diagnosed with type 2 diabetes [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Therefore, GLP-1RAs, being able to induce both weight loss and a reduction in visceral fat, would seem to play a dual role in cardiovascular prevention.\u003c/p\u003e \u003cp\u003eAnother favorable result which underlines the contribute of GLP-1RAs in the improvement of cardio metabolic risk is represented by the significant reduction in serum values of both LDL-cholesterol and triglycerides ​​ after one year of therapy with GLP-1RAs despite the absence of changes in lipid-lowering treatment compared to baseline. These results regarding the impact of GLP-1RAs on lipid parameters appear to be in agreement with several previous studies [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The important effect of GLP-1RAs on lipid metabolism could open a new perspective for their use in hepatic steatosis which is a frequent complication of T2DM and represents an important cardiovascular risk factor in both diabetic and non-diabetic populations [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA statistically significant reduction in microalbuminuria levels was also observed in our study population; this data is also of considerable importance: microalbuminuria is considered a marker of vascular dysfunction and atherogenesis and it is an independent risk factor for all cardiovascular diseases [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Therefore, the reduction of microalbuminuria observed in our patients after one year treatment with GLP-1RAs would be the mirror of a reduction of vascular inflammation and atherosclerosis. Another result which would confirm this reduction of vascular inflammation and the proinflammatory state is the increase in adiponectin levels after 12 months of GLP-1RAs therapy [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Furthermore, in our study population the increase in adiponectin was greater in the group of patients who presented a weight loss\u0026thinsp;\u0026gt;\u0026thinsp;5%. Adiponectin is a secretory product of adipocytes of white adipose tissue, which, unlike other adipokines, is produced and secreted at higher rates in the presence of a low white (in particular, visceral) adipose tissue mass [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Its role involves directing triglyceride storage toward subcutaneous adipose tissue, thereby reducing lipid overload and the associated lipotoxicity and dysfunction in muscle, liver, and the pancreas [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The elevation of adiponectin levels plays a positive role in reducing cardiovascular risk. In fact, low levels of adiponectin are linked to an increased cardiovascular risk and greater insulin resistance [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatients affected by T2DM who are overweight or obese have reduced serum adiponectin values which however present a significant increase in the presence of adequate weight loss [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Literature data indicate that GLP-1RAs increase adiponectin levels presumably through a direct effect on adipocytes [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. A recent meta-analysis has highlighted that the increase in adiponectin induced by GLP-1RAs depends on the potency and dose of the drugs, being modest and inconsistent with exenatide and much more marked with liraglutide and semaglutide [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The role of adiponectine on insulin resistance in our study could be also perfectly pointed out by the statistically significant inverse correlation between adiponectin and blood fasting glucose values and glycated hemoglobin [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis is the first \"in vivo\" study that has analyzed the changes in serum myostatin induced by GLP-1RAs therapies, reporting a reduction in myostatin at the end of 12 months of therapy, although it did not reach statistical significance. However, this data may represent a stimulus for further studies aimed at evaluating the effect of GLP-1RAs on myostatin and diabetic muscular atrophy [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. At baseline, our patients with type 2 diabetes and an average disease duration of over 13 years exhibited average IMT values elevated and indicative of carotid atherosclerosis. In agreement with some previous reports our study highlighted that one-year treatment with GLP-1RAs determined a statistically significant reduction in carotid IMT, a surrogate marker of atherosclerosis [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Although the mechanisms by which GLP-1RAs drugs determine an antiatherosclerotic effect have not yet been well defined, it is conceivable that the improvement of the lipid profile, the reduction of inflammation and the modifications of the cytokine profile play an important role [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. This data, contributes to underlining the favorable role of GLP-1RAs in reducing the risk of major cardiovascular events.\u003c/p\u003e \u003cp\u003eOur study presents some limitations. Firstly, the number of patients enrolled in the present study is relatively small. Secondly, the absence of a control group undergoing weight loss solely through lifestyle modifications prevents us from determining whether the alterations in both IMT and biochemical parameters are due to the direct effects of GLP-1RAs or to weight loss. However, this study also has several strengths, including its longitudinal design, a prolonged duration of follow-up, and the assessment of intima-media thickness at a single center by a skilled operator who was external to the study.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe ability to reduce cardiovascular risk is one of the most important characteristics currently required for antidiabetic drugs. The results of this study indicate that in patients with T2DM a one-year therapy with GLP-1RAs exerts a positive influence on several key determinants of cardiovascular risk, including body weight, visceral fat, dyslipidemia, and atherosclerosis.. The significant increase in adiponectin levels may also play a pivotal role in controlling the inflammatory state and the mechanisms of vascular damage in diabetic patients. Future randomized controlled studies on larger patient cohorts are needed to confirm and develop the findings of this study.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e AA: Conceptualization, Methodology, Resources, Writing \u0026ndash; review \u0026amp; editing; LB: Resources, Methodology, Writing. CM: Resources, Writing; EC: Resources; LG: review \u0026amp; editing; RT: review \u0026amp; editing; SG: Conceptualization, Supervision, Writing \u0026ndash; review. CC: Conceptualization, Methodology, Statistical analysis, Writing \u0026ndash; review \u0026amp; editing; All authors approved the final version to be published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding.\u0026nbsp;\u003c/strong\u003eNo funds, grants or other support was received\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with ethical standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u0026nbsp;\u003c/strong\u003eThe authors declare no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003eThe study was performed in line with the principles of the 1964 Helsinki Declaration and its later amendments. Institutional Review Board approval was obtained for the study protocol (ID 14783/19). \u0026nbsp;All the study patients gave their written informed consent to participate in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e The data that support the findings of this study are available from the corresponding author, [CC], upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAmerican Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 37 Suppl 1:S81-90 (2014)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eH. Sun, P. Saeedi, S. Karuranga, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res. Clin. 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Physiol. 326:H1159-H1176 (2024) \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi:10.1152/ajpheart.00574.2023\u003c/span\u003e\u003cspan address=\"https://doi:10.1152/ajpheart.00574.2023\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"endocrine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"endo","sideBox":"Learn more about [Endocrine](https://www.springer.com/journal/12020)","snPcode":"12020","submissionUrl":"https://submission.nature.com/new-submission/12020/3","title":"Endocrine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Type 2 Diabetes Mellitus (T2DM), atherosclerosis, GLP1-RAs (Dulaglutide, Semaglutide), Adiponectin, Lipids, Body Composition","lastPublishedDoi":"10.21203/rs.3.rs-4584263/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4584263/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eType 2 diabetes mellitus (T2DM) stands as the most prevalent metabolic disorder globally. T2DM entails numerous cardiovascular complications, which contribute significantly to morbidity, mortality, and increased public spending worldwide. The real challenge for new diabetes drugs lies not only in reducing blood glucose levels and glycated hemoglobin but also in preventing cardiovascular risk. Emerging receptor agonists for glucagon-like peptide-1 (GLP-1RAs) have demonstrated a pivotal role in diabetes management and mitigating cardiovascular risk.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a 12-month longitudinal investigation evaluating the cardio-metabolic effects of GLP-1RAs on a cohort 65 Caucasian patients diagnosed with T2DM who were scheduled for treatment with GLP-1RAs. Fifty-four T2DM patients successfully completed the 12-month study period, with 30 receiving dulaglutide and 24 receiving semaglutide.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn our study population, GLP-1RAs resulted in several positive changes beyond the observed weight loss: a shift in fat distribution, indicated by a reduction in the percentage of visceral fat (1.21 vs 1.17, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05); a significant decrease in LDL cholesterol levels (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and triglycerides (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01); and a significant increase in serum adiponectin levels (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), potentially indicating a reduction in insulin resistance and inflammation. Additionally, we observed a significant decrease in microalbuminuria and media-intimal thickness at the carotid vessel level (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn patients with T2DM 1-year therapy with GLP-1RAs has a positive effect on the main determinants of cardiovascular risk including body weight, visceral fat, dyslipidemia and atherosclerosis. Moreover, the increase in adiponectin may play a pivotal role in controlling the inflammatory state and the mechanisms of vascular damage.\u003c/p\u003e","manuscriptTitle":"Adiponectin may play a crucial role in the metabolic effects of GLP-1RAs treatment in patients with Type 2 Diabetes Mellitus: a preliminary longitudinal study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-15 17:40:39","doi":"10.21203/rs.3.rs-4584263/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-28T18:09:16+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-28T14:23:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"96731563003828197464407158726766589675","date":"2024-08-27T16:44:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"290262318059566228714527519430311216770","date":"2024-07-02T14:06:50+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-15T19:56:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-15T08:39:54+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-15T08:39:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"Endocrine","date":"2024-06-14T23:01:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"endocrine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"endo","sideBox":"Learn more about [Endocrine](https://www.springer.com/journal/12020)","snPcode":"12020","submissionUrl":"https://submission.nature.com/new-submission/12020/3","title":"Endocrine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"2651338a-7900-4310-b44b-0d08a412446c","owner":[],"postedDate":"July 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-11T16:03:40+00:00","versionOfRecord":{"articleIdentity":"rs-4584263","link":"https://doi.org/10.1007/s12020-024-04085-8","journal":{"identity":"endocrine","isVorOnly":false,"title":"Endocrine"},"publishedOn":"2024-11-09 15:58:15","publishedOnDateReadable":"November 9th, 2024"},"versionCreatedAt":"2024-07-15 17:40:39","video":"","vorDoi":"10.1007/s12020-024-04085-8","vorDoiUrl":"https://doi.org/10.1007/s12020-024-04085-8","workflowStages":[]},"version":"v1","identity":"rs-4584263","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4584263","identity":"rs-4584263","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}