{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T23:58:08Z","timestamp":1780444688357,"version":"3.54.1"},"reference-count":48,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T00:00:00Z","timestamp":1630886400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cLadarixin as new Juvenile Diabetes Inhibitory Agent \u2013 LJDIA\u201d Fondo crescita sostenibile","award":["DM 02\/08\/2019"],"award-info":[{"award-number":["DM 02\/08\/2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Type 2 diabetes mellitus is a severe public health issue worldwide. It displays a harmful effect on different organs as the eyes, kidneys and neural cells due to insulin resistance and high blood glucose concentrations. To date, the available treatments for this disorder remain limited. Several reports have correlated obesity with type 2 diabetes. Mainly, dysfunctional adipocytes and the regulation of high secretion of inflammatory cytokines are the crucial links between obesity and insulin resistance. Several clinical and epidemiological studies have also correlated the onset of type 2 diabetes with inflammation, which is now indicated as a new target for type 2 diabetes treatment. Thus, it appears essential to discover new drugs able to inhibit the secretion of proinflammatory adipocytokines in type 2 diabetes. Adipocytes produce inflammatory cytokines in response to inflammation or high glucose levels. Once activated by a specific ligand, CXCR1 and CXCR2 mediate some cytokines\u2019 effects by activating an intracellular signal cascade once activated by a specific ligand. Therefore, it is conceivable to hypothesize that a specific antagonist of these receptors may ameliorate type 2 diabetes and glucose metabolism. Herein, differentiated 3T3-L1-adipocytes were subjected to high glucose or inflammatory conditions or the combination of both and then treated with ladarixin, a CXCR1\/2 inhibitor. The results obtained point towards the positive regulation by ladarixin on insulin sensitivity, glucose transporters GLUT1 and GLUT4, cytokine proteome profile and lipid metabolism, thus suggesting ladarixin as a potentially helpful treatment in type 2 diabetes mellitus and obesity.<\/jats:p>","DOI":"10.3390\/cells10092324","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T10:59:12Z","timestamp":1630925952000},"page":"2324","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["CXCR1\/2 Inhibitor Ladarixin Ameliorates the Insulin Resistance of 3T3-L1 Adipocytes by Inhibiting Inflammation and Improving Insulin Signaling"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7005-3218","authenticated-orcid":false,"given":"Vanessa","family":"Castelli","sequence":"first","affiliation":[{"name":"Department of Life, Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Brandolini","sequence":"additional","affiliation":[{"name":"Domp\u00e8 Farmaceutici SpA, Via Campo di Pile, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3693-840X","authenticated-orcid":false,"given":"Michele","family":"d\u2019Angelo","sequence":"additional","affiliation":[{"name":"Department of Life, Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Giorgio","sequence":"additional","affiliation":[{"name":"Domp\u00e8 Farmaceutici SpA, Via Campo di Pile, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0261-3148","authenticated-orcid":false,"given":"Margherita","family":"Alfonsetti","sequence":"additional","affiliation":[{"name":"Department of Life, Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Cocchiaro","sequence":"additional","affiliation":[{"name":"Domp\u00e8 Farmaceutici SpA, Via Campo di Pile, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0551-5076","authenticated-orcid":false,"given":"Francesca","family":"Lombardi","sequence":"additional","affiliation":[{"name":"Department of Life, Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2737-7970","authenticated-orcid":false,"given":"Annamaria","family":"Cimini","sequence":"additional","affiliation":[{"name":"Department of Life, Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"},{"name":"Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0617-0233","authenticated-orcid":false,"given":"Marcello","family":"Allegretti","sequence":"additional","affiliation":[{"name":"Domp\u00e8 Farmaceutici SpA, Via Campo di Pile, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s40519-018-0481-6","article-title":"Insulin Resistance in Obesity: An Overview of Fundamental Alterations","volume":"23","author":"Barazzoni","year":"2018","journal-title":"Eat. Weight Disord."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3611","DOI":"10.2147\/DMSO.S275898","article-title":"Obesity, Insulin Resistance, and Type 2 Diabetes: Associations and Therapeutic Implications","volume":"13","author":"Wondmkun","year":"2020","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/j.1559-4572.2008.00044.x","article-title":"The Obesity, Metabolic Syndrome, and Type 2 Diabetes Mellitus Pandemic: Part I. Increased Cardiovascular Disease Risk and the Importance of Atherogenic Dyslipidemia in Persons with the Metabolic Syndrome and Type 2 Diabetes Mellitus","volume":"4","author":"Ginsberg","year":"2009","journal-title":"J. Cardiometab. Syndr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"802078","DOI":"10.1155\/2010\/802078","article-title":"The Role of Adipose Tissue and Adipokines in Obesity-Related Inflammatory Diseases","volume":"2010","author":"Balistreri","year":"2010","journal-title":"Mediat. Inflamm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3389\/fcvm.2020.00022","article-title":"Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease","volume":"7","author":"Chait","year":"2020","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_6","first-page":"637","article-title":"The Macrophage Switch in Obesity Development","volume":"6","author":"Castoldi","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1161\/CIRCRESAHA.115.306885","article-title":"Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease","volume":"118","author":"Fuster","year":"2016","journal-title":"Circ. Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jo, J., Gavrilova, O., Pack, S., Jou, W., Mullen, S., Sumner, A.E., Cushman, S.W., and Periwal, V. (2009). Hypertrophy and\/or Hyperplasia: Dynamics of Adipose Tissue Growth. PLoS Comput. Biol., 5.","DOI":"10.1371\/journal.pcbi.1000324"},{"key":"ref_9","unstructured":"Vargas, E., Podder, V., and Carrillo Sepulveda, M.A. (2021). Physiology, Glucose Transporter Type 4. StatPearls, StatPearls Publishing."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/sj.ijo.0800606","article-title":"Development of Insulin-Responsive Glucose Uptake and GLUT4 Expression in Differentiating Human Adipocyte Precursor Cells","volume":"22","author":"Hauner","year":"1998","journal-title":"Int. J. Obes."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"76","DOI":"10.4331\/wjbc.v11.i3.76","article-title":"Current Understanding of Glucose Transporter 4 Expression and Functional Mechanisms","volume":"11","author":"Wang","year":"2020","journal-title":"World J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Favaretto, F., Milan, G., Collin, G.B., Marshall, J.D., Stasi, F., Maffei, P., Vettor, R., and Naggert, J.K. (2014). GLUT4 Defects in Adipose Tissue Are Early Signs of Metabolic Alterations in Alms1GT\/GT, a Mouse Model for Obesity and Insulin Resistance. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109540"},{"key":"ref_13","first-page":"465","article-title":"Adipose Tissue Regulates Insulin Sensitivity: Role of Adipogenesis, de Novo Lipogenesis and Novel Lipids","volume":"280","author":"Smith","year":"2016","journal-title":"J. Internet Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10697","DOI":"10.1074\/jbc.271.18.10697","article-title":"AdipoQ Is a Novel Adipose-Specific Gene Dysregulated in Obesity","volume":"271","author":"Hu","year":"1996","journal-title":"J. Biol Chem"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"26746","DOI":"10.1074\/jbc.270.45.26746","article-title":"A Novel Serum Protein Similar to C1q, Produced Exclusively in Adipocytes","volume":"270","author":"Scherer","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"18556","DOI":"10.1074\/jbc.M117.791970","article-title":"Glucose Availability Controls Adipogenesis in Mouse 3T3-L1 Adipocytes via up-Regulation of Nicotinamide Metabolism","volume":"292","author":"Jackson","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.3389\/fphys.2019.01607","article-title":"Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes","volume":"10","author":"Zatterale","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Szablewski, L. (2020). Role of PI3K\/AKT Pathway in Insulin-Mediated Glucose Uptake. Blood Glucose Levels, IntechOpen.","DOI":"10.5772\/intechopen.73823"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"E8","DOI":"10.1152\/ajpendo.00269.2003","article-title":"Higher Production of IL-8 in Visceral vs. Subcutaneous Adipose Tissue. Implication of Nonadipose Cells in Adipose Tissue","volume":"286","author":"Bruun","year":"2004","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/1476-9255-6-25","article-title":"Inhibitory Effect of IL-8 on Insulin Action in Human Adipocytes via MAP Kinase Pathway","volume":"6","author":"Kobashi","year":"2009","journal-title":"J. Inflamm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1007\/s00592-017-1039-1","article-title":"Circulating IL-8 Levels Are Increased in Patients with Type 2 Diabetes and Associated with Worse Inflammatory and Cardiometabolic Profile","volume":"54","author":"Cimini","year":"2017","journal-title":"Acta Diabetol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.cmet.2009.03.002","article-title":"CXC Ligand 5 Is an Adipose-Tissue Derived Factor That Links Obesity to Insulin Resistance","volume":"9","author":"Chavey","year":"2009","journal-title":"Cell Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"20692","DOI":"10.1074\/jbc.M109.018556","article-title":"Keratinocyte-Derived Chemokine in Obesity","volume":"284","author":"Neels","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3647","DOI":"10.1172\/JCI63089","article-title":"CXCR1\/2 Inhibition Enhances Pancreatic Islet Survival after Transplantation","volume":"122","author":"Citro","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1111\/j.1476-5381.2011.01566.x","article-title":"Receptor Binding Mode and Pharmacological Characterization of a Potent and Selective Dual CXCR1\/CXCR2 Non-Competitive Allosteric Inhibitor: Therapeutic Potential of a CXCR1\/CXCR2 Inhibitor","volume":"165","author":"Bertini","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"566953","DOI":"10.3389\/fimmu.2020.566953","article-title":"CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil-Dependent Airway Inflammation in Mice","volume":"11","author":"Mattos","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"27998","DOI":"10.18632\/oncotarget.25524","article-title":"Probiotic DSF Counteracts Chemotherapy Induced Neuropathic Pain","volume":"9","author":"Castelli","year":"2018","journal-title":"Oncotarget"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1974","DOI":"10.1002\/jcp.24965","article-title":"In Vitro Evaluation of Different Methods of Handling Human Liposuction Aspirate and Their Effect on Adipocytes and Adipose Derived Stem Cells","volume":"230","author":"Palumbo","year":"2015","journal-title":"J. Cell Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1194\/jlr.M300084-JLR200","article-title":"Adipogenic Differentiating Agents Regulate Expression of Fatty Acid Binding Protein and CD36 in the J744 Macrophage Cell Line","volume":"44","author":"Sun","year":"2003","journal-title":"J. Lipid Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"C1355","DOI":"10.1152\/ajpcell.00125.2006","article-title":"AKT Phosphorylation Is Essential for Insulin-Induced Relaxation of Rat Vascular Smooth Muscle Cells","volume":"291","author":"Lee","year":"2006","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"575","DOI":"10.3389\/fimmu.2018.00575","article-title":"Molecular Mechanisms of Human Disease Mediated by Oncogenic and Primary Immunodeficiency Mutations in Class IA Phosphoinositide 3-Kinases","volume":"9","author":"Dornan","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.7150\/ijbs.27173","article-title":"The PI3K\/AKT Pathway in Obesity and Type 2 Diabetes","volume":"14","author":"Huang","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17605","DOI":"10.1074\/jbc.271.30.17605","article-title":"Activated Phosphatidylinositol 3-Kinase Is Sufficient to Mediate Actin Rearrangement and GLUT4 Translocation in 3T3-L1 Adipocytes","volume":"271","author":"Martin","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1007\/s00125-002-0974-7","article-title":"Insulin Regulation of Glucose Uptake: A Complex Interplay of Intracellular Signalling Pathways","volume":"45","author":"Khan","year":"2002","journal-title":"Diabetologia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cmet.2010.12.008","article-title":"NF-\u039aB, Inflammation, and Metabolic Disease","volume":"13","author":"Baker","year":"2011","journal-title":"Cell Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"E794","DOI":"10.1152\/ajpendo.00776.2009","article-title":"NF-\u039aB Activity in Muscle from Obese and Type 2 Diabetic Subjects under Basal and Exercise-Stimulated Conditions","volume":"299","author":"Tantiwong","year":"2010","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1111\/j.1600-0838.2006.00602.x","article-title":"Plasma Levels of Interleukin-6 and C-Reactive Protein Are Associated with Physical Inactivity Independent of Obesity","volume":"17","author":"Fischer","year":"2007","journal-title":"Scand. J. Med. Sci. Sports"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"156","DOI":"10.3389\/fendo.2020.00156","article-title":"Inflammatory Signaling and Brown Fat Activity","volume":"11","author":"Omran","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.cyto.2015.05.005","article-title":"IL-1 Family Members in the Pathogenesis and Treatment of Metabolic Disease: Focus on Adipose Tissue Inflammation and Insulin Resistance","volume":"75","author":"Ballak","year":"2015","journal-title":"Cytokine"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s00421-009-1140-4","article-title":"Influence of Exercise on the Circulating Levels and Macrophage Production of IL-1\u03b2 and IFN\u03b3 Affected by Metabolic Syndrome: An Obese Zucker Rat Experimental Animal Model","volume":"107","author":"Garcia","year":"2009","journal-title":"Eur J. Appl. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"a016303","DOI":"10.1101\/cshperspect.a016303","article-title":"The Chemokine System in Innate Immunity","volume":"7","author":"Sokol","year":"2015","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"E1205","DOI":"10.1152\/ajpendo.00117.2019","article-title":"The Antagonist of CXCR1 and CXCR2 Protects Db\/Db Mice from Metabolic Diseases through Modulating Inflammation","volume":"317","author":"Cui","year":"2019","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1530\/JOE-14-0126","article-title":"Increased Serum CXCL1 and CXCL5 Are Linked to Obesity, Hyperglycemia, and Impaired Islet Function","volume":"222","author":"Nunemaker","year":"2014","journal-title":"J. Endocrinol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1186\/s40168-021-01097-8","article-title":"Novel Insights into the Genetically Obese (Ob\/Ob) and Diabetic (Db\/Db) Mice: Two Sides of the Same Coin","volume":"9","author":"Suriano","year":"2021","journal-title":"Microbiome"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Bachmaier, K., Toya, S., and Malik, A.B. (2014). Therapeutic Administration of the Chemokine CXCL1\/KC Abrogates Autoimmune Inflammatory Heart Disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089647"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1002\/JLB.1A0618-216RR","article-title":"The Chemokine Receptor CXCR2 Contributes to Murine Adipocyte Development","volume":"105","author":"Dyer","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/obr.12242","article-title":"Macrophage Recruitment in Obese Adipose Tissue","volume":"16","author":"Bai","year":"2015","journal-title":"Obes Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"347","DOI":"10.2337\/diabetes.53.2.347","article-title":"Leptin Impairs Insulin Signaling in Rat Adipocytes","volume":"53","author":"Perez","year":"2004","journal-title":"Diabetes"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/9\/2324\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:57:06Z","timestamp":1760165826000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/9\/2324"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,6]]},"references-count":48,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["cells10092324"],"URL":"https:\/\/doi.org\/10.3390\/cells10092324","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,6]]}}}