{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T12:30:54Z","timestamp":1763728254117,"version":"3.41.2"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T00:00:00Z","timestamp":1658102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Latent Autoimmune Diabetes in Adults (LADA) constitutes around 10% of all diabetes. Many LADA patients gradually lose their insulin secretion and progress to insulin dependency. In a recent trial BALAD (Behandling Av LADa) early insulin treatment compared with sitagliptin failed to preserve insulin secretion, which deteriorated in individuals displaying high levels of antibodies to GAD (GADA). These findings prompted us to evaluate a treatment that directly affects autoimmunity. Intra-lymphatic GAD-alum treatment has shown encouraging results in Type 1 diabetes patients. We therefore tested the feasibility of such therapy in LADA-patients (the GADinLADA pilot study).<\/jats:p><\/jats:sec><jats:sec><jats:title>Material and Methods<\/jats:title><jats:p>Fourteen GADA-positive (&amp;gt;190 RU\/ml), insulin-independent patients 30-70 years old, with LADA diagnosed within &amp;lt; 36 months were included in an open-label feasibility trial. They received an intra-nodal injection of 4 \u03bcg GAD-alum at Day 1, 30 and 60 plus oral Vitamin D 2000 U\/d from screening 30 days before (Day -30) for 4 months if the vitamin D serum levels were below 100 nmol\/L (40 ng\/ml). Primary objective is to evaluate safety and feasibility. Mixed Meal Tolerance Test and i.v. Glucagon Stimulation Test at baseline and after 5 and 12 months are used for estimation of beta cell function. Results will be compared with those of the recent BALAD study with comparable patient population. Immunological response is followed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Preliminary results show feasibility and safety, with almost stable beta cell function and metabolic control during follow-up so far (5 months).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Intra-lymphatic GAD-alum treatment is an option to preserve beta cell function in LADA-patients. An ongoing trial in 14 LADA-patients show feasibility and safety. Clinical and immunological responses will determine how to proceed with future trials.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2022.926021","type":"journal-article","created":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T05:18:36Z","timestamp":1658121516000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Latent Autoimmune Diabetes in Adults: Background, Safety and Feasibility of an Ongoing Pilot Study With Intra-Lymphatic Injections of GAD-Alum and Oral Vitamin D"],"prefix":"10.3389","volume":"13","author":[{"given":"Anneli","family":"Bj\u00f6rklund","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingrid K.","family":"Hals","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valdemar","family":"Grill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johnny","family":"Ludvigsson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.2337\/dbi20-0017","article-title":"Management of Latent of Latent Autoimmune Diabetes in Adults: A Consensus Statement From an International Expert Panel","volume":"69","author":"Buzzetti","year":"2020","journal-title":"Diabetes"},{"key":"B2","doi-asserted-by":"crossref","DOI":"10.1007\/5584_2020_533","article-title":"\u201cLatent Autoimmune Diabetes in Adults: A Review of Clinically Relevant Issues\u201d","volume-title":"Adv. Exp. Med. Biol. - Advances in Internal Medicine","author":"Hern\u00e1ndez","year":"2020"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2174\/1573399814666180716144429","article-title":"Treatment of Latent Autoimmune Diabetes in A: What Is Best","volume":"15","author":"Hals","year":"2019","journal-title":"Curr Diabetes Rev"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.2174\/1573399814666180716152342","article-title":"A Form of Autoimmune Diabetes in Adults Named LADA-An Update on Essential Features and Controversies","volume":"15","author":"Grill","year":"2019","journal-title":"Curr Diabetes Rev"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/dom.13797","article-title":"Investigating Optimal Beta-Cell-Preserving Treatment in Latent Autoimmune Diabetes in Adults: Results From a 21-Month Randomized Trial","volume":"21","author":"Hals","year":"2019","journal-title":"Diabetes Obes Metab"},{"key":"B6","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1056\/NEJM198809083191002","article-title":"Immunosuppression With Azathioprine and Prednisone in Recent-Onset Insulin-Dependent Diabetes Mellitus","volume":"319","author":"Silverstein","year":"1988","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s001250051028","article-title":"Low Dose Linomide in Type I Juvenile Diabetes of Recent Onset: A Randomised Placebo-Controlled Double Blind Trial","volume":"41","author":"Coutant","year":"1998","journal-title":"Diabetologia"},{"key":"B8","article-title":"Anti-Thymocyte Globulin and Prednisone Immunotherapy of Recent Onset Type 1 Diabetes Mellitus","volume":"2","author":"Eisenbarth","year":"1985","journal-title":"Diabetes Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa012864","article-title":"Anti-CD3 Monoclonal Antibody in New-Onset Type 1 Diabetes Mellitus","volume":"346","author":"Herold","year":"2002","journal-title":"N Engl J Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa043980","article-title":"Insulin Needs After CD3-Antibody Therapy in New-Onset Type 1 Diabetes","volume":"352","author":"Keymeulen","year":"2005","journal-title":"N Engl J Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60931-8","article-title":"Teplizumab for Treatment of Type 1 Diabetes (Protege Study): 1-Year Results From a Randomised, Placebo-Controlled Trial","volume":"378","author":"Sherry","year":"2011","journal-title":"Lancet"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.2337\/db13-0236","article-title":"Teplizumab Preserves C-Peptide in Recent-Onset Type 1 Diabetes: Two-Year Results From the Randomized, Placebo-Controlled Prot\u00e9g\u00e9 Trial","volume":"62","author":"Hagopian","year":"2013","journal-title":"Diabetes"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2337\/dc13-0327","article-title":"Low-Dose Otelixizumab Anti-CD3 Monoclonal Antibody DEFEND-1 Study: Results of the Randomized Phase III Study in Recent-Onset Human Type 1 Diabetes","volume":"37","author":"Aronson","year":"2014","journal-title":"Diabetes Care"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.2337\/dc09-0054","article-title":"Etanercept Treatment in Children With New-Onset Type 1 Diabetes: Pilot Randomized, Placebo-Controlled, Double-Blind Study","volume":"32","author":"Mastrandrea","year":"2009","journal-title":"Diabetes Care"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2006136","article-title":"Golimumab and Beta-Cell Function in Youth With New-Onset Type 1 Diabetes","volume":"383","author":"Quattrin","year":"2020","journal-title":"N Engl J Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1172\/JCI78492","article-title":"Anti-Thymocyte Globulin\/G-CSF Treatment Preserves B Cell Function in Patients With Established Type 1 Diabetes","volume":"125","author":"Haller","year":"2015","journal-title":"J Clin Investig"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1172\/JCI81722","article-title":"Alefacept Provides Sustained Clinical and Immunological Effects in New-Onset Type 1 Diabetes Patients.J","volume":"125","author":"Rigby","year":"2015","journal-title":"Clin Investig"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0904452","article-title":"Rituximab, B-Lymphocyte Depletion, and Preservation of Beta-Cell Function","volume":"361","author":"Pescovitz","year":"2009","journal-title":"N Engl J Med"},{"key":"B19","doi-asserted-by":"publisher","first-page":"53","DOI":"10.4161\/isl.24785","article-title":"Antigen-Based vs. Systemic Immunomodulation in Type 1 Diabetes: The Pros and Cons","volume":"5","author":"Robert","year":"2013","journal-title":"Islets"},{"key":"B20","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/S2213-8587(18)30109-8","article-title":"Antigen-Based Immune Modulation Therapy for Type 1 Diabetes: The Era of Precision Medicine","volume":"7","author":"Roep","year":"2019","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdiacomp.2004.12.003","article-title":"Clinical Evidence for the Safety of GAD65 Immunomodulation in Adult-Onset Autoimmune Diabetes","volume":"19","author":"Agardh","year":"2005","journal-title":"J Diabetes Complications"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-009-1371-2","article-title":"GAD65 Vaccination: 5 Years of Follow-Up in a Randomised Dose-Escalating Study in Adult-Onset Autoimmune Diabetes","volume":"52","author":"Agardh","year":"2009","journal-title":"Diabetologia"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0804328","article-title":"GAD Treatment and Insulin Secretion in Recent-Onset Type 1 Diabetes","volume":"359","author":"Ludvigsson","year":"2008","journal-title":"N Engl J Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60895-7","article-title":"Antigen-Based Therapy With Glutamic Acid Decarboxylase (GAD) Vaccine in Patients With Recent-Onset Type 1 Diabetes: A Randomised Double-Blind Trial","volume":"378","author":"Wherrett","year":"2011","journal-title":"Lancet"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1107096","article-title":"GAD65 Antigen Therapy in Recently Diagnosed Type 1 Diabetes Mellitus","volume":"366","author":"Ludvigsson","year":"2012","journal-title":"N Engl J Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-016-4122-1","article-title":"GAD Vaccine Reduces Insulin Loss in Recently Diagnosed Type 1 Diabetes: Findings From a Bayesian Meta-Analysis","volume":"60","author":"Beam","year":"2017","journal-title":"Diabetologia"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21051598","article-title":"Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route.Int","volume":"21","author":"Ludvigsson","year":"2020","journal-title":"J Mol Sci"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.564921","article-title":"Glutamic Acid Decarboxylase Injection Into Lymph Nodes: Beta Cell Function and Immune Responses in Recent Onset Type 1 Diabetes Patients","volume":"11","author":"Casas","year":"2020","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.3500","article-title":"Immune Response Differs Between Intralymphatic or Subcutaneous Administration of GAD-Alum in Individuals With Recent Onset Type 1 Diabetes","volume":"5","author":"Dietrich","year":"2021","journal-title":"Diabetes Metab Res Rev"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s00592-022-01852-9","article-title":"Intra-Lymphatic Administration of GAD-Alum in Type 1 Diabetes: Long Term Follow-Up and Effect of a Late Booster Dose (the DIAGNODE Extension Trial)","volume":"59","author":"Casas","year":"2022","journal-title":"Acta Diabetol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.2337\/dc21-0318","article-title":"Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial","volume":"44","author":"Ludvigsson","year":"2021","journal-title":"Diabetes Care"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/S01406736(97)03062-6","article-title":"UKPDS 25: Autoantibodies to Islet-Cell Cytoplasm and Glutamic Acid Decarboxylase for Prediction of Insulin Requirement in Type 2 Diabetes. UK Prospective Diabetes Study Group","volume":"350","author":"Turner","year":"1997","journal-title":"Lancet"},{"key":"B33","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1530\/EJE-14-0342","article-title":"High GADA Titer Increases the Risk of Insulin Requirement in LADA Patients: A 7-Year Follow-Up (NIRAD Study 7)","volume":"171","author":"Zampetti","year":"2014","journal-title":"Eur J Endocrinol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.2337\/dc07-2451","article-title":"Type 1 Diabetes Trial Net Research Group Et al. Mixed-Meal Tolerance Test Versus Glucagon Stimulation Test for the Assessment of Beta-Cell Function in Therapeutic Trials in Type Diabetes","volume":"31","author":"Greenbaum","year":"2008","journal-title":"Diabetes Care"},{"key":"B35","first-page":"397","article-title":"Assessment of Residual Insulin Secretion in Diabetic Patients Using the Intravenous Glucagon Stimulatory Test: Methodological Aspects and Clinical Applications","volume":"22","author":"Scheen","year":"1996","journal-title":"Diabetes Metab"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.2337\/dc12-2251","article-title":"Cellular and Humoral Immune Responses in Type 1 Diabetic Patients Participating in a Phase III GAD-Alum Intervention Trial","volume":"36","author":"Axelsson","year":"2013","journal-title":"Diabetes Care"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-020-05227-z","article-title":"Efficacy of GAD-Alum Immunotherapy Associated With HLA-DR3-DQ2 in Recently Diagnosed Type 1 Diabetes","volume":"63","author":"Hannelius","year":"2020","journal-title":"Diabetologia"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(20)3000","article-title":"Time-Varying Risk of Microvascular Complications in Latent Autoimmune Diabetes of Adulthood Compared With Type 2 Diabetes in Adults: A Post-Hoc Analysis of the UK Prospective Diabetes Study 30-Year Follow-Up Data (UKPDS 86)","volume":"8","author":"Maddaloni","year":"2020","journal-title":"Lancet Diabetes Endocrinol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.926021\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T05:18:40Z","timestamp":1658121520000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.926021\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,18]]},"references-count":38,"alternative-id":["10.3389\/fendo.2022.926021"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2022.926021","relation":{},"ISSN":["1664-2392"],"issn-type":[{"type":"electronic","value":"1664-2392"}],"subject":[],"published":{"date-parts":[[2022,7,18]]},"article-number":"926021"}}