Latent Autoimmune Diabetes in Adults

IDF 2025微专辑扫描二维码可查看更多内容编者按：胰岛素泵和血糖动态监测，使糖尿病患者不再真正遭受低血糖和高血糖的困扰。但在提升生活质量的同时，因不合理饮食导致肥胖，新表型双重糖尿病带来了新的临床挑战，同一患者可能同时出现1型糖尿病（T1D）和2型糖尿病（T2D）的并发症。在2025年4月7~10日曼谷举办的2025年国际糖尿病联盟世界糖尿病大会上（IDF2025），我们特邀意大利罗马生物医学自由大学 Paolo Pozzilli教授做客“遇见IDF·每日精粹”直播间，就该话题进行了深入探讨，相关核心内容整理如下。《国际糖尿病》Q1您团队提出的“双重糖尿病”概念将肥胖与β细胞自身免疫结合，提示患者心血管风险显著增加。请问“双重糖尿病”这一新临床表型具有哪些临床意义？Pozzilli教授：T1D与肥胖问题在疾病管理中正扮演着新角色。过去，典型T1D患者通常消瘦，并缺乏胰岛素。而现在，许多患者出现肥胖。由于胰岛素泵的使用，患者可以自由饮食，血糖监测和自动调节胰岛素量使低血糖风险降低，看似完美。但进食增加及伴随的外源性胰岛素用量上升，促使体重增长，导致技术诱导的T1D新表型。这带来了很多问题，特别是，同一患者可能同时出现1型和T2D的并发症。传统1型并发症主要是视网膜病变、肾病和神经病变，现在却新增了T2D的典型并发症，以心血管风险为特征的大血管病变。虽然在治疗方面，我们有大量讨论关于GLP-1受体激动剂可否批准用于T1D，但最迫切的问题是，患者需要减重，否则心血管并发症的风险将增加。我认为，对于今天的T1D患者，胰岛素泵这项新技术让生活更轻松和美好，但在提升生活质量的同时，也带来了新的挑战。我们需要根据法律法规，合理地运用现有药物进行规范治疗。《国际糖尿病》Q2您认为是否需要针对“双重糖尿病”调整传统血糖控制目标，并整合减重与免疫调节的双重干预？Pozzilli教授：免疫调节取决于β细胞功能障碍的进程。在疾病早期，T1D有典型的自身免疫过程。但若饮食不当导致超重，就会增加自身免疫过程，并导致β细胞功能障碍。人们会失去更多的β细胞，进而再需要更多的胰岛素。因此，对于T1D高危人群，如T1D患者的一级亲属，预防超重和肥胖非常重要。总之，肥胖会刺激自身免疫进程，导致β细胞功能障碍，以及促使T1D发病。《国际糖尿病》Q3现有免疫疗法难以长期维持β细胞功能，联合治疗与精准医疗已成为趋势。请问，您认为下一代免疫治疗的核心突破点是什么？Pozzilli教授：自80年代，我参与的首个环孢素国际试验开始，就已经投身于糖尿病的免疫治疗了。四十年来，许多药物试验都未能有效保护残余的β细胞功能，也无法通过刺激残余的β细胞功能来恢复其部分功能。而近期，抗CD3抗体在新诊断患者和T1D高危人群中，都显示出了治疗前景。未来，我认为可能需要联合靶向不同病理机制的抗体，因为β细胞损伤是涉及多重机制的。当下，使用抗CD3似乎很有希望，因为它可以延缓糖尿病的进程。尽管最终可能仍会患糖尿病，但早期干预可以保留更多的内源性β细胞功能。已有研究证实，保留β细胞功能的患者，长期并发症更少。一项通过在50岁的T1D患者中测量β细胞功能标志物C肽的研究发现，保留C肽的患者并发症更少，如更少的视网膜病变和神经病变。总之，我们的目标不是完全停用胰岛素，而是通过适量的胰岛素，来增强保护残余β细胞功能。《国际糖尿病》Q4您始终将患者放在首位并以患者为中心。请问，如何实现"在正确时间为合适患者选择恰当疗法"？Pozzilli教授：对患者进行分层，首先我们必须记住，T1D具有高度异质性。基本上，我们有4个不同的T1D发病年龄，即青春期前、青春期、青年成人以及50-60岁后，如成人隐匿性自身免疫糖尿病（LADA）。不同发病年龄需要差异化治疗。以LADA为例，患者在40岁或以上时发展为自身免疫性糖尿病，他们基本上是T2D患者。但因持续的自身免疫过程，他们又是T1D。对于这类患者，免疫干预能有效保护C肽水平，从而预防并发症。《国际糖尿病》Q1从teplizumab获批到干细胞教育疗法的探索，T1D治疗正在进入疾病治疗的新阶段。请问，您最期待未来哪种技术会变革T1D的治疗格局？Pozzilli教授：一方面，遗传操作在I期试验中展现了潜力，在疾病非常早期阶段，改变疾病过程，该方法虽然有趣但应用可能尚远。另一方面，人工智能（AI）对疾病其异质性也有良好处理能力，通过分析患者基因表型特征，能给我们启发来决定特定患者的最佳治疗方案，从临床角度，这很有用。当然，这并非简单听AI说，而是参考它提供的文献并独立判断。因此，我相信临床和科研都能获益于AI使用带来的便捷和优势。结语抗CD3单克隆抗体突破四十年来的治疗瓶颈，在新诊断患者和T1D高危人群中均显示出了治疗前景。期待更多药物开发，联合靶向不同病理机制，有效保护残余的β细胞功能；再通过AI技术的合理利用，早日解决双重糖尿病难题，惠及患者。专家简介Paolo Pozzilli教授意大利罗马生物医学自由大学意大利罗马生物医学自由大学内分泌学教授英国伦敦玛丽女王大学糖尿病和临床研究教授专注于1型糖尿病（T1D）的发病机制和预防发表超过560篇关于糖尿病的科学文章、书籍和综述积极参与1型和2型糖尿病新型疗法的临床试验《糖尿病代谢研究与评论》杂志主编声明：本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。最新《国际糖尿病》读者专属微信交流群建好了，快快加入吧！扫描左边《国际糖尿病》小助手二维码（微信号：guojitnb），回复“国际糖尿病读者”，ta会尽快拉您入群滴！（来源：《国际糖尿病》编辑部）版权声明版权属《国际糖尿病》所有。欢迎个人转发分享。其他任何媒体、网站未经授权，禁止转载。

STOCKHOLM, April 21, 2025 /PRNewswire/ -- In a recent investor interview, Diamyd Medical Board Member Professor Mark Atkinson and CEO Ulf Hannelius shared key insights into the Company's positioning as a first-mover in precision medicine-based, disease-modifying and preventive treatment for Type 1 Diabetes. The discussion covered the strong safety profile and genetically targeted approach of the Diamyd Medical's investigational therapy Diamyd®, the opportunity to expand into the adult-onset autoimmune diabetes (LADA) segment increasingly recognized as part of the Type 1 Diabetes spectrum, and the major milestones ahead - including a registrational Phase 3 readout expected within 12 months. "We are not just treating Type 1 Diabetes - we're actually aiming to prevent and cure it," says Ulf Hannelius, CEO of Diamyd Medical. "And with LADA now increasingly recognized as Type 1 Diabetes, the potential market more than doubles." Positioning of Diamyd® Diamyd® is a precision immunotherapy targeting individuals with a specific HLA genotype associated with Type 1 Diabetes. Over 1,000 patients have been treated with Diamyd®, a durable investigational antigen-specific GAD-based therapy, giving it a robust safety track record. The treatment aims to preserve endogenous insulin production by reprogramming the immune system-addressing the root cause of the disease rather than just managing blood glucose. "Diamyd has one of the strongest safety profiles of any drug that I'm aware of seeking to prevent Type 1 Diabetes," says Professor Mark Atkinson, Board Member and Chair of Diamyd Medical's Scientific Advisory Board. "The combination of safety and therapeutic durability makes Diamyd a very attractive treatment." A precision platform with broad reach Diamyd Medical's approach is built around matching therapy to the patient's genetic profile. The Company is currently enrolling only patients with the appropriate HLA genotype in its Phase 3 trial DIAGNODE-3. Diamyd Medical is also taking steps to broaden its precision medicine platform. "With GAD we target about 40 % of Type 1 Diabetics in the Western world. By adding insulin as a second antigen, we can potentially reach 90 %," says Ulf Hannelius. "This antigen-specific approach also makes Diamyd® an ideal candidate for future combination therapies-given its safety, durability and lack of systemic immune suppression." "Some of the other candidates don't afford the ability for as a safe combination, because of toxicity or immune system compromise", says Professor Atkinson. "Given its strong safety profile and precision mechanism, I believe Diamyd has real potential as part of combination treatments." Indications: From newly diagnosed to prevention and adult-onset Type 1 Diabetes While Diamyd Medical's Phase 3 trial focuses on newly diagnosed Type 1 Diabetes (Stage 3), the Company's pipeline spans the full disease continuum - from at-risk individuals to slow-progressing adult-onset cases. Increasing scientific consensus now recognizes LADA (Latent Autoimmune Diabetes in Adults) as a form of Type 1 Diabetes. "The American Diabetes Association now includes LADA under the Type 1 Diabetes umbrella," Ulf Hannelius emphasizes. Professor Atkinson adds: "We now believe that it's just a population of slow-progressing individuals with Type 1 Diabetes that happen to occur in adults. Many of these patients are GAD antibody-positive, making Diamyd a unique and optimal drug." Diamyd Medical is one of the very few - and possibly the only - companies to have conducted interventional trials in LADA patients, with safety data extending up to age 70. "If we secure regulatory approval in Type 1 Diabetes, we will explore extending our label to include adult-onset Type 1 Diabetes," says Ulf Hannelius. "This could more than double the addressable market for Diamyd." Diamyd Medical has conducted market research in the United States that supports peak sales potential of USD 2 billion in the Stage 3 Type 1 Diabetes population targeted as the initial indication. The same research shows that extending the label to adult-onset Type 1 Diabetes could more than double the commercial opportunity. Milestones ahead Diamyd Medical expects several key milestones within the next 12 months including: Top-line results from its single pivotal Phase 3 trial DIAGNODE-3 to support an accelerated approval pathway in the U.S. GMP certification of its biologics manufacturing facility in Sweden "DIAGNODE-3 is the first-ever precision medicine Phase 3 trial in Type 1 Diabetes," says Ulf Hannelius. "We've screened over 600 patients to identify the right genetic match." "This trial is not a Hail Mary pass," adds Professor Atkinson. "Countless months went into designing this trial based on past data, experience, and genetics. Everything pragmatically possible has been done to maximize the chances of success." A strong case for impact and market adoption Beyond the scientific and regulatory readiness, the Company sees strong commercial potential. "We've conducted market research in the U.S. with providers and payers," Ulf Hannelius says. "The feedback has been very positive - they see a significant need and view this as a strong candidate for adoption." Professor Atkinson closes with a broader reflection: "This is not just an investment opportunity. It's a chance to improve lives, prevent disease, and be part of something that has real societal benefit." Watch the full 60-minute interview at: About Diamyd Medical Diamyd Medical develops precision medicine therapies to prevent and treat Type 1 Diabetes. Diamyd® is an investigational antigen-specific immunomodulatory therapeutic for the preservation of endogenous insulin production specifically for individuals carrying a HLA DR3-DQ2 gene. Diamyd® has been granted Orphan Drug Designation in the U.S. as well as Fast Track Designation by the U.S. FDA for the treatment of Stage 3 (clinically diagnosed symptomatic) Type 1 Diabetes. Diamyd® has also been granted Fast Track Designation for the treatment of Stage 1 and 2 (pre-symptomatic) Type 1 Diabetes. DIAGNODE-3, a confirmatory Phase III trial is actively recruiting patients with recent-onset (Stage 3) Type 1 Diabetes at 60 clinics in eight European countries and in the US. An early read-out of the Phase 3 trial is expected in March 2026. Significant results in preserving endogenous insulin production have previously been shown in a large genetically predefined patient group - both in a large-scale meta-analysis as well as in the Company's prospective European Phase IIb trial. The DIAGNODE-3 trial is recruiting only this patient group that carries the common genotype known as HLA DR3-DQ2, which constitutes approximately 40 % of patients with Type 1 Diabetes in Europe and the US. A biomanufacturing facility is under development in Umeå, Sweden, for the manufacture of recombinant GAD65 protein, the active ingredient in the antigen-specific immunotherapy Diamyd®. Diamyd Medical is a major shareholder in the stem cell company NextCell Pharma AB and in the artificial intelligence company MainlyAI AB. Diamyd Medical's B share is traded on Nasdaq First North Growth Market under the ticker DMYD B. FNCA Sweden AB is the Company's Certified Adviser. For further information, please contact: Ulf Hannelius, President and CEO Phone: +46 736 35 42 41 E-mail: [email protected] This information was brought to you by Cision The following files are available for download: WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

点击“蓝字”关注我们 编者按 成人隐匿性自身免疫性糖尿病（latent autoimmune diabetes in adult，LADA）是由于成年期胰岛β细胞破坏导致胰岛素分泌绝对不足的自身免疫性疾病，中老年人多发，属于1型糖尿病（T1DM）的亚型，需要完全依赖胰岛素治疗。LADA的临床表现与2型糖尿病（T2DM）类似，疾病初期临床症状具有隐匿性，经口服降糖药治疗不佳且并发症和继发症较多而就医，多数患者因早期未出现典型症状易被误诊、漏诊[1]。本文中，广东医科大学附属医院骆梓恒医生分享一例LADA患者的临床诊疗经过，并回顾性分析该患者的临床表现、相关检验检查手段及诊断标准。 患者基本信息 患者男性，45岁。主因“发现血糖升高3年，恶心、呕吐1天”，以“糖尿病酮症酸中毒”由急诊收入院。 现病史 患者3年前体检时发现血糖升高，数值不详，在外院门诊诊断为“2型糖尿病”，给予二甲双胍、阿卡波糖治疗。患者未规律用药，未积极控制饮食及运动，未监测血糖。半年内2次因饮食不当出现恶心、呕吐胃内容物，于急诊诊断为“2型糖尿病、糖尿病酮症”，给予补液、降糖治疗后好转，继续口服降糖药治疗。1天前再次因胃部不适伴恶心呕吐于急诊就诊，检查结果见下文。 既往史 体健，否认高血压、心脑血管疾病病史。 家族史 否认糖尿病家族史。 体格检查 体重73kg，身高172cm，BMI 24.67kg/m2。体温35.9℃，心率94次/分，呼吸25次/分，血压120/70mmHg，腰围89cm，臀围94cm。发育正常，营养良好，神志清楚，呼之能应，精神弱，平卧位。全身皮肤黏膜无苍白、黄染、发绀，无色素沉着、皮疹、蜘蛛痣、出血点、瘢痕。全身浅表淋巴结未触及。头颅无畸形，眼睑无水肿，结膜无苍白，巩膜无黄染，双侧瞳孔等大等圆，对光反射灵敏。外耳道、鼻无畸形。口唇无发绀，咽部无充血，双侧扁桃腺未见肿大。颈部无强直，气管居中，未见颈静脉充盈及颈动脉异常搏动。双侧甲状腺未及肿大。双侧呼吸运动对称，呼吸深快，双肺呼吸音粗，未闻及干湿啰音。叩诊心界不大，律齐，未闻及异常心音及杂音。腹软，肝脾肋下未及，未触及包块，无压痛、肌紧张；全腹叩诊鼓音，移动性浊音阴性；肠鸣音5次/分。双下肢无水肿，双足背动脉搏动正常。 检查结果 随机血糖24.9mmol/L，糖化血红蛋白13.2%，尿糖（++++），尿酮体（++++）。血气分析：pH 7.22，PO2 125mmHg，PCO2 26.7mmHg，BE -10.1mmol/L。入院诊断：糖尿病酮症酸中毒。 治疗方案 入院后完善各项检查，空腹血糖19.9mmol/L，尿糖（++++），尿酮体（++）。血气分析：pH 7.3，PO2 105mmHg，PCO2 23.7mmHg，BE -4.3mmol/L。空腹C肽0.03ng/L，餐后2小时C肽0.03ng/L。胰岛自身抗体：ICA（-）、IAA（-）、GAD（+）。尿微量白蛋白定量12.6mg/g，Ccr 76μmol/L，BUN 7.56μmol/L，ALT 11U/L，AST 24U/L，GGT 17U/L，TC 7.3mmol/L，TG 2.7mmol/L，LDL-C 5.3mmol/L，HDL-C 1.91mmol/L，钠132mmol/L，氯97mmol/L，钾5.8mmol/L，血白细胞12.15x109/L，N% 78%。 治疗 ①去除诱因，大量补液，纠正酸中毒及电解质紊乱；静脉应用小剂量胰岛素治疗。酮症酸中毒纠正后给予基础+餐时多次胰岛素皮下注射治疗。②他汀调脂。 出院诊断 糖尿病酮症酸中毒，LADA，血脂异常。 病例诊疗思考与总结 患者空腹血糖高达19.9mmol/L，尿糖阳性，酮体阳性，血气分析提示代谢性酸中毒，故糖尿病、糖尿病酮症酸中毒诊断明确。但患者多次出现糖尿病急性并发症（糖尿病酮症）甚至酮症酸中毒，考虑有T1DM的可能。住院后患者的检查结果显示其胰岛功能C肽几乎为零，糖尿病自身抗体GAD（+），结合患者的年龄和糖尿病病程，可以明确诊断为LADA。 LADA是T1DM中的一个特殊亚型，是早期胰岛细胞自身免疫性损伤缓慢进展引起的糖尿病，多成年发病、胰岛自身抗体阳性、进展缓慢、早期不需要胰岛素治疗，初发时临床特征与T2DM相似，不易区分。对于T1DM研究大多在于儿童及青少年时期，但研究发现中国30岁以上新诊断T2DM患者中LADA患病率为5.9%，LADA患者占全国新诊断T1DM患者65%，由于缺乏对LADA诊断及临床特点的深入研究，部分患者在疾病初期可能被错误地诊断为T2DM。当这些患者出现酮症酸中毒症状或胰岛细胞衰竭至需要依赖胰岛素控制血糖时，他们的诊断才会被更正为LADA。然而对于胰岛功能的严重衰竭，往往都是不可逆性的损伤，长期高血糖侵犯损伤神经、大血管、微血管，导致多种并发症的产生，包括：糖尿病肾病、糖尿病视网膜病变、糖尿病大血管病变、糖尿病周围神经病变、酮症酸中毒等。因此，临床上应尽早明确诊断，延缓患者胰岛细胞功能衰竭，以期延缓LADA患者病情发展[2-4]。 关于LADA的诊断标准，目前尚未有明确的定论，相关研究领域对其了解也相对有限。LADA患者与T1DM患者在遗传背景和免疫特征上展现出相似性，其共同特点在于免疫介导的胰岛细胞病理进展相对缓慢，进而导致胰岛细胞功能逐渐下降。然而，最近几年的研究揭示了一个重要发现：超过半数的T1DM病例发生在成年期。LADA的早期临床特征与T2DM相似，而在成人中>95%的糖尿病病例为T2DM，造成了临床鉴别的困难。2021年中国专家共识推荐LADA的诊断标准为：（1）发病年龄>18岁；（2）胰岛自身抗体阳性，或胰岛自身免疫T细胞阳性；（3）诊断糖尿病后至少半年不依赖胰岛素治疗。具备上述标准3项，即可以诊断LADA。ADA发布的2024年糖尿病诊疗指南中新增了对成人疑似T1DM的筛查流程，表型和T1DM重叠的成人应进行胰岛自身抗体检测，对于胰岛素自身抗体阴性患者，若C肽<200pmol/L，即诊断为T1DM；C肽>200pmol/L，进行单基因糖尿病检测；对于3年内200pmol/L