Automated insulin delivery by closed-loop systems (CLS) improves metabolic control in Type 1 diabetes (T1D), providing a flexible platform capable of matching their changing insulin requirements.¹ We hereby report the case of a 24-year-old woman being adequately controlled by a CLS, whose T1D became unstable following a tumor necrosis factor alpha inhibitor (iTNF-α). After onset of diabetes at the age of 12, her metabolic control worsened progressively, with mean glycated hemoglobin (HbA_1c) reaching 8.4% despite on multiple daily insulin injections supported by a carbohydrate counting plan. Accordingly, the patient started MiniMed 780G (Medtronic Northridge, California) in April 2022. After 1 month of CLS, HbA_1c decreased to 7.3%. She progressively developed severe hidradenitis suppurativa (HS). Having failed conventional management, her dermatologist prescribed adalimumab, starting on September 14, 2023. The patient experienced substantial glycemic variability (GV), increasing time below range (TBR) within 2 weeks of starting adalimumab. Data from continuous glucose monitoring confirmed the increase in TBR from 2% to 7% and GV from 31% to 39% when comparing the 2 weeks with adalimumab with the 2 weeks preceding its start. The risk of hypoglycemia showed an overlap of several automatic self-correcting insulin boluses, despite adequate suspension of the automatic basal rate and late postprandial hypoglycemia despite basal insulin delivery being discontinued (Figure 1). Suspecting an increase in insulin sensitivity due adalimumab, the configuration of CLS was changed, increasing the target to 120 mg/dL, active insulin duration to 4 h, and canceling the corrective boluses. Finally, we recommended her dermatologist to find a pharmacological alternative for HS.

Cell immunity and proinflammatory cytokines including TNF-α are involved in the pathogenic process of HS.^{2, 3} Data on sex hormones suggest that androgen excess may favor HS development in female patients. In conceptual agreement, the presence of functional hyperandrogenism in one out of every four female patients with T1D may underline the high frequency of newly diagnosed HS among these women.⁴

Hypoglycemia induced by iTNF-α is related to reduction in inflammation-induced insulin resistance. TNF-α induces insulin resistance by serine/threonine phosphorylation of the insulin receptor 1 substrate, interferes with normal phosphorylation of tyrosine, and impairs signal transduction of insulin resulting in insulin resistance through increasing the activities of the NF-κB transcriptional factor, protein kinase C, amino terminal kinase, and inhibitor kinase.⁵ We hypothesized that adalimumab led to a sudden increase in insulin sensitivity in our patient, not adequately compensated by the CLS, increasing the risk of hypoglycemia.

The main concept underlying learning is “run-to-run control”, widely applied in batch processes, where adjustments are made after each batch. In the context of a CLS, a “batch” is considered as a given past-time window, where specific glycemic control features are measured making parameters adjustments accordingly, usually with constraints for the sake of safety. This requires batch-to-batch repeatability for convergence, as high variability is a challenge for self-learning. This clinical case illustrates the limitation of current CLS in adapting to sudden changes in insulin sensitivity. We must advise patients with a CLS and iTNF-α to make preventive adjustments to the algorithm configuration to avoid hypoglycemic events.

闭环系统 (CLS) 的自动胰岛素输送改善了 1 型糖尿病 (T1D) 的代谢控制，提供了一个能够满足不断变化的胰岛素需求的灵活平台。¹我们特此报告一名 24 岁女性的病例，该患者通过 CLS 得到充分控制，但在使用肿瘤坏死因子 α 抑制剂 (iTNF-α) 后，她的 T1D 变得不稳定。12 岁时患上糖尿病后，她的代谢控制逐渐恶化，尽管在碳水化合物计数计划的支持下每天注射多次胰岛素，但平均糖化血红蛋白 (HbA _{1c ) 仍达到 8.4%。}因此，患者于 2022 年 4 月开始使用 MiniMed 780G（加利福尼亚州北岭美敦力）。CLS 1 个月后，HbA _1c下降至 7.3%。她逐渐患上严重的化脓性汗腺炎（HS）。由于常规治疗失败，她的皮肤科医生从 2023 年 9 月 14 日开始给她开了阿达木单抗。该患者在开始使用阿达木单抗后 2 周内经历了显着的血糖变异性 (GV)，低于范围的时间 (TBR) 增加。连续血糖监测数据证实，使用阿达木单抗治疗 2 周与开始治疗前 2 周相比，TBR 从 2% 增加至 7%，GV 从 31% 增加至 39%。尽管自动基础率已充分暂停，但低血糖风险仍显示出多次自动自我校正胰岛素推注的重叠，以及尽管基础胰岛素输送已停止但仍出现餐后低血糖（图1）。由于怀疑阿达木单抗导致胰岛素敏感性增加，因此改变了 CLS 的配置，将目标增加到 120 mg/dL，活性胰岛素持续时间增加到 4 小时，并取消校正推注。最后，我们建议她的皮肤科医生寻找治疗 HS 的药物替代方案。

细胞免疫和TNF-α等促炎细胞因子参与HS的发病过程。^{2, 3}性激素数据表明，雄激素过多可能有利于女性患者发生 HS。在概念上一致，每 4 名女性 T1D 患者中就有 1 人存在功能性高雄激素血症，这可能突显了这些女性新诊断 HS 的频率很高。⁴

iTNF-α 引起的低血糖与炎症诱导的胰岛素抵抗的减少有关。TNF-α通过胰岛素受体1底物的丝氨酸/苏氨酸磷酸化诱导胰岛素抵抗，干扰酪氨酸的正常磷酸化，并通过增加NF-κB转录因子、蛋白激酶C的活性损害胰岛素信号转导，导致胰岛素抵抗、氨基末端激酶和抑制剂激酶。⁵我们假设阿达木单抗导致患者的胰岛素敏感性突然增加，但 CLS 无法充分补偿，从而增加了低血糖的风险。

学习的主要概念是“运行间控制”，广泛应用于批处理过程，在每个批处理后进行调整。在 CLS 的背景下，“批次”被视为给定的过去时间窗口，其中测量特定的血糖控制特征并相应地调整参数，通常出于安全考虑而进行限制。这需要批次间的可重复性以实现收敛，因为高可变性是自学习的挑战。这一临床案例说明了当前 CLS 在适应胰岛素敏感性突然变化方面的局限性。我们必须建议患有 CLS 和 iTNF-α 的患者对算法配置进行预防性调整，以避免低血糖事件。