Department of Medicine, University of Washington, Seattle, WA, United States.
Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States.
Front Immunol. 2021 Apr 26;12:640251. doi: 10.3389/fimmu.2021.640251. eCollection 2021.
The presence of islet autoantibodies and islet reactive T cells (T+) in adults with established type 2 diabetes (T2D) have been shown to identify those patients with more severe β-cell dysfunction. However, at what stage in the progression toward clinical T2D does islet autoimmunity emerge as an important component influencing β-cell dysfunction? In this ancillary study to the Restoring Insulin SEcretion (RISE) Study, we investigated the prevalence of and association with β-cell dysfunction of T+ and autoantibodies to the 65 kDa glutamic acid decarboxylase antigen (GADA) in obese pre-diabetes adults with impaired glucose tolerance (IGT) and recently diagnosed treatment naïve (Ndx) T2D. We further investigated the effect of 12 months of RISE interventions (metformin or liraglutide plus metformin, or with 3 months of insulin glargine followed by 9 months of metformin or placebo) on islet autoimmune reactivity. We observed GADA(+) in 1.6% of NdxT2D and 4.6% of IGT at baseline, and in 1.6% of NdxT2D and 5.3% of IGT at 12 months, but no significant associations between GADA(+) and β-cell function. T(+) was observed in 50% of NdxT2D and 60.4% of IGT at baseline, and in 68.4% of NdxT2D and 83.9% of IGT at 12 months. T(+) NdxT2D were observed to have significantly higher fasting glucose ( = 0.004), and 2 h glucose ( = 0.0032), but significantly lower steady state C-peptide (sscpep, = 0.007) compared to T(-) NdxT2D. T(+) IGT participants demonstrated lower but not significant ( = 0.025) acute (first phase) C-peptide response to glucose (ACPRg) compared to T(-) IGT. With metformin treatment, T(+) participants were observed to have a significantly lower Hemoglobin A1c (HbA1c, = 0.002) and fasting C-peptide ( = 0.002) compared to T(-), whereas T(+) treated with liraglutide + metformin had significantly lower sscpep ( = 0.010) compared to T(-) participants. In the placebo group, T(+) participants demonstrated significantly lower ACPRg ( = 0.001) compared to T(-) participants. In summary, T(+) were found in a large percentage of obese pre-diabetes adults with IGT and in recently diagnosed T2D. Moreover, T(+) were significantly correlated with treatment effects and β-cell dysfunction. Our results demonstrate that T(+) are an important component in T2D.
在已确诊的 2 型糖尿病（T2D）患者中，胰岛自身抗体和胰岛反应性 T 细胞（T+）的存在已被证明可识别那些β细胞功能障碍更严重的患者。然而，在向临床 T2D 进展的哪个阶段，胰岛自身免疫作为影响β细胞功能的重要因素出现？在这项针对 RISE 研究的辅助研究中，我们调查了肥胖前期糖尿病患者（IGT）和最近确诊未经治疗（Ndx）T2D 患者中 T+和 65kDa 谷氨酸脱羧酶抗原（GADA）自身抗体与β细胞功能障碍的相关性及其患病率。我们还进一步研究了 RISE 干预（二甲双胍或利拉鲁肽加二甲双胍，或 3 个月甘精胰岛素后 9 个月二甲双胍或安慰剂）对胰岛自身免疫反应的影响。我们发现，NdxT2D 中基线 GADA（+）为 1.6%，IGT 为 4.6%，而 12 个月时 NdxT2D 为 1.6%，IGT 为 5.3%，但 GADA（+）与β细胞功能之间无显著相关性。NdxT2D 中基线 T+为 50%，IGT 为 60.4%，而 12 个月时 NdxT2D 为 68.4%，IGT 为 83.9%。与 NdxT2D 的 T（-）相比，NdxT2D 的 T（+）表现出更高的空腹血糖（=0.004）和 2 小时血糖（=0.0032），但稳态 C 肽（sscpep，=0.007）更低。与 T（-）IGT 相比，T（+）IGT 参与者的葡萄糖急性（第一相）C 肽反应（ACPRg）较低，但无统计学意义（=0.025）。与二甲双胍治疗相比，T（+）参与者的血红蛋白 A1c（HbA1c，=0.002）和空腹 C 肽（=0.002）明显低于 T（-），而 T（+）用利拉鲁肽+二甲双胍治疗的患者的 sscpep（=0.010）明显低于 T（-）参与者。在安慰剂组中，与 T（-）相比，T（+）参与者的 ACPRg（=0.001）明显更低。总之，在患有 IGT 的肥胖前期糖尿病患者和最近确诊的 T2D 患者中，发现 T（+）的比例较大。此外，T（+）与治疗效果和β细胞功能障碍显著相关。我们的结果表明，T（+）是 T2D 的一个重要组成部分。
