Institute for Clinical Diabetology at the German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany.
Diabetologia. 2013 Jun;56(6):1356-63. doi: 10.1007/s00125-013-2883-3. Epub 2013 Mar 15.
AIMS/HYPOTHESIS: Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and meal-stimulated beta cell function in patients with longer term type 1 diabetes.
The beta cell function of 118 patients with type 1 diabetes of duration of 0.75-4.97 years was tested using a standardised liquid mixed meal test (MMT). Serum samples obtained at -5 to 120 min were analysed by multiplex bead-based technology for proinflammatory (IL-6, TNF-α), anti-inflammatory (IL-1 receptor antagonist [IL-1RA]) and regulatory (IL-10, TGF-β1-3) cytokines, and by standard procedures for C-peptide. Differences in beta cell function between patient groups were assessed using stepwise multiple regression analysis adjusting for sex, age, duration of diabetes, BMI, HbA1c and fasting blood glucose.
High fasting systemic concentrations of the proinflammatory cytokines IL-6 and TNF-α were associated with increased fasting and stimulated C-peptide concentrations even after adjustment for confounders (p < 0.03). Interestingly, increased concentrations of anti-inflammatory/regulatory IL-1RA, IL-10, TGF-β1 and TGF-β2 were associated with lower fasting and stimulated C-peptide levels (p < 0.04), losing significance on adjustment for anthropometric variables. During the MMT, circulating concentrations of IL-6 and TNF-α increased (p < 0.001) while those of IL-10 and TGF-β1 decreased (p < 0.02) and IL-1RA and TGF-β2 remained unchanged.
CONCLUSIONS/INTERPRETATION: The association between better preserved beta cell function in longer term type 1 diabetes and increased systemic proinflammatory cytokines and decreased anti-inflammatory and regulatory cytokines is suggestive of ongoing inflammatory disease activity that might be perpetuated by the remaining beta cells. These findings should be considered when designing immune intervention studies aimed at patients with longer term type 1 diabetes and residual beta cell function.
目的/假设：细胞因子可能促进或抑制 1 型糖尿病的疾病进展。我们研究了在患有 1 型糖尿病时间较长的患者中，与空腹和餐刺激β细胞功能相关的全身性促炎、抗炎和调节性细胞因子是否存在差异。
使用标准化的液体混合餐测试（MMT）测试了 118 例病程为 0.75-4.97 年的 1 型糖尿病患者的β细胞功能。在 -5 至 120 分钟时采集血清样本，采用基于微珠的多重分析技术分析促炎细胞因子（IL-6、TNF-α）、抗炎细胞因子（IL-1 受体拮抗剂 [IL-1RA]）和调节细胞因子（IL-10、TGF-β1-3），并采用标准程序分析 C 肽。通过逐步多元回归分析，在校正性别、年龄、糖尿病病程、BMI、HbA1c 和空腹血糖后，评估患者组之间的β细胞功能差异。
高空腹系统性促炎细胞因子 IL-6 和 TNF-α浓度与空腹和刺激 C 肽浓度增加相关，即使在校正混杂因素后也是如此（p <0.03）。有趣的是，抗炎/调节细胞因子 IL-1RA、IL-10、TGF-β1 和 TGF-β2 浓度增加与空腹和刺激 C 肽水平降低相关（p <0.04），但在校正人体测量学变量后失去意义。在 MMT 期间，循环中的 IL-6 和 TNF-α浓度增加（p <0.001），而 IL-10 和 TGF-β1 浓度降低（p <0.02），IL-1RA 和 TGF-β2 保持不变。
结论/解释：在病程较长的 1 型糖尿病患者中，更好的β细胞功能与全身性促炎细胞因子增加和抗炎及调节性细胞因子减少相关，提示炎症性疾病活动持续存在，这可能由剩余的β细胞维持。在设计针对病程较长的 1 型糖尿病和残余β细胞功能的免疫干预研究时，应考虑这些发现。
