Supplementary Material for: Central GLP-1 Resistance Induced by Severe Traumatic Brain Injury was Associated with Persistent Hyperglycemia in Humans

Introduction: Whether central glucagon-like peptide 1 (GLP-1)/GLP-1 receptor system mediated peripheral glucose homeostasis in patients with traumatic brain injury (TBI) is not clear. We aim to determine if plasma GLP-1 level could distinguish the non-survivors from the survivors during the first 14 days after TBI that could prognose 6 months mortality. Methods: Metabolic, inflammatory, and hematological profiles were examined in 73 patients with TBI in neuro-ICU. Factors that discriminate non-survivors from survivors were determined by Two-way ANOVA. Biomarkers associated with mortality were determined by Binary logistic regression and Cox proportional hazard regression. Results: The non-survivors had higher infectious SOFA scores (P<0.001), lower first 3 days’ body temperature (P=0.017), greater chance of cerebral hernia (P=0.048) and decompressive craniectomy (P=0.001) than the survivors. Higher 14-days plasma GLP-1 (P<0.0001), glucose (P=0.002) and IL-6 (P=0.005) levels, in contrast with lower insulin level at days 4-7 (P=0.020) were found in non-survivors than in survivors. Except the survivors had an increased 14-days platelet number (P<0.001), the two groups did not differ in hematological profile and intestinal barrier function. Although GLP-1 correlated closely with IL-6 in both the two groups, it correlated with neither insulin nor glucose in each group. GLP-1 on days 8-10 and IL-6 on days 1-3 were positively, while insulin on days 4-7 was negatively associated with mortality. Conclusion：Persistent higher GLP-1 level in non-survivors over the survivors may present more severe central resistance to endogenous GLP-1 in non-survivors, which may be associated with progressive hyperglycemia with increased mortality in TBI.

引言：中枢胰高血糖素样肽1（glucagon-like peptide 1, GLP-1）/GLP-1受体系统是否介导创伤性脑损伤（traumatic brain injury, TBI）患者的外周血糖稳态，目前尚无定论。本研究旨在明确创伤性脑损伤后前14天内的血浆GLP-1水平是否可区分存活者与非存活者，进而预测患者6个月的死亡率。
方法：纳入神经重症监护室（neuro-intensive care unit, neuro-ICU）的73例创伤性脑损伤患者，对其代谢、炎症及血液学特征进行检测。采用双因素方差分析（Two-way ANOVA）筛选可区分存活者与非存活者的相关因素；通过二元logistic回归（Binary logistic regression）与Cox比例风险回归模型（Cox proportional hazard regression）明确与死亡率相关的生物标志物。
结果：与存活者相比，非存活者的感染相关序贯器官衰竭评分更高（P<0.001），伤后前3日体温更低（P=0.017），脑疝发生率更高（P=0.048），且接受去骨瓣减压术的比例更高（P=0.001）。非存活者的伤后14天血浆GLP-1（P<0.0001）、血糖（P=0.002）及白细胞介素6（interleukin-6, IL-6）水平均显著高于存活者，而第4~7日的胰岛素水平则更低（P=0.020）。除存活者的伤后14天血小板计数更高（P<0.001）外，两组的血液学指标与肠屏障功能均无显著差异。尽管两组患者的GLP-1水平均与IL-6呈显著正相关，但GLP-1在各组内均与胰岛素或血糖无相关性。伤后第8~10日的GLP-1水平与第1~3日的IL-6水平均与死亡率呈正相关，而第4~7日的胰岛素水平则与死亡率呈负相关。
结论：非存活者体内GLP-1水平持续高于存活者，提示非存活者对内源性GLP-1存在更严重的中枢抵抗，这可能与创伤性脑损伤患者的进行性高血糖及死亡率升高相关。