Mulla Christopher M, Goldfine Allison B, Dreyfuss Jonathan M, Houten Sander, Pan Hui, Pober David M, Wewer Albrechtsen Nicolai J, Svane Maria S, Schmidt Julie B, Holst Jens Juul, Craig Colleen M, McLaughlin Tracey L, Patti Mary-Elizabeth
Research Division, Joslin Diabetes Center, and Harvard Medical School, 1 Joslin Place, Boston, MA, 02215, USA.
Department of Biomedical Engineering, Boston University, Boston, MA, USA.
Obes Surg. 2019 Jul;29(7):2092-2099. doi: 10.1007/s11695-019-03845-0.
Hypoglycemia is an increasingly recognized complication of bariatric surgery. Mechanisms contributing to glucose lowering remain incompletely understood. We aimed to identify differentially abundant plasma proteins in patients with post-bariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB), compared to asymptomatic post-RYGB.
Proteomic analysis of blood samples collected after overnight fast and mixed meal challenge in individuals with PBH, asymptomatic RYGB, severe obesity, or overweight recruited from outpatient hypoglycemia or bariatric clinics.
The top-ranking differentially abundant protein at 120 min after mixed meal was fibroblast growth factor 19 (FGF-19), an intestinally derived hormone regulated by bile acid-FXR signaling; levels were 2.4-fold higher in PBH vs. asymptomatic post-RYGB (mean + SEM, 1094 ± 141 vs. 428 ± 45, P < 0.001, FDR < 0.01). FGF-19 ELISA confirmed 3.5-fold higher concentrations in PBH versus asymptomatic (360 ± 70 vs. 103 ± 18, P = 0.025). To explore potential links between increased FGF-19 and GLP-1, residual samples from other human studies in which GLP-1 was modulated were assayed. FGF-19 levels did not change in response to infusion of GLP-1 and PYY in overweight/obese individuals. Infusion of the GLP-1 receptor antagonist exendin 9-39 in recently operated asymptomatic post-RYGB did not alter FGF-19 levels after mixed meal. By contrast, GLP-1 receptor antagonist infusion yielded a significant increase in FGF-19 levels after oral glucose in individuals with PBH. While plasma bile acids did not differ between PBH and asymptomatic post-RYGB, these data suggest unique interrelationships between GLP-1 and FGF-19 in PBH.
Taken together, these data support FGF-19 as a potential contributor to insulin-independent pathways driving postprandial hypoglycemia in PBH.
低血糖是减重手术日益被认识到的一种并发症。导致血糖降低的机制仍未完全明确。我们旨在确定与无症状的Roux-en-Y胃旁路术（RYGB）术后患者相比，RYGB术后低血糖（PBH）患者血浆中丰度存在差异的蛋白质。
对从门诊低血糖或减重诊所招募的PBH患者、无症状RYGB患者、重度肥胖患者或超重患者，在过夜禁食和混合餐激发后采集的血样进行蛋白质组学分析。
混合餐后120分钟时，丰度差异最大的蛋白质是成纤维细胞生长因子19（FGF-19），这是一种由胆汁酸-FXR信号通路调节的肠道衍生激素；PBH患者的水平比无症状RYGB术后患者高2.4倍（均值±标准误，1094±141对428±45，P<0.001，FDR<0.01）。FGF-19酶联免疫吸附测定（ELISA）证实PBH患者的浓度比无症状患者高3.5倍（360±70对103±18，P=0.025）。为探究FGF-19升高与胰高血糖素样肽-1（GLP-1）之间的潜在联系，对其他涉及GLP-1调节的人体研究的剩余样本进行了检测。超重/肥胖个体中，FGF-19水平在输注GLP-1和肽YY（PYY）后未发生变化。在近期接受手术的无症状RYGB术后患者中输注GLP-1受体拮抗剂艾塞那肽9-39，混合餐后FGF-19水平未改变。相比之下，在PBH患者中输注GLP-1受体拮抗剂后，口服葡萄糖后FGF-19水平显著升高。虽然PBH患者与无症状RYGB术后患者的血浆胆汁酸无差异，但这些数据表明PBH患者中GLP-1与FGF-19之间存在独特的相互关系。
综上所述，这些数据支持FGF-19是驱动PBH患者餐后低血糖的胰岛素非依赖途径的潜在因素。
