妊娠期不同糖耐量状态下胰高血糖素和胰高血糖素样肽1分泌特点

Secretion of glucagon and glucagon-like peptide-1 in different glucose tolerance status during pregnancy

目的评估不同糖耐量状态下孕妇临床及生化特征，以及糖负荷后胰岛素、胰高血糖素及胰高血糖素样肽1（GLP-1）的分泌特点。方法选取2009年1月至2012年6月北京协和医院定期规律随诊的孕妇，纳入妊娠24—28周50g葡萄糖负荷试验（GCT）阳性者74例，进一步行100g口服葡萄糖耐量试验（OGTT），将孕妇分为妊娠糖尿病（GDM）组（25例）、糖耐量异常（IGT）组（25例）和糖耐量正常（NGT）组（24例）。比较3组孕妇的一般临床资料和生化指标，计算及评估胰岛素抵抗和胰岛B细胞分泌功能相关指数。OGTT中，同时测定血糖、胰岛素、胰高血糖素和GLP-1水平，评估各激素的分泌特点，分析其与其他指标的相关性。结果GDM组孕妇的GCT血糖值、糖化血红蛋白高于NGT组[（9．21±0．75）mmol／L比（8．52±0．50）mmol／L，（5．39±0．34）％比（5．18±0．20）％，均P〈0.05]。OGTY中，GDM组血糖曲线下面积显著高于IGT组和NGT组[（26．58±2．02）mmol／（L·h）比（23．20±1．51）、（19．84±1．95）mmol／（L·h），均P〈0．05]。GDM和IGT两组的胰岛素分泌高峰延迟至糖负荷后2h，GDM组3h胰岛素水平显著高于NGT组（P〈0．05）。与NGT组相比，GDM组和IGT组OGTT各点胰高血糖素水平及曲线下面积有降低趋势，但差异无统计学意义。各组胰高血糖素水平均在糖负荷后3h出现峰值。与NGT组相比，从IGT组至GDM组OGTT各点GLP-1水平有逐渐升高趋势，但差异无统计学意义。GLP-1分泌峰值在NGT组和IGT组出现于糖负荷后1h，在GDM组出现于糖负荷后2h，各组GLP-1水平均在糖负荷后3h达到谷值。GDM组1和2hGLP-1与血糖比值（GLP／BG）显著低于NGT组（P〈0．05）。OGTT胰高血糖素曲线下面积与空腹血糖（r=-0．287，P=0．013）及OGTT1h血糖（r=-0．266，P=0．022）水平呈负相关，与胰岛素分泌敏感性指数（ISSI）（r=0．297，P=0．010）和稳态模型胰岛β细胞功能指数（r=0．236，P=0．043）呈正相关。OGTY中GLP-1曲线下面积与C反应蛋白水平呈负相关（r=-0．264，P=0．035）。OGTT中GLP／BG曲线下面积与ISSI呈正相关（r=0．406，P〈0．001）。结论中孕期GDM和IGT患者均存在胰岛素抵抗和胰岛B细胞功能缺陷，GDM患者可能存在潜在的GLP-1抵抗和分泌不足，GLP／BG可能是评价妊娠期L细胞分泌功能的更佳指标，以及间接评价胰岛β细胞代偿分泌能力的有效指标。而胰高血糖素水平可能由于孕周不足尚未出现明显的变化。

Objective To evaluate the clinical and biochemical characteristics of pregnant women with different glucose tolerance status, and their secretion characteristics of insulin, glucagon and glucagon-like peptide- 1 （GLP- 1 ） after oral glucose challenge. Methods We analyzed 74 cases pregnant women with positive results of 50 g glucose challenge test in 24 - 28 gestational weeks, who received regular obstetrical follow-up in Peking Union Medical College Hospital from January 2009 to June 2012. A further 100 g oral glucose tolerance test （OGTT） was performed, based on which the included women were divided into three groups, namely gestational diabetes mellitus （GDM） group （n =25 ）, impaired glucose tolerance （IGT） group （n = 25 ） and normal glucose tolerance （NGT） group （ n = 24 ）. The general clinical data and biochemical indexes of the three groups were compared, and the indexes about insulin resistance and the function of pancreatic islet beta cells were calculated. Glucose, insulin, glucagon and GLP-1 were measured in OGTT. The secretion characteristics of each of these hormones and their correlation with other indicators were evaluated. Results Compared with the NGT group, the GCT [ （9. 21 ＋-0. 75） mmol/L vs. （8.52 ＋-0. 50） mmol/L, P 〈0. 05] and glycosylated hemoglobin Alc [ （5. 39 ＋-. 34）% vs. （5.18 ＋- 0. 20） %, P 〈 0. 05 ] were significantly higher in the GDM group. In OGTY, the area under curve （AUC） of glucose in the GDM group was significantly higher than that in the IGT group and NGT group [ （26.58 ＋-2.02） mmol/（L · h） vs. （23.20 ＋- 1.51） mmol/（L· h）, （26. 58 ＋- 2. 02） mmol/（L · h） vs. （ 19. 84 ＋- 1.95） mmol/（ L · h）, both P 〈 0. 05 ]. The peak values of insulin＇ secretion in the GDM group and IGT group were delayed to 2 hours after OGTL The 3-hour insulin level in the GDM group was significantly higher than that in the NGT group （P 〈 0. 05）. Compared with the NGT group, the glucagon levels in each time point after OGTr and the AUC of glucagon levels were reduced in the GDM group and the IGT group, but with no significant differences. The peak glucagon levels in the 3 groups all appeared at 3 hours after OGTr. The GLP-1 levels in each time point of OGTT were gradually increased from the NGT group to the IGT group to the GDM group, but no significant differences were found. The peak value of GLP-1 level was presented at 1 hour after OGTT in the NGT group and the IGT group and at 2 hours after OGTT in the GDM group. The valley values of GLP-1 level in the 3 groups all appeared at 3 hours after OGTr. In comparison with the NGT group, the ratios of GLP-1 to blood glucose levels （GLP/BG） at 1-hour and 2-hour were significantly decreased in the GDM group （P 〈0. 05）. The AUC of glucagon levels in OGTT were negatively correlated with fasting blood glucose （r = -0. 287, P =0. 013） and 1-hour glucose levels （r = -0. 266, P =0. 022） in OGTT and positively correlated with insulin secretion sensitivity index （ISSI） （ r = 0. 297, P = 0. 010） and HOMA-13 （r = 0. 236, P = 0. 043 i. Moreover, the AUC of GLP-1 levels in OGTF was negatively correlated with the levels of C-reactive protein （r = -0. 264, P =0. 035）. The AUC of GLP/BG in OGTT was positively correlated with ISSI （r =0.406, P〈0.001）. Conclusions Pregnant women with GDM and IGT in the second trimester have insulin resistance and dysfunction of pancreatic islet [3 cells. Potential GLP-1 resistance and inadequate secretion may exist in GDM patients. GLP/BG may be a better parameter to evaluate the secretion function of L cells in pregnancy and an effective parameter to estimate the compensatory function of pancreatic β cells indirectly. Glu- cagon levels may not start to change obviously before 28 gestational weeks. [ Key words] Gestational diabetes mellitus; Insulin resistance; Glucagon; Glucagon-like peptide-1