Meier J J, Gallwitz B, Askenas M, Vollmer K, Deacon C F, Holst J J, Schmidt W E, Nauck M A
Department of Medicine I, St Josef Hospital, Ruhr-University of Bochum, Bochum, Germany.
Diabetologia. 2005 Sep;48(9):1872-81. doi: 10.1007/s00125-005-1863-7. Epub 2005 Jul 12.
AIMS/HYPOTHESIS: The insulinotropic effect of gastric inhibitory polypeptide (GIP) is reduced in patients with type 2 diabetes and around 50% of their first-degree relatives under hyperglycaemic conditions. It is unknown whether this is a result of a specific defect in GIP action or of a general reduction in beta cell function. Moreover, impaired secretion of glucagon-like peptide 1 (GLP-1) has been described in patients with type 2 diabetes. Therefore, we studied the insulinotropic effect of GIP in women with previous gestational diabetes (pGDM) under euglycaemic fasting conditions and during a hyperglycaemic clamp experiment. The secretion of GIP and GLP-1 was assessed following oral glucose ingestion.
On separate occasions we performed an OGTT and administered an i.v. bolus of 20 pmol GIP/kg body weight in 20 women with pGDM and 20 control women. An additional hyperglycaemic clamp experiment (140 mg/dl [7.8 mmol/l] over 120 min) with i.v. infusion of GIP (2 pmol kg(-1) min(-1); 30-90 min) was performed in 14 women in each group. Capillary and venous blood samples were drawn for the measurement of glucose (glucose oxidase), insulin, C-peptide, GIP and GLP-1 (specific immunoassays). Indices of insulin sensitivity and beta cell function were calculated. Statistical analyses were carried out using repeated measures ANOVA.
Following oral glucose ingestion, plasma glucose, insulin and C-peptide concentrations increased to higher levels in the women with pGDM than in the control women (p<0.05). The women with pGDM were characterised by a higher degree of insulin resistance than the control women (p=0.007 for the Matsuda index), but showed no overt defects in glucose-stimulated insulin secretion (p=0.40 for the insulinogenic index following i.v. glucose). The secretion of GLP-1 and GIP was not different between the groups (p=0.87 and p=0.57, respectively). The insulin secretory response to GIP administration was similar in the two groups both after GIP bolus administration and during the hyperglycaemic clamp experiment (p=0.99 and p=0.88, respectively). A hyperbola-like relationship was found between the degree of insulin sensitivity (Matsuda index) and the insulin secretory response to GIP and i.v. glucose administration.
CONCLUSIONS/INTERPRETATION: These results do not support the hypothesis of an early defect in GIP action as a risk factor for subsequent development of diabetes in women with previous gestational diabetes. The inverse relationship between insulin resistance and the insulin secretory response to glucose or GIP suggests that beta cell secretory function in response to different stimuli increases adaptively when insulin sensitivity is diminished.
目的/假设：在2型糖尿病患者及其约50%的一级亲属中，在高血糖条件下，胃抑制多肽（GIP）的促胰岛素作用降低。目前尚不清楚这是GIP作用的特定缺陷还是β细胞功能普遍降低的结果。此外，2型糖尿病患者中已发现胰高血糖素样肽1（GLP-1）分泌受损。因此，我们研究了既往有妊娠期糖尿病（pGDM）的女性在正常血糖空腹条件下和高血糖钳夹实验期间GIP的促胰岛素作用。口服葡萄糖后评估GIP和GLP-1的分泌。
在不同时间，我们对20名pGDM女性和20名对照女性进行了口服葡萄糖耐量试验（OGTT），并静脉注射20 pmol GIP/kg体重的推注剂量。每组14名女性还进行了额外的高血糖钳夹实验（120分钟内血糖维持在140 mg/dl [7.8 mmol/l]），静脉输注GIP（2 pmol kg⁻¹ min⁻¹；30 - 90分钟）。采集毛细血管和静脉血样以测量葡萄糖（葡萄糖氧化酶法）、胰岛素、C肽、GIP和GLP-1（特异性免疫分析法）。计算胰岛素敏感性和β细胞功能指标。使用重复测量方差分析进行统计分析。
口服葡萄糖后，pGDM女性的血浆葡萄糖、胰岛素和C肽浓度升高至高于对照女性的水平（p<0.05）。pGDM女性的胰岛素抵抗程度高于对照女性（松田指数p = 0.007），但在葡萄糖刺激的胰岛素分泌方面未显示明显缺陷（静脉注射葡萄糖后的胰岛素生成指数p = 0.40）。两组之间GLP-1和GIP的分泌无差异（分别为p = 0.87和p = 0.57）。在推注GIP后和高血糖钳夹实验期间，两组对GIP给药的胰岛素分泌反应相似（分别为p = 0.99和p = 0.88）。发现胰岛素敏感性程度（松田指数）与对GIP和静脉注射葡萄糖给药的胰岛素分泌反应之间呈双曲线样关系。
结论/解读：这些结果不支持GIP作用早期缺陷作为既往有妊娠期糖尿病女性后续发生糖尿病危险因素的假设。胰岛素抵抗与对葡萄糖或GIP的胰岛素分泌反应之间的负相关表明，当胰岛素敏感性降低时，β细胞对不同刺激的分泌功能会适应性增加。
