ISIB-CNR, Corso Stati Uniti 4, 35127 Padua, Italy.
Diabetologia. 2010 Apr;53(4):749-56. doi: 10.1007/s00125-009-1647-6. Epub 2010 Jan 9.
AIMS/HYPOTHESIS: It is commonly thought that hyperglycaemia results from insufficient compensation of insulin secretion for insulin resistance. To verify this hypothesis, we assessed beta cell function and insulin sensitivity (IS) in a large cohort of volunteers with normal glucose tolerance (NGT) or impaired glucose regulation (IGR), i.e. impaired glucose tolerance or impaired fasting glucose.
In men and women with NGT (n=1,123) or IGR(n=156) (age 44 +/- 8 years, BMI 25+/-4 kg/m2, mean +/- SD)we measured: (1) IS by clamp; (2) insulin secretion rates(ISR) and beta cell glucose sensitivity (=slope of the insulin secretion/plasma glucose dose-response) by C-peptide deconvolution and OGTT modelling; and (3) acute insulin response to intravenous glucose.
After controlling for centre, sex, age and BMI, fasting and total ISR were inversely related to IS in both groups,whereas beta cell glucose sensitivity was not. Acute insulin response was reciprocally related to IS in both groups, but the relationships were incompatible with inadequate compensation and significance was lost after controlling for fasting ISR. InIGR vs NGT, IS was impaired (92 [75] vs 133 [86] micromol min(-1)kg fat-free mass nmol/l, median [interquartile range],p<0.0001) as was beta cell glucose sensitivity (69 [46] vs 119[83] pmol min(-1) m(-2) nmol/l, p<0.0001), whereas fasting and total ISR were increased (35% and 25%, respectively, p<0.0001). In fully adjusted models, beta cell glucose sensitivity was the strongest determinant of OGTT glucose levels.
CONCLUSIONS/INTERPRETATION: Insulin resistance normally upregulates the secretory tone, with no evidence of defective compensation in IGR. In contrast, beta cell glucose sensitivity is independent of insulin resistance, but a key determinant of glucose tolerance. This suggests that hyperglycaemia results from an intrinsic beta cell defect rather than from inadequate compensation for insulin resistance.
目的/假设：人们普遍认为高血糖是由于胰岛素分泌对胰岛素抵抗的补偿不足所致。为了验证这一假设，我们评估了糖耐量正常（NGT）或糖调节受损（IGR）的志愿者（即糖耐量受损或空腹血糖受损）中大量队列的β细胞功能和胰岛素敏感性（IS）。
在 NGT（n=1123）或 IGR（n=156）的男性和女性中（年龄 44±8 岁，BMI 25±4kg/m2，平均值±标准差），我们测量了：（1）通过钳夹法测定 IS；（2）通过 C 肽反卷积和 OGTT 模型测定胰岛素分泌率（ISR）和β细胞葡萄糖敏感性（=胰岛素分泌/血浆葡萄糖剂量反应的斜率）；（3）静脉注射葡萄糖后的急性胰岛素反应。
在控制中心、性别、年龄和 BMI 后，空腹和总 ISR 与两组中的 IS 呈负相关，而β细胞葡萄糖敏感性则不然。急性胰岛素反应与两组中的 IS 呈反向相关，但这些关系与补偿不足不符，且在控制空腹 ISR 后，其意义丧失。在 IGR 与 NGT 相比，IS 受损（92[75]与 133[86]μmol min-1·kg 去脂体重-1·nmol/L-1，中位数[四分位数间距]，p<0.0001），β细胞葡萄糖敏感性降低（69[46]与 119[83]pmol min-1·m-2·nmol/L-1，p<0.0001），而空腹和总 ISR 增加（分别为 35%和 25%，p<0.0001）。在完全调整的模型中，β细胞葡萄糖敏感性是 OGTT 葡萄糖水平的最强决定因素。
结论/解释：胰岛素抵抗通常会上调分泌音调，IGR 中没有证据表明补偿不足。相比之下，β细胞葡萄糖敏感性与胰岛素抵抗无关，但却是葡萄糖耐量的关键决定因素。这表明高血糖是由内在的β细胞缺陷引起的，而不是由于对胰岛素抵抗的补偿不足引起的。
