Clément K, Pueyo M E, Vaxillaire M, Rakotoambinina B, Thuillier F, Passa P, Froguel P, Robert J J, Velho G
CNRS EP-10, Institut Pasteur de Lille, France.
Diabetologia. 1996 Jan;39(1):82-90. doi: 10.1007/BF00400417.
The chronic hyperglycaemia of glucokinase-deficient diabetes results from a glucose-sensing defect in pancreatic beta cells and abnormal hepatic glucose phosphorylation. We have evaluated the contribution of insulin resistance to this form of chronic hyperglycaemia. Insulin sensitivity, assessed by the homeostasis model assessment (HOMA) method in 35 kindreds with glucokinase mutations, was found to be significantly decreased in 125 glucokinase-deficient subjects as compared to 141 unaffected first-degree relatives. Logistic regression analysis showed that in glucokinase-deficient subjects a decrease in insulin sensitivity was associated with deterioration of the glucose tolerance status. A euglycaemic hyperinsulinaemic clamp was performed in 14 glucokinase-deficient subjects and 12 unrelated control subjects. In six patients and six control subjects the clamp was coupled to dideutero-glucose infusion to measure glucose turnover. Average glucose infusion rates (GIR) at 1 and 5 mU.kg body weight.min-1 insulin infusion rates were significantly lower in (the glucokinase-deficient) patients than in control subjects. Although heterogeneous results were observed, in 8 out of the 14 patients GIRs throughout the experiment were lower than 1 SD below the mean of the control subjects. Hepatic glucose production at 1 mU.kg body weight-1.min-1 insulin-infusion rate was significantly higher in patients than in control subjects. In conclusion, insulin resistance correlates with the deterioration of glucose tolerance and contributes to the hyperglycaemia of glucokinase-deficient diabetes. Taken together, our results are most consistent with insulin resistance being considered secondary to the chronic hyperglycaemia and/or hypoinsulinaemia of glucokinase-deficiency. Insulin resistance might also result from interactions between the unbalanced glucose metabolism and susceptibility gene(s) to low insulin sensitivity likely to be present in this population.
葡萄糖激酶缺乏型糖尿病的慢性高血糖源于胰腺β细胞的葡萄糖感应缺陷和肝脏葡萄糖磷酸化异常。我们评估了胰岛素抵抗对这种慢性高血糖形式的影响。通过稳态模型评估（HOMA）方法对35个携带葡萄糖激酶突变的家族进行评估，发现125名葡萄糖激酶缺乏的受试者的胰岛素敏感性与141名未受影响的一级亲属相比显著降低。逻辑回归分析表明，在葡萄糖激酶缺乏的受试者中，胰岛素敏感性降低与糖耐量状态恶化相关。对14名葡萄糖激酶缺乏的受试者和12名无关对照受试者进行了正常血糖高胰岛素钳夹试验。在6名患者和6名对照受试者中，钳夹试验与双氘葡萄糖输注相结合以测量葡萄糖周转率。在胰岛素输注速率为1和5 mU.kg体重.min-1时，（葡萄糖激酶缺乏的）患者的平均葡萄糖输注速率（GIR）显著低于对照受试者。尽管观察到结果存在异质性，但在14名患者中的8名患者中，整个实验过程中的GIR低于对照受试者平均值的1个标准差。在胰岛素输注速率为1 mU.kg体重-1.min-1时，患者的肝脏葡萄糖生成显著高于对照受试者。总之，胰岛素抵抗与糖耐量恶化相关，并导致葡萄糖激酶缺乏型糖尿病的高血糖。综上所述，我们的结果最符合胰岛素抵抗被认为是葡萄糖激酶缺乏所致慢性高血糖和/或低胰岛素血症的继发表现这一观点。胰岛素抵抗也可能源于该人群中不平衡的葡萄糖代谢与可能存在的低胰岛素敏感性易感基因之间的相互作用。
