Weng J, Macfarlane W M, Lehto M, Gu H F, Shepherd L M, Ivarsson S A, Wibell L, Smith T, Groop L C
Department of Endocrinology, Malmö University Hospital, Lund University, Sweden.
Diabetologia. 2001 Feb;44(2):249-58. doi: 10.1007/s001250051608.
AIMS/HYPOTHESIS: The aim of this study was to examine the putative role of mutations in the insulin promoter 1 (IPF1) gene in early-onset diabetes.
We carried out mutation screening of the IPF1 gene in 115 Scandinavian families with at least two members with onset of diabetes younger than 40 years. The allele frequencies were also tested in 183 unrelated patients with late-onset Type II (non-insulin-dependent) diabetes mellitus and in 92 non-diabetic control subjects.
Two novel IPF1 variants (G212R and P239Q) and one previously reported (D76N) IPF1 variant were identified in the 115 families (3.5%). The D76N variant was found in one MODY3 family (S315fsinsA of HNF1alpha) and also in two families with late-onset Type II diabetes. The P239Q variant was identified in two families with early-onset diabetes including one with MODY3 (R272C of HNF1alpha) and in three families with late-onset Type II diabetes. Despite the fact that the variants did not segregate completely with diabetes, the non-diabetic carriers of the IPF1 variants had increased blood glucose concentrations (p < 0.05) and reduced insulin:glucose ratios (p < 0.05) during an oral glucose tolerance test compared with non-diabetic family members without these variants. In addition, when the G212R and P239Q variants were expressed in cells without IPF1 i.e.. Nes2y cells, both variants showed about a 50% reduction in their ability to activate insulin gene transcription compared to wild-type IPF1, as measured by reporter gene assay.
CONCLUSION/INTERPRETATION: Although mutations in the IPF-1 gene are rare in early- (3.5 %) and late-onset (2.7 % ) Type II diabetes, they are functionally important and occur also in families with other MODY mutations.
目的/假设：本研究旨在探讨胰岛素启动子1（IPF1）基因突变在早发性糖尿病中的假定作用。
我们对115个斯堪的纳维亚家庭的IPF1基因进行了突变筛查，这些家庭中至少有两名成员在40岁之前发病。还对183例晚发性II型（非胰岛素依赖型）糖尿病患者和92例非糖尿病对照者进行了等位基因频率检测。
在115个家庭（3.5%）中鉴定出两个新的IPF1变异体（G212R和P239Q）以及一个先前报道的（D76N）IPF1变异体。D76N变异体在一个MODY3家庭（HNF1α的S315fsinsA）以及两个晚发性II型糖尿病家庭中被发现。P239Q变异体在两个早发性糖尿病家庭中被鉴定出来，其中一个家庭患有MODY3（HNF1α的R272C），在三个晚发性II型糖尿病家庭中也被发现。尽管这些变异体与糖尿病并非完全共分离，但与没有这些变异体的非糖尿病家庭成员相比，IPF1变异体的非糖尿病携带者在口服葡萄糖耐量试验期间血糖浓度升高（p < 0.05），胰岛素与葡萄糖比值降低（p < 0.05）。此外，当G212R和P239Q变异体在没有IPF1的细胞即Nes2y细胞中表达时，通过报告基因测定，与野生型IPF1相比，这两个变异体激活胰岛素基因转录的能力均降低了约50%。
结论/解读：尽管IPF-1基因突变在早发性（3.5%）和晚发性（2.7%）II型糖尿病中较为罕见，但它们在功能上具有重要意义，并且也出现在具有其他MODY突变的家庭中。
