Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (Insulin promoter factor 1 gene)
Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (Insulin promoter factor 1 gene)
复制标题
DOI：
10.2337/diabetes.49.11.1856
复制
发表时间：
2000-11-01
期刊：
影响因子：
7.7
通讯作者：
Elahi, D
中科院分区：
文献类型：
--
作者：
Clocquet, AR;Egan, JM;Elahi, D
由同源域转录因子胰岛素启动子因子1（IPF-1）的失活突变的杂合性导致的糖尿病是由于β细胞功能的遗传缺陷，称为年轻人的成熟型糖尿病4，IPF-1是胰腺发育所需的，并介导胰岛素基因转录的葡萄糖响应性刺激。为了定量在IPF-1中携带Pro63 fsdelC突变的家族中的胰岛细胞反应，我们对7个杂合成员（NM）和8个正常基因型成员（NN）进行了5步（1小时间隔）高血糖钳夹。kg（-1）。min（-1））。NM组的空腹血糖水平高于NN组（分别为9.2和5.9 mmol/l; P < 0.05）。两组的空腹胰岛素水平相似（NN和NM分别为72 pmol/l和105 pmol/l）。与NN组相比，NM组的个体中不存在第一时相胰岛素和C肽反应，其对单独葡萄糖的胰岛素反应显著减弱。在高于空腹水平16.8 mmol/l的葡萄糖水平下，GLP-1等同地增加胰岛素分泌在两个组中，胰岛素和C肽对GLP-1的反应是NN受试者的1/7（倍数增加），但NM受试者中对GLP-1的胰岛素和C肽反应比NN受试者低7倍。在两个组中，胰高血糖素水平在每个血糖平台期间下降，并且在GLP-1输注期间发生进一步降低。在两个小组中的高血糖钳夹期间葡萄糖清除率对胰岛素水平的S形剂量-反应曲线显示与NN组相比NM组中左移和较低的最大反应，这与NM受试者中增加的胰岛素敏感性一致，在NM组中，非酯化脂肪酸与胰岛素水平抑制的剂量-反应曲线出现急剧下降。我们得出的结论是，Pro63 fsdelC IPF-1突变与细胞对葡萄糖敏感性的严重损害以及外周组织对胰岛素敏感性的明显增加有关，并且是β细胞功能障碍的遗传决定原因。
Diabetes resulting from heterozygosity for an inactivating mutation of the homeodomain transcription factor insulin promoter factor 1 (IPF-1) is due to a genetic defect of beta -cell function referred to as maturity-onset diabetes of the young 4, IPF-1 is required for the development of the pancreas and mediates glucose-responsive stimulation of insulin gene transcription. To quantitate islet cell responses in a family harboring a Pro63fsdelC mutation in IPF-1, we performed a five-step (1-h intervals) hyperglycemic clamp on seven heterozygous members (NM) and eight normal genotype members (NN), During the last 30 min of the fifth glucose step, glucagon-like peptide 1 (GLP-1) was also infused (1.5 pmol . kg(-1) . min(-1)). Fasting plasma glucose levels were greater in the NM group than in the NN group (9.2 vs. 5.9 mmol/l, respectively; P < 0.05). Fasting insulin levels were similar in both groups (72 vs. 105 pmol/l for NN vs. NM, respectively). First-phase insulin and C-peptide responses were absent in individuals in the NM group, who had markedly attenuated insulin responses to glucose alone compared with the NN group, At a glucose level of 16.8 mmol/l above fasting level, GLP-1 augmented insulin secretion equivalently (fold increase) in both groups, but the insulin and C-peptide responses to GLP-1 were sevenfold less in the NM subjects than in the NN subjects. In both groups, glucagon levels fell during each glycemic plateau, and a further reduction occurred during the GLP-1 infusion, Sigmoidal dose-response curves of glucose clearance versus insulin levels during the hyperglycemic clamp in the two small groups showed both a left shift and a lower maximal response in the NM group compared with the NN group, which is consistent with an increased insulin sensitivity in the NM subjects, A sharp decline occurred in the dose-response curve for suppression of nonesterified fatty acids versus insulin levels in the NM group. We conclude that the Pro63fsdelC IPF-1 mutation is associated with a severe impairment of -cell sensitivity to glucose and an apparent increase in peripheral tissue sensitivity to insulin and is a genetically determined cause of beta -cell dysfunction.