Defective insulin secretion in hepatocyte nuclear factor 1α-deficient mice
Defective insulin secretion in hepatocyte nuclear factor 1α-deficient mice
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DOI：
10.1172/jci2548
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发表时间：
1998-05-15
影响因子：
15.9
通讯作者：
Polonsky, KS
中科院分区：
文献类型：
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作者：
Pontoglio, M;Sreenan, S;Polonsky, KS
转录因子肝细胞核因子（HNF）1 α的基因突变会导致年轻人成熟型糖尿病（MODY）3，这是一种由胰岛素分泌缺陷引起的糖尿病。由于这些缺陷的性质尚未确定，我们比较了HNF-1 α基因无效突变的杂合[HNF-1 α（+/-）]或纯合[HNF-1 α（-/-）]小鼠与其野生型同窝小鼠[HNF-1 α（+/+）]的胰岛素分泌功能。HNF-1 α（+/+）和（+/-）小鼠的血糖浓度相似（7.8+/-0.2和7.9+/-0.3 mM），但HNF-1 α（-/-）小鼠的血糖浓度显著较高（13.1+/-0.7 mM，P < 0.001）。HNF-1 alpha（（-/-）小鼠的灌注胰腺和灌流胰岛中对葡萄糖和精氨酸的胰岛素分泌反应<其他两组值的15%，并且与细胞内Ca 2+反应的类似减少相关。这些缺陷不是由于葡萄糖激酶或胰岛素基因转录的减少。在（-/-）动物中，尽管根据胰腺重量调整的胰腺胰岛素含量略低，但根据体重调整的P细胞质量没有减少（0.06+/-0.01对0.10+/-0.01 μ g/mg，P < 0.01）。纯合小鼠中HNF-1 α基因的无效突变由于调节β细胞对促分泌素（包括葡萄糖和精氨酸）应答的途径的改变而导致糖尿病，这些结果提供了进一步的证据，支持HNF-1 α在维持正常β细胞功能中的关键作用。
Mutations in the gene for the transcription factor hepatocyte nuclear factor (HNF) 1 alpha cause maturity-onset diabetes of the young (MODY) 3, a form of diabetes that results from defects in insulin secretion. Since the nature of these defects has not been defined, we compared insulin secretory function in heterozygous [HNF-1 alpha (+/-)] or homozygous [HNF-1 alpha (-/-)] mice with null mutations in the HNF-1 alpha gene with their wild-type littermates [HNF-1 alpha (+/+)]. Blood glucose concentrations were similar in HNF-1 alpha (+/+) and (+/-) mice (7.8+/-0.2 and 7.9+/-0.3 mM), but were significantly higher in the HNF-1 alpha (-/-) mice (13.1+/-0.7 mM, P < 0.001). Insulin secretory responses to glucose and arginine in the perfused pancreas and perifused islets from HNF-1 alpha( (-/-) mice were < 15% of the values in the other two groups and were associated with similar reductions in intracellular Ca2+ responses, These defects were not due to a decrease in glucokinase or insulin gene transcription. P cell mass adjusted for body weight was not reduced in the (-/-) animals, although pancreatic insulin content adjusted for pancreas weight was slightly lower (0.06+/-0.01 vs. 0.10+/-0.01 mu g/mg, P < 0.01) than in the (+/+) animals.In summary, a null mutation in the HNF-1 alpha gene in homozygous mice leads to diabetes due to alterations in the pathways that regulate beta cell responses to secretagogues including glucose and arginine, These results provide further evidence in support of a key role for HNF-1 alpha in the maintenance of normal beta cell function.