Pax6 Haploinsufficiency Causes Abnormal Metabolic Homeostasis by Down-Regulating Glucagon-Like Peptide 1 in Mice
Pax6 Haploinsufficiency Causes Abnormal Metabolic Homeostasis by Down-Regulating Glucagon-Like Peptide 1 in Mice
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Pax6 单倍体不足通过下调胰高血糖素样肽 1 导致小鼠代谢稳态异常
DOI：
10.1210/en.2008-1006
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发表时间：
2009-05-01
期刊：
影响因子：
4.8
通讯作者：
Gao, Xiang
中科院分区：
文献类型：
--
作者：
Ding, Jun;Gao, Yan;Gao, Xiang
Pax 6等位基因的杂合性与人类葡萄糖耐量受损相关通过Pax 6突变小鼠模型，我们发现许多代谢异常与下调胰高血糖素样肽1（GLP-1）表达的影响一致。除了葡萄糖耐量受损外，与对照小鼠相比，成年杂合突变小鼠（Pax 6（m/+））分泌的胰岛素对葡萄糖和精氨酸给药的反应更少。此外，与对照小鼠相比，Pax 6（m/+）小鼠表现出食物摄入量增加，尽管它们对饮食诱导的脂肪积累有抵抗力。事实上，Pax 6（m/+）小鼠的循环GLP-1水平和Gcg/胰高血糖素原的肠道转录水平显著降低。通过体外转染测定，突变的Pax 6也未能激活Gcg/胰高血糖素原启动子。最后，对Pax 6（m/+）小鼠给予GLP-1受体激动剂exendin-4，在很大程度上逆转了其异常摄食、血糖波动和胰岛素分泌。我们的研究表明，主要由Pax 6单倍不足引起的代谢稳态破坏主要是通过GLP-1的下调介导的。exendin-4的管理可能是一个有用的治疗人类与类似的突变。（内分泌学150：2136-2144，2009）
Heterozygosity for the Pax6 allele is associated with impaired glucose tolerance in humans. With a Pax6 mutant mouse model, we found many of the metabolic abnormalities were consistent with the effects of down-regulating the expression of glucagon-like peptide 1 (GLP-1). In addition to impaired glucose tolerance, adult heterozygous mutant mice (Pax6(m/+)) secreted less insulin responding to glucose and arginine administration compared with control mice. Moreover, Pax6(m/+) mice showed increased food intake compared with control mice, although they were resistant to diet-induced fat accumulation. Indeed, levels of circulating GLP-1 and intestinal transcription of Gcg/Proglucagon were dramatically reduced in Pax6(m/+) mice. Mutated Pax6 also failed to activate the Gcg/Proglucagon promoter by in vitro transfection assay. Finally, administering the GLP-1 receptor agonist exendin-4 to Pax6(m/+) mice largely reversed their abnormal food intake, glycemic excursion, and insulin secretion. Our studies suggested that disruption of metabolic homeostasis mainly caused by Pax6 haploinsufficiency was mainly mediated by down-regulation of GLP-1. Administration of exendin-4 may be a useful therapy in humans with a similar mutation. (Endocrinology 150: 2136-2144, 2009)