A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice
A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice
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DOI：
10.1007/s00125-005-1680-z
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发表时间：
2005-04-01
期刊：
影响因子：
8.2
通讯作者：
Cox, RD
中科院分区：
文献类型：
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作者：
Toye, AA;Lippiat, JD;Cox, RD
目的/假设：C57BL/6J 小鼠表现出糖耐量受损。本研究的目的是绘制该表型背后的遗传位点图谱，进一步表征生理缺陷并确定候选基因。方法：通过腹膜内葡萄糖耐量试验测量葡萄糖耐量，并在 F2 杂交中绘制遗传决定因素。通过注射胰岛素并从血浆中处理葡萄糖来测量胰岛素敏感性。为了测量β细胞功能，对分离的胰岛进行了胰岛素分泌和电生理学研究。通过测序和定量 RNA 分析研究候选基因。结果：C57BL/6J 小鼠表现出正常的胰岛素敏感性和胰岛素分泌受损。在β细胞中，葡萄糖不会刺激细胞内钙的增加，并且其关闭K-ATP通道的能力受到损害。我们确定了三个导致糖耐量受损的遗传位点。烟酰胺核苷酸转氢酶 (Nnt) 位于一个基因座内，是一种核编码的线粒体质子泵。 C57BL/6J 肝脏和胰岛中 Nnt 的表达分别降低七倍和五倍以上。 C57BL/6J 基因的外显子 1 存在错义突变，多外显子缺失。葡萄糖激酶位于 Gluchos2 基因座内，肝脏中酶活性降低。结论/解释：C57BL/6J 小鼠品系表现出类似于人类 2 型糖尿病的血浆葡萄糖不耐受。我们的数据表明β细胞葡萄糖代谢存在缺陷，导致电活动和胰岛素分泌减少。我们已经确定了三个导致遗传性血浆葡萄糖耐量受损的基因座，并确定了一个通过降低β细胞活性导致葡萄糖不耐症的新候选基因。
Aims/hypothesis: C57BL/6J mice exhibit impaired glucose tolerance. The aims of this study were to map the genetic loci underlying this phenotype, to further characterise the physiological defects and to identify candidate genes. Methods: Glucose tolerance was measured in an intraperitoneal glucose tolerance test and genetic determinants mapped in an F2 intercross. Insulin sensitivity was measured by injecting insulin and following glucose disposal from the plasma. To measure beta cell function, insulin secretion and electrophysiological studies were carried out on isolated islets. Candidate genes were investigated by sequencing and quantitative RNA analysis. Results: C57BL/6J mice showed normal insulin sensitivity and impaired insulin secretion. In beta cells, glucose did not stimulate a rise in intracellular calcium and its ability to close K-ATP channels was impaired. We identified three genetic loci responsible for the impaired glucose tolerance. Nicotinamide nucleotide transhydrogenase (Nnt) lies within one locus and is a nuclear-encoded mitochondrial proton pump. Expression of Nnt is more than sevenfold and fivefold lower respectively in C57BL/6J liver and islets. There is a missense mutation in exon 1 and a multi-exon deletion in the C57BL/6J gene. Glucokinase lies within the Gluchos2 locus and shows reduced enzyme activity in liver. Conclusions/interpretation: The C57BL/6J mouse strain exhibits plasma glucose intolerance reminiscent of human type 2 diabetes. Our data suggest a defect in beta cell glucose metabolism that results in reduced electrical activity and insulin secretion. We have identified three loci that are responsible for the inherited impaired plasma glucose tolerance and identified a novel candidate gene for contribution to glucose intolerance through reduced beta cell activity.