Toye A A, Lippiat J D, Proks P, Shimomura K, Bentley L, Hugill A, Mijat V, Goldsworthy M, Moir L, Haynes A, Quarterman J, Freeman H C, Ashcroft F M, Cox R D
Medical Research Council, Harwell, Didcot, Oxfordshire, UK.
Diabetologia. 2005 Apr;48(4):675-86. doi: 10.1007/s00125-005-1680-z. Epub 2005 Feb 24.
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.
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.
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 KATP 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.
目的/假设：C57BL/6J小鼠表现出糖耐量受损。本研究的目的是定位导致该表型的基因位点，进一步描述生理缺陷并鉴定候选基因。
通过腹腔葡萄糖耐量试验测量葡萄糖耐量，并在F2杂交中定位遗传决定因素。通过注射胰岛素并跟踪血浆中葡萄糖的清除来测量胰岛素敏感性。为了测量β细胞功能，对分离的胰岛进行胰岛素分泌和电生理研究。通过测序和定量RNA分析研究候选基因。
C57BL/6J小鼠表现出正常的胰岛素敏感性，但胰岛素分泌受损。在β细胞中，葡萄糖不能刺激细胞内钙升高，其关闭KATP通道的能力受损。我们鉴定出三个导致糖耐量受损的基因位点。烟酰胺核苷酸转氢酶（Nnt）位于其中一个位点，是一种核编码的线粒体质子泵。Nnt在C57BL/6J肝脏和胰岛中的表达分别降低了7倍多和5倍多。C57BL/6J基因的外显子1存在错义突变，并且有多个外显子缺失。葡萄糖激酶位于Gluchos2位点，在肝脏中的酶活性降低。
结论/解读：C57BL/6J小鼠品系表现出类似人类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。我们已经鉴定出三个导致遗传性血浆葡萄糖耐量受损的位点，并鉴定出一个新的候选基因，该基因通过降低β细胞活性导致葡萄糖不耐受。
