Noormets K, Kõks S, Muldmaa M, Mauring L, Vasar E, Tillmann V
Department of Paediatrics, University of Tartu, 6 Lunini Street, Tartu, Estonia.
Exp Clin Endocrinol Diabetes. 2011 May;119(5):271-5. doi: 10.1055/s-0030-1265163. Epub 2010 Oct 28.
Wolfram syndrome, caused by mutations in the wolframin (Wfs1) gene, is characterised by juvenile-onset diabetes mellitus, progressive optic atrophy, diabetes insipidus and deafness. Diabetes tend to start earlier in boys. This study investigated sex differences in longitudinal changes in blood glucose concentration (BGC) in wolframin-deficient mice (Wfs1KO) and compared their plasma proinsulin and insulin levels with those of wild-type (wt) mice. Non-fasting BGC was measured weekly in 42 (21 males) mice from both groups at nine weeks of age. An intraperitoneal glucose tolerance test (IPGTT) was conducted at the 30 (th) week and plasma insulin, c-peptide and proinsulin levels were measured at the 32 (nd) week. At the 32 (nd) week, Wfs1KO males had increased BGC compared to wt males (9.40±0.60 mmol/l vs. 7.91±0.20 mmol/l; p<0.05). The opposite tendency was seen in females. Both male and female Wfs1KO mice had impaired glucose tolerance on IPGTT. Wfs1KO males had significantly lower mean plasma insulin levels than wt males (57.78±1.80 ng/ml vs. 69.42±3.06 ng/ml; p<0.01) and Wfs1KO females (70.30±4.42 ng/ml; p<0.05). Wfs1KO males had a higher proinsulin/insulin ratio than wt males (0.09±0.02 vs. 0.05±0.01; p=0.05) and Wfs1KO females (0.04±0.01; p<0.05). Plasma c-peptide levels in males were lower in Wfs1KO males (mean 55.3±14.0 pg/ml vs. 112.7±21.9 pg/ml; p<0.05). Male Wfs1KO mice had a greater risk of developing diabetes than female Wfs1KO mice. Low plasma insulin concentration with an increased proinsulin/insulin ratio in Wfs1KO males indicates possible disturbances in converting proinsulin to insulin which in long-term may lead to insulin deficiency. Further investigation is needed to clarify the mechanism for the sex differences in the development of diabetes in Wolfram syndrome.
沃夫勒姆综合征由沃尔弗拉姆蛋白（Wfs1）基因突变引起，其特征为青少年期发病的糖尿病、进行性视神经萎缩、尿崩症和耳聋。糖尿病在男孩中往往发病更早。本研究调查了沃尔弗拉姆蛋白缺陷小鼠（Wfs1KO）血糖浓度（BGC）纵向变化的性别差异，并将其血浆胰岛素原和胰岛素水平与野生型（wt）小鼠进行比较。在两组42只（21只雄性）9周龄小鼠中每周测量非空腹血糖浓度。在第30周进行腹腔葡萄糖耐量试验（IPGTT），并在第32周测量血浆胰岛素、C肽和胰岛素原水平。在第32周时，与wt雄性小鼠相比，Wfs1KO雄性小鼠的血糖浓度升高（9.40±0.60 mmol/l对7.91±0.20 mmol/l；p<0.05）。在雌性小鼠中观察到相反的趋势。雄性和雌性Wfs1KO小鼠在IPGTT中葡萄糖耐量均受损。Wfs1KO雄性小鼠的平均血浆胰岛素水平显著低于wt雄性小鼠（57.78±1.80 ng/ml对69.42±3.06 ng/ml；p<0.01）以及Wfs1KO雌性小鼠（70.30±4.42 ng/ml；p<0.05）。Wfs1KO雄性小鼠的胰岛素原/胰岛素比值高于wt雄性小鼠（0.09±0.02对0.05±0.01；p=0.05）以及Wfs1KO雌性小鼠（0.04±0.01；p<0.05）。Wfs1KO雄性小鼠的血浆C肽水平较低（平均55.3±14.0 pg/ml对112.7±21.9 pg/ml；p<0.05）。雄性Wfs1KO小鼠患糖尿病的风险高于雌性Wfs1KO小鼠。Wfs1KO雄性小鼠血浆胰岛素浓度低且胰岛素原/胰岛素比值升高表明胰岛素原转化为胰岛素可能存在障碍，长期来看可能导致胰岛素缺乏。需要进一步研究以阐明沃夫勒姆综合征糖尿病发生中性别差异的机制。
