Bonfleur Maria Lúcia, Vanzela Emerielle Cristine, Ribeiro Rosane Aparecida, de Gabriel Dorighello Gabriel, de França Carvalho Carolina Prado, Collares-Buzato Carla Beatriz, Carneiro Everardo Magalhães, Boschero Antonio Carlos, de Oliveira Helena Coutinho Franco
Departamento de Anatomia, Biologia Celular, Fisiologia e Biofísica, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
Biochim Biophys Acta. 2010 Feb;1801(2):183-90. doi: 10.1016/j.bbalip.2009.10.012. Epub 2009 Nov 12.
We investigated whether primary hypercholesterolaemia per se affects glucose homeostasis and insulin secretion in low-density lipoprotein receptor knockout mice (LDLR(-/-)). Glucose plasma levels were increased and insulin decreased in LDLR(-/-) compared to the wild-type mice. LDLR(-/-) mice presented impaired glucose tolerance, but normal whole body insulin sensitivity. The dose-response curve of glucose-stimulated insulin secretion was shifted to the right in LDLR(-/-) islets. Significant reductions in insulin secretion in response to l-leucine or 2-ketoisocaproic acid were also observed in LDLR(-/-). Islet morphometric parameters, total insulin and DNA content were similar in both groups. Glucose uptake and oxidation were reduced in LDLR(-/-) islets. Removal of cholesterol from LDLR(-/-) islets corrected glucose-stimulated insulin secretion. These results indicate that enhanced membrane cholesterol content due to hypercholesterolaemia leads to a lower insulin secretion and glucose intolerance without affecting body insulin sensitivity. This represents an additional risk factor for diabetes and atherosclerosis in primary hypercholesterolaemia.
我们研究了原发性高胆固醇血症本身是否会影响低密度脂蛋白受体基因敲除小鼠（LDLR(-/-)）的葡萄糖稳态和胰岛素分泌。与野生型小鼠相比，LDLR(-/-)小鼠的血糖水平升高而胰岛素水平降低。LDLR(-/-)小鼠表现出葡萄糖耐量受损，但全身胰岛素敏感性正常。在LDLR(-/-)胰岛中，葡萄糖刺激的胰岛素分泌剂量反应曲线向右移动。在LDLR(-/-)中还观察到，对L-亮氨酸或2-酮异己酸的胰岛素分泌显著减少。两组的胰岛形态计量学参数、总胰岛素和DNA含量相似。LDLR(-/-)胰岛中的葡萄糖摄取和氧化减少。从LDLR(-/-)胰岛中去除胆固醇可纠正葡萄糖刺激的胰岛素分泌。这些结果表明，高胆固醇血症导致的膜胆固醇含量增加会导致胰岛素分泌减少和葡萄糖不耐受，而不影响机体胰岛素敏感性。这是原发性高胆固醇血症中糖尿病和动脉粥样硬化的另一个危险因素。
