Transgenic reexpression of GLUT1 or GLUT2 in pancreatic β cells rescues GLUT2-null mice from early death and restores normal glucose-stimulated insulin secretion
Transgenic reexpression of GLUT1 or GLUT2 in pancreatic β cells rescues GLUT2-null mice from early death and restores normal glucose-stimulated insulin secretion
复制标题
DOI：
10.1074/jbc.m002908200
复制
发表时间：
2000-08-04
影响因子：
4.8
通讯作者：
Jaquet, M
中科院分区：
文献类型：
--
作者：
Thorens, B;Guillam, MT;Jaquet, M
glut2缺失小鼠出现高血糖、低胰岛素血症、高胰高血糖和高糖血症，并在出生后3周内死亡。他们的内分泌胰腺显示第一阶段葡萄糖刺激胰岛素分泌（GSIS）的损失和反向的α细胞与β细胞的比例。本研究表明，在这些小鼠的胰腺β细胞中，通过转基因GLUT1或GLUT2的重新表达可以使小鼠存活和繁殖。被救出的小鼠血糖正常，但空腹时出现低血糖、糖尿和胰高血糖素与胰岛素比值升高。然而，葡萄糖耐量正常。高血糖钳夹后体内胰岛素分泌正常。体外胰岛浸润研究显示，GLUT1或GLUT2也能恢复胰岛素分泌的第一阶段，并伴有葡萄糖利用率的正常化。然而，胰腺胰岛素与胰高血糖素的比例以及α细胞与β细胞的体积密度没有得到修正。这些数据表明：1)在β细胞中重新表达GLUT1或GLUT2足以使GLUT2缺失的小鼠免于死亡；2)GLUT1和GLUT2可以恢复正常的GSIS； 3) GSIS的恢复并不能纠正内分泌胰腺的异常组成。因此，正常的GSIS不依赖于转运蛋白的亲和力，而是依赖于刺激葡萄糖浓度下的摄取速率。
GLUT2-null mice are hyperglycemic, hypoinsulinemic, hyperglucagonemic, and glycosuric and die within the first 3 weeks of life. Their endocrine pancreas shows a loss of first phase glucose stimulated insulin secretion (GSIS) and inverse alpha to beta cell ratio. Here we show that reexpression by transgenesis of either GLUT1 or GLUT2 in the pancreatic beta cells of these mice allowed mouse survival and breeding. The rescued mice had normal-fed glycemia but fasted hypoglycemia, glycosuria, and an elevated glucagon to insulin ratio. Glucose tolerance was, however, normal. In vivo insulin secretion assessed following hyperglycemic clamps was normal. In vitro, islet perifusion studies revealed that first phase of insulin secretion was restored as well by GLUT1 or GLUT2, and this was accompanied by normalization of the glucose utilization rate. The ratio of pancreatic insulin to glucagon and volume densities of alpha to beta cells were, however, not corrected. These data demonstrate that 1) reexpression of GLUT1 or GLUT2 in beta cells is sufficient to rescue GLUT2-null mice from lethality, 2) GLUT1 as well as GLUT2 can restore normal GSIS, 3) restoration of GSIS does not correct the abnormal composition of the endocrine pancreas. Thus, normal GSIS does not depend on transporter affinity but on the rate of uptake at stimulatory glucose concentrations.