Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
Endocrinology. 2011 Jun;152(6):2184-96. doi: 10.1210/en.2010-1324. Epub 2011 Mar 29.
Human IGF binding protein-3 (hIGFBP-3) overexpression in mice causes hyperglycemia, but its effect on β-cell function is unknown. We compared wild-type mice with mice overexpressing hIGFBP-3 [phoshoglycerate kinase (PGK)BP3] and mutant (Gly⁵⁶/Gly⁸⁰/Gly⁸¹)hIGFBP-3 devoid of IGF binding affinity (PGKmBP3). Intraperitoneal glucose and insulin tolerance tests were performed, and glucose, IGFBP-3, IGF-I, and insulin were determined. Pancreatic sections were used for islet histomorphometry and stained with antibodies against insulin, glucagon, and hIGFBP-3. Pancreatic islets were isolated to determine the expression of IGFBP-3, and glucose-stimulated insulin secretion was measured using both islet batch incubation and perifusion. IGFBP-3 was expressed in β-cells but not in other islet cell types. Fasting glucose concentration was elevated in PGKBP3 mice (6.27 ± 0.31 mm) compared with PGKmBP3 mice (3.98 ± 0.36 mm) and wild-type mice (4.84 ± 0.07 mm). During glucose tolerance test, glucose declined more slowly in PGKBP3 and PGKmBP3 mice than in wild-type mice, and insulin secretion was impaired in PGKBP3 mice. During insulin tolerance test, insulin declined more slowly in both transgenic mice compared with wild-type mice. Insulin secretion in islets incubated with 3.3 mm glucose was similar among groups, but islet insulin response to 16.7 mm glucose alone, or with carbachol and cAMP enhancers, was reduced in PGKBP3 and PGKmBP3 mice compared with wild-type controls. ATP content, Akt phosphorylation, and phosphoglucose isomerase activity were reduced in islets from both transgenic mice. Thus, overexpression of hIGFBP-3 in mice delays in vivo insulin clearance and reduces glucose-stimulated insulin secretion in pancreatic islets by both IGF-dependent and IGF-independent mechanisms.
人 IGF 结合蛋白-3（hIGFBP-3）在小鼠中的过表达会导致高血糖，但它对β细胞功能的影响尚不清楚。我们比较了野生型小鼠与过表达 hIGFBP-3[磷酸甘油酸激酶（PGK）BP3]和缺乏 IGF 结合亲和力的突变体（Gly⁵⁶/Gly⁸⁰/Gly⁸¹）hIGFBP-3（PGKmBP3）的小鼠。进行了腹腔内葡萄糖和胰岛素耐量试验，并测定了葡萄糖、IGFBP-3、IGF-I 和胰岛素。使用针对胰岛素、胰高血糖素和 hIGFBP-3 的抗体对胰腺切片进行胰岛组织形态计量学染色。分离胰岛以确定 IGFBP-3 的表达，并使用胰岛批量孵育和灌注来测量葡萄糖刺激的胰岛素分泌。IGFBP-3 在β细胞中表达，但不在其他胰岛细胞类型中表达。PGKBP3 小鼠的空腹血糖浓度升高（6.27 ± 0.31 mm），高于 PGKmBP3 小鼠（3.98 ± 0.36 mm）和野生型小鼠（4.84 ± 0.07 mm）。在葡萄糖耐量试验中，PGKBP3 和 PGKmBP3 小鼠的血糖下降速度比野生型小鼠慢，PGKBP3 小鼠的胰岛素分泌受损。在胰岛素耐量试验中，与野生型小鼠相比，两种转基因小鼠的胰岛素下降速度较慢。用 3.3 mm 葡萄糖孵育的胰岛的胰岛素分泌在各组之间相似，但 PGKBP3 和 PGKmBP3 小鼠的胰岛对 16.7 mm 葡萄糖单独或与卡巴胆碱和 cAMP 增强剂的胰岛素反应降低。两种转基因小鼠的胰岛中 ATP 含量、Akt 磷酸化和磷酸葡萄糖异构酶活性降低。因此，hIGFBP-3 在小鼠中的过表达会延迟体内胰岛素清除，并通过 IGF 依赖和 IGF 非依赖机制降低胰腺胰岛中葡萄糖刺激的胰岛素分泌。
