Reduced glucose-stimulated insulin secretion following a 1-wk IGF-1 infusion in late gestation fetal sheep is due to an intrinsic islet defect.
Reduced glucose-stimulated insulin secretion following a 1-wk IGF-1 infusion in late gestation fetal sheep is due to an intrinsic islet defect.
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妊娠晚期胎羊注射 1 周 IGF-1 后，葡萄糖刺激的胰岛素分泌减少是由于固有的胰岛缺陷所致。
DOI：
10.1152/ajpendo.00623.2020
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Rozance,PaulJ
中科院分区：
文献类型：
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作者：
White,Alicia;Stremming,Jane;Boehmer,BritH;Chang,EileenI;Jonker,SonnetS;Wesolowski,StephanieR;Brown,LauraD;Rozance,PaulJ
胰岛素和胰岛素样生长因子-1 (IGF-1) 是对胎儿正常生长至关重要的胎儿激素。妊娠后期实验性升高的 IGF-1 浓度会增加胎儿体重，但会降低胎儿血浆胰岛素浓度。因此，我们假设向妊娠晚期胎羊输注 IGF-1 类似物 1 周会减弱胎儿葡萄糖刺激的胰岛素分泌 (GSIS) 以及从这些胎儿分离的胰岛中的胰岛素分泌。妊娠晚期胎羊接受 IGF-1 LR3 (IGF-1,n= 8) 输注，IGF-1 LR3 是一种 IGF-1 类似物，对 IGF 结合蛋白具有低亲和力，对 IGF-1 受体具有高亲和力，或载体对照 (CON,n= 9)。使用高血糖钳测量胎儿 GSIS（IGF-1，n = 8；CON，n = 7）。分离胎儿胰岛，并在静态培养中测定胰岛素分泌（IGF-1，n = 8；CON，n = 7）。与 CON 相比，IGF-1 胎儿的血浆胰岛素和葡萄糖浓度较低（分别为 P= 0.0135 和 P= 0.0012）。在 GSIS 研究期间，与 CON 相比，IGF-1 胎儿的胰岛素分泌量较低（P = 0.0453）。在体外，从 IGF-1 胎儿分离的胰岛中，葡萄糖刺激的胰岛素分泌仍然较低（P = 0.0447）。总之，向胎羊输注 IGF-1 LR3 1 周可降低胰岛素浓度并减少胎儿 GSIS。孤立的胎儿胰岛中的胰岛素分泌持续受损，表明当暴露于 IGF-1 LR3 输注 1 周时，胰岛素释放存在固有的胰岛缺陷。我们推测，胰岛素/IGF-1轴的这种改变导致妊娠后并发糖尿病或其他与胎儿过度生长相关的疾病后出生的IGF-1浓度升高的新生儿的β细胞功能的长期降低。新与值得注意的是，在注射IGF-1 LR3 1周后，妊娠晚期胎羊的血浆胰岛素和葡萄糖浓度较低，胎儿葡萄糖刺激的胰岛素分泌减少，并且离体胎儿的胰岛素分泌分数减少胰岛的胰岛素含量没有差异。
Insulin and insulin-like growth factor-1 (IGF-1) are fetal hormones critical to establishing normal fetal growth. Experimentally elevated IGF-1 concentrations during late gestation increase fetal weight but lower fetal plasma insulin concentrations. We therefore hypothesized that infusion of an IGF-1 analog for 1 wk into late gestation fetal sheep would attenuate fetal glucose-stimulated insulin secretion (GSIS) and insulin secretion in islets isolated from these fetuses. Late gestation fetal sheep received infusions with IGF-1 LR3 (IGF-1,n= 8), an analog of IGF-1 with low affinity for the IGF binding proteins and high affinity for the IGF-1 receptor, or vehicle control (CON,n= 9). Fetal GSIS was measured with a hyperglycemic clamp (IGF-1,n= 8; CON,n= 7). Fetal islets were isolated, and insulin secretion was assayed in static incubations (IGF-1,n= 8; CON,n= 7). Plasma insulin and glucose concentrations in IGF-1 fetuses were lower compared with CON (P= 0.0135 andP= 0.0012, respectively). During the GSIS study, IGF-1 fetuses had lower insulin secretion compared with CON (P= 0.0453). In vitro, glucose-stimulated insulin secretion remained lower in islets isolated from IGF-1 fetuses (P= 0.0447). In summary, IGF-1 LR3 infusion for 1 wk into fetal sheep lowers insulin concentrations and reduces fetal GSIS. Impaired insulin secretion persists in isolated fetal islets indicating an intrinsic islet defect in insulin release when exposed to IGF-1 LR3 infusion for 1 wk. We speculate this alteration in the insulin/IGF-1 axis contributes to the long-term reduction in β-cell function in neonates born with elevated IGF-1 concentrations following pregnancies complicated by diabetes or other conditions associated with fetal overgrowth.NEW & NOTEWORTHYAfter a 1-wk infusion of IGF-1 LR3, late gestation fetal sheep had lower plasma insulin and glucose concentrations, reduced fetal glucose-stimulated insulin secretion, and decreased fractional insulin secretion from isolated fetal islets without differences in pancreatic insulin content.