Targeted deletion of the PRL receptor: Effects on islet development, insulin production, and glucose tolerance
Targeted deletion of the PRL receptor: Effects on islet development, insulin production, and glucose tolerance
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DOI：
10.1210/en.143.4.1378
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发表时间：
2002-04-01
期刊：
影响因子：
4.8
通讯作者：
Kelly, PA
中科院分区：
文献类型：
--
作者：
Freemark, M;Avril, I;Kelly, PA
PRL 和胎盘催乳素 (PL) 可刺激离体胰岛和大鼠胰岛素瘤细胞中的 β 细胞增殖和胰岛素基因转录，但催乳激素在胰岛发育和体内胰岛素产生中的作用仍不清楚。为了阐明催乳素在胰腺发育和功能中的作用，我们在催乳素抵抗的实验模型：PRL 受体 (PRLR) 缺陷小鼠中测量了胰岛密度（胰岛数量/cm(2)）和平均胰岛大小、β 细胞质量、胰腺胰岛素 mRNA 水平、胰岛胰岛素含量以及对葡萄糖的胰岛素分泌反应。然后我们测量腹腔注射葡萄糖或胰岛素后的血浆葡萄糖浓度。与野生型同窝小鼠相比，PRLR 缺陷小鼠的胰岛密度和 β 细胞质量减少了 26-42%（P < 0.01）。早在 3 周龄时就观察到胰岛密度和 β 细胞质量的减少，并持续到 8 个月龄，并且在雄性和雌性小鼠中均观察到。 PRLR缺陷小鼠的胰岛在断奶时比野生型小鼠小，但在成年期则不然。成年PRLR缺陷小鼠的胰腺胰岛素mRNA水平比野生型小鼠低20-30%（P < 0.05），并且离体胰岛的胰岛素含量降低16-25%。在 PRLR 缺陷的雄性体内（P < 0.05）以及体外 PRLR 缺陷的雌性和雄性的离体胰岛中，对腹膜内葡萄糖的胰岛素分泌反应减弱（P < 0.01）。 PRLR缺陷小鼠的空腹血糖浓度正常，但腹膜内葡萄糖负荷后的血糖水平比野生型小鼠高10-20% (P < 0.02)。另一方面，腹膜内胰岛素的葡萄糖反应正常。我们的观察证实了催乳素在胰岛发育和功能中的生理作用。
PRL and placental lactogen (PL) stimulate beta-cell proliferation and insulin gene transcription in isolated islets and rat insulinoma cells, but the roles of the lactogenic hormones in islet development and insulin production in vivo remain unclear. To clarify the roles of the lactogens in pancreatic development and function, we measured islet density (number of islets/cm(2)) and mean islet size, beta-cell mass, pancreatic insulin mRNA levels, islet insulin content, and the insulin secretory response to glucose in an experimental model of lactogen resistance: the PRL receptor (PRLR) -deficient mouse. We then measured plasma glucose concentrations after ip injections of glucose or insulin. Compared with wild-type littermates, PRLR-deficient mice had 26-42% reductions (P < 0.01) in islet density and beta-cell mass. The reductions in islet density and beta-cell mass were noted as early as 3 wk of age and persisted through 8 months of age and were observed in both male and female mice. Pancreatic islets of PRLR-deficient mice were smaller than those of wild-type mice at weaning but not in adulthood. Pancreatic insulin mRNA levels were 20-30% lower (P < 0.05) in adult PRLR-deficient mice than in wild-type mice, and the insulin content of isolated islets was reduced by 16-25%. The insulin secretory response to ip glucose was blunted in PRLR-deficient males in vivo (P < 0.05) and in isolated islets of PRLR-deficient females and males in vitro (P < 0.01). Fasting blood glucose concentrations in PRLR-deficient mice were normal, but glucose levels after an ip glucose load were 10-20% higher (P < 0.02) than those in wild-type mice. On the other hand, the glucose response to ip insulin was normal. Our observations establish a physiologic role for lactogens in islet development and function.