Parathyroid hormone-related protein enhances human ß-cell proliferation and function with associated induction of cyclin-dependent kinase 2 and cyclin E expression.
Parathyroid hormone-related protein enhances human ß-cell proliferation and function with associated induction of cyclin-dependent kinase 2 and cyclin E expression.
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DOI：
10.2337/db09-1796
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发表时间：
2010-12
期刊：
影响因子：
7.7
通讯作者：
Vasavada RC
中科院分区：
文献类型：
--
作者：
Guthalu Kondegowda N;Joshi-Gokhale S;Harb G;Williams K;Zhang XY;Takane KK;Zhang P;Scott DK;Stewart AF;Garcia-Ocaña A;Vasavada RC
诱导人β细胞生长同时增强功能是糖尿病治疗的主要目标。甲状旁腺激素相关蛋白（PTHrP）通过甲状旁腺激素-1受体（PTH1R）促进啮齿动物β细胞的生长和功能。基于此，我们假设PTH1R在人β-细胞中表达，并且PTHrP具有增强人β-细胞增殖和/或功能的潜力。用腺病毒PTHrP构建物或PTHrP肽转染人胰岛，分析PTH1R的表达、β细胞增殖、葡萄糖刺激胰岛素分泌（GSIS）、分化和细胞周期基因的表达。我们还评估了过表达G1/S细胞周期晚期分子对人β细胞增殖的影响。我们发现人类β-细胞表达PTH1R。更重要的是，PTHrP的过表达导致人β细胞增殖显著增加约三倍。此外，氨基端PTHrP（1-36）肽足以增加人类胰岛中G1/S细胞周期晚期蛋白cyclin E和cyclin依赖性激酶2 （cdk2）的复制和表达。值得注意的是，PTHrP（1-36）也增强了GSIS。最后，cyclin E单独过表达，而cdk2不表达，增加了人β细胞的增殖，当这两种分子同时表达时，复制进一步显着协同增加。PTHrP（1-36）肽增强人β细胞的增殖和功能，与两种特异性细胞周期激活因子相关的上调可以共同诱导人β细胞增殖数倍。鉴于PTHrP（1-36）对绝经后骨质疏松症的补充治疗效果，PTHrP（1-36）治疗糖尿病的未来治疗潜力尤其重要。
Inducing human β-cell growth while enhancing function is a major goal in the treatment of diabetes. Parathyroid hormone–related protein (PTHrP) enhances rodent β-cell growth and function through the parathyroid hormone-1 receptor (PTH1R). Based on this, we hypothesized that PTH1R is expressed in human β-cells and that PTHrP has the potential to enhance human β-cell proliferation and/or function. PTH1R expression, β-cell proliferation, glucose-stimulated insulin secretion (GSIS), and expression of differentiation and cell-cycle genes were analyzed in human islets transduced with adenoviral PTHrP constructs or treated with PTHrP peptides. The effect of overexpression of late G1/S cell cycle molecules was also assessed on human β-cell proliferation. We found that human β-cells express PTH1R. More importantly, overexpression of PTHrP causes a significant approximately threefold increase in human β-cell proliferation. Furthermore, the amino terminus PTHrP(1-36) peptide is sufficient to increase replication as well as expression of the late G1/S cell-cycle proteins cyclin E and cyclin-dependent kinase 2 (cdk2) in human islets. Notably, PTHrP(1-36) also enhances GSIS. Finally, overexpression of cyclin E alone, but not cdk2, augments human β-cell proliferation, and when both molecules are expressed simultaneously there is a further marked synergistic increase in replication. PTHrP(1-36) peptide enhances human β-cell proliferation as well as function, with associated upregulation of two specific cell-cycle activators that together can induce human β-cell proliferation several fold. The future therapeutic potential of PTHrP(1-36) for the treatment of diabetes is especially relevant given the complementary therapeutic efficacy of PTHrP(1-36) in postmenopausal osteoporosis.