Insulin and glucagon regulate pancreatic α-cell proliferation.
Insulin and glucagon regulate pancreatic α-cell proliferation.
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DOI：
10.1371/journal.pone.0016096
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发表时间：
2011-01-25
期刊：
影响因子：
3.7
通讯作者：
Egan JM
中科院分区：
文献类型：
--
作者：
Liu Z;Kim W;Chen Z;Shin YK;Carlson OD;Fiori JL;Xin L;Napora JK;Short R;Odetunde JO;Lao Q;Egan JM
2型糖尿病(T2 DM)是由胰岛素抵抗和β细胞功能障碍引起的高血糖素血症。高血糖素是一种由29个氨基酸组成的多肽激素，由胰腺α细胞分泌：循环中的高血糖素水平过高会导致肝脏葡萄糖输出过多。我们研究了T2 DM患者α细胞数量是否增加，以及是什么因素(S)调节α细胞的周转。以Leprdb/Leprdb(db/db)小鼠为T2 DM模型，用αTc1细胞研究潜在的α细胞营养因子。在这里，我们证明了在db/db小鼠中，α细胞数量和血浆胰高血糖素水平随着糖尿病的进展而增加。胰岛素处理(EC_(50) = _2 nM)的α细胞与非胰岛素处理的α细胞相比，以浓度依赖的方式显著促进α细胞的增殖。胰岛素通过IR/IR_2/AKT/mTOR信号通路上调α细胞的增殖，而特异性mTOR抑制剂雷帕霉素可阻止胰岛素诱导的细胞增殖。GCGR拮抗导致αTc1细胞增殖率降低。此外，阻断db/db小鼠的GcgRs可改善血糖稳态，减缓α细胞的增殖，并增加db/db小鼠β细胞的胰岛内胰岛素含量。这些研究表明，随着糖尿病的发展，胰腺α细胞的增殖增加，导致血浆胰高血糖素水平升高，而胰岛素和胰升糖素都是α细胞的营养因子。我们目前的发现表明，治疗T2 DM的新治疗策略可能包括靶向α细胞和胰高血糖素。
Type 2 diabetes mellitus (T2DM) results from insulin resistance and β-cell dysfunction, in the setting of hyperglucagonemia. Glucagon is a 29 amino acid peptide hormone, which is secreted from pancreatic α cells: excessively high circulating levels of glucagon lead to excessive hepatic glucose output. We investigated if α-cell numbers increase in T2DM and what factor (s) regulate α-cell turnover. Leprdb/Leprdb (db/db) mice were used as a T2DM model and αTC1 cells were used to study potential α-cell trophic factors. Here, we demonstrate that in db/db mice α-cell number and plasma glucagon levels increased as diabetes progressed. Insulin treatment (EC50 = 2 nM) of α cells significantly increased α-cell proliferation in a concentration-dependent manner compared to non-insulin-treated α cells. Insulin up-regulated α-cell proliferation through the IR/IRS2/AKT/mTOR signaling pathway, and increased insulin-mediated proliferation was prevented by pretreatment with rapamycin, a specific mTOR inhibitor. GcgR antagonism resulted in reduced rates of cell proliferation in αTC1 cells. In addition, blockade of GcgRs in db/db mice improved glucose homeostasis, lessened α-cell proliferation, and increased intra-islet insulin content in β cells in db/db mice. These studies illustrate that pancreatic α-cell proliferation increases as diabetes develops, resulting in elevated plasma glucagon levels, and both insulin and glucagon are trophic factors to α-cells. Our current findings suggest that new therapeutic strategies for the treatment of T2DM may include targeting α cells and glucagon.