Insulin promotes proliferation and fibrosing responses in activated pancreatic stellate cells
Insulin promotes proliferation and fibrosing responses in activated pancreatic stellate cells
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胰岛素促进活化的胰腺星状细胞的增殖和纤维化反应
DOI：
10.1152/ajpgi.00251.2016
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发表时间：
2016-10-01
影响因子：
4.5
通讯作者：
Pandol, Stephen J.
中科院分区：
文献类型：
--
作者：
Yang, Jiayue;Waldron, Richard T.;Pandol, Stephen J.
流行病学研究支持肥胖、糖尿病和胰腺疾病（包括胰腺炎和胰腺癌 (PDAC)）之间的密切联系。 2 型糖尿病 (T2DM) 与胰岛素抵抗、高血糖和高胰岛素血症有关，后者是由于胰腺 β 细胞胰岛素分泌增加所致。我们报道，高脂肪饮食诱导的小鼠 PDAC 进展与高血糖、高胰岛素血症和胰腺星状细胞 (PaSC) 的激活有关。我们在此研究了高浓度胰岛素和葡萄糖对小鼠和人类 PaSC 生长和纤维化反应的影响。我们发现，与正常人相比，T2DM 患者的胰腺在胰岛和胰岛周围的外分泌胰腺中表现出广泛的胶原沉积和激活的 PaSC。与饲喂对照饮食的小鼠相比，饲喂高脂肪饮食长达 12 个月的小鼠同样表现出胰岛周围纤维化的增加。静态和激活的 PaSC 均表达胰岛素（IR；主要是 A 型）和 IGF (IGF-1R) 受体，并且胰岛素和葡萄糖均调节受体表达。在培养的 PaSC 中，胰岛素诱导特定激酶结构域激活环位点 IR/IGF-1R 的快速酪氨酸自磷酸化，激活 Akt/mTOR/p70S6K 信号传导，并使 FoxO1（一种抑制细胞生长的转录因子）失活。在含有 5 mM 或 25 mM 葡萄糖的培养基中，胰岛素不会促进静态 PaSC 的激活。然而，在激活的 PaSC 中，胰岛素增强了细胞增殖并增加了细胞外基质蛋白的产生，而这些作用被 mTORC1 和 mTORC2 的特异性抑制所消除。总之，我们的数据支持这样的概念：与肥胖和 T2DM 相关的局部葡萄糖和胰岛素浓度增加可促进 PaSC 生长和纤维化反应。
Epidemiological studies support strong links between obesity, diabetes, and pancreatic disorders including pancreatitis and pancreatic adenocarcinoma (PDAC). Type 2 diabetes (T2DM) is associated with insulin resistance, hyperglycemia, and hyperinsulinemia, the latter due to increased insulin secretion by pancreatic beta-cells. We reported that high-fat diet-induced PDAC progression in mice is associated with hyperglycemia, hyperinsulinemia, and activation of pancreatic stellate cells (PaSC). We investigated here the effects of high concentrations of insulin and glucose on mouse and human PaSC growth and fibrosing responses. We found that compared with normal, pancreata from T2DM patients displayed extensive collagen deposition and activated PaSC in islet and peri-islet exocrine pancreas. Mice fed a high-fat diet for up to 12 mo similarly displayed increasing peri-islet fibrosis compared with mice fed control diet. Both quiescent and activated PaSC coexpress insulin (IR; mainly A type) and IGF (IGF-1R) receptors, and both insulin and glucose modulate receptor expression. In cultured PaSC, insulin induced rapid tyrosine autophosphorylation of IR/IGF-1R at specific kinase domain activation loop sites, activated Akt/mTOR/p70S6K signaling, and inactivated FoxO1, a transcription factor that restrains cell growth. Insulin did not promote activation of quiescent PaSC in either 5 mM or 25 mM glucose containing media. However, in activated PaSC, insulin enhanced cell proliferation and augmented production of extracellular matrix proteins, and these effects were abolished by specific inhibition of mTORC1 and mTORC2. In conclusion, our data support the concept that increased local glucose and insulin concentrations associated with obesity and T2DM promote PaSC growth and fibrosing responses.