Long-term exposure to glucose and lipids inhibits glucose-induced insulin secretion downstream of granule fusion with plasma membrane
Long-term exposure to glucose and lipids inhibits glucose-induced insulin secretion downstream of granule fusion with plasma membrane
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DOI：
10.2337/db06-1150
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发表时间：
2007-07-01
期刊：
影响因子：
7.7
通讯作者：
Rorsman, Patrik
中科院分区：
文献类型：
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作者：
Olofsson, Charlotta S.;Collins, Stephan;Rorsman, Patrik
在15 mmol/l葡萄糖条件下培养72小时的小鼠β细胞，与在4.5 mmol/l葡萄糖条件下培养的细胞相比，其atp敏感K+ (K- atp)通道活性降低（-30%），电压门控Ca2+电流增加，细胞内游离Ca2+浓度升高（[Ca-i(2+]) +160%），胞外分泌增多（通过电容测量监测，+100%），胰岛素含量增加（+230%）。然而，当摄入20毫摩尔/升的葡萄糖时，它们释放的胰岛素减少了20%。在4.5或15 mmol/l葡萄糖和油酸盐或棕榈酸盐（0.5 mmol/l）下共培养的胰岛中，葡萄糖诱导（20 mmol/l）胰岛素分泌减少了60-90%。游离脂肪酸（FFA）诱导的分泌抑制与[Ca2+](i)或胰岛ATP含量的任何重大变化无关。棕榈酸酯刺激胞吐两倍或更多，但减少v诱导的分泌高达60%。基础（1 mmol/l葡萄糖）K-ATP通道活性在4.5 mmol/l葡萄糖+棕榈酸培养的胰岛降低40%，在15 mmol/l葡萄糖+任意一种FFAs培养的胰岛降低60%。在葡萄糖浓度高（15 mmol/l）但不低（4.5 mmol/l）的情况下，暴露于FFAs的胰岛胰岛素含量下降了75%，但分泌颗粒的数量不变。ffa诱导的胰岛素分泌抑制与凋亡标志物Bax （bclii相关X蛋白）和caspase-3的转录水平升高无关。我们得出结论，葡萄糖和游离脂肪酸通过干扰胰岛素通过融合孔的出口来减少胰岛素分泌。
Mouse beta-cells cultured at 15 mmol/l glucose for 72 h had reduced ATP-sensitive K+ (K-ATP) channel activity (-30%), increased voltage-gated Ca2+ currents, higher intracellular free Ca2+ concentration ([Ca-i(2+]) +160%), more exocytosis (monitored by capacitance measurements, +100%), and greater insulin content (+230%) than those cultured at 4.5 mmol/l glucose. However, they released 20% less insulin when challenged with 20 mmol/l glucose. Glucose-induced (20 mmol/l) insulin secretion was reduced by 60-90% in islets cocultured at 4.5 or 15 mmol/l glucose and either oleate or palmitate (0.5 mmol/l). Free fatty acid (FFA)induced inhibition of secretion was not associated with any major changes in [Ca2+](i) or islet ATP content. Palmitate stimulated exocytosis by twofold or more but reduced V-induced secretion by up to 60%. Basal (1 mmol/l glucose) K-ATP channel activity was 40% lower in islets cultured at 4.5 mmol/l glucose plus palmitate and 60% lower in islets cultured at 15 mmol/l glucose plus either of the FFAs. Insulin content decreased by 75% in islets exposed to FFAs in the presence of high (15 mmol/l), but not low (4.5 mmol/l), glucose concentrations, but the number of secre tory granules was unchanged. FFA-induced inhibition of insulin secretion was not associated with increased tran script levels of the apoptosis markers Bax (BclII-associated X protein) and caspase-3. We conclude that glucose and FFAs reduce insulin secretion by interference with the exit of insulin via the fusion pore.