Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose -: A direct metformin effect on pancreatic β-cells
Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose -: A direct metformin effect on pancreatic β-cells
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DOI：
10.2337/diabetes.49.5.735
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发表时间：
2000-05-01
期刊：
影响因子：
7.7
通讯作者：
Purrello, F
中科院分区：
文献类型：
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作者：
Patanè, G;Piro, S;Purrello, F
由于二甲双胍影响外周胰岛素靶组织中的葡萄糖和游离脂肪酸 (FFA) 代谢，因此我们研究了该药物在恢复大鼠胰岛正常分泌模式方面的作用，这些胰岛的功能因长期暴露于升高的 FFA 或葡萄糖浓度而受损。我们在有或没有二甲双胍（0.25-12.5 μg/ml）存在或不存在的情况下培养大鼠胰岛，有或没有FFA（2 mmol/l油酸/棕榈酸2:1）或高浓度葡萄糖（16.7 mmol/l），然后测量胰岛素释放、葡萄糖利用率、葡萄糖和FFA氧化。与对照胰岛相比，暴露于高 FFA 或葡萄糖浓度的胰岛表现出基础胰岛素释放增加和葡萄糖诱导的胰岛素释放减少。在二甲双胍（2.5μg/ml）存在下，用FFA或葡萄糖再培养24小时的胰岛中，基础和葡萄糖诱导的胰岛素分泌均得到恢复。在预先暴露于高 FFA 或葡萄糖浓度的胰岛中，葡萄糖利用和葡萄糖氧化都发生了改变。特别是，对于对照胰岛，葡萄糖利用率在2.8 mmol/l葡萄糖时增加，在16.7 mmol/l葡萄糖时减少；葡萄糖氧化在 2.8 mmol/l 葡萄糖时与对照胰岛相似，但在 16.7 mmol/l 葡萄糖时下降。相反，在预先暴露于 FFA 的胰岛中，油酸氧化增加。在二甲双胍（2.5μg/ml）存在下，在高FFA或葡萄糖浓度下再培养24小时的胰岛中，所有这些异常都被逆转。总之，我们的数据表明，二甲双胍能够恢复葡萄糖和 FFA 代谢的细胞内异常，并恢复大鼠胰岛的正常分泌模式，这些胰岛的分泌功能因长期暴露于升高的 FFA 或葡萄糖水平而受损。这些数据提出了这样的可能性：在糖尿病患者中，二甲双胍除了其外周作用外，还可能对 β 细胞分泌功能产生直接有益的影响。
Because metformin affects glucose and free fatty acid (FFA) metabolism in peripheral insulin target tissues, we investigated the effect of this drug in restoring a normal secretory pattern in rat pancreatic islets whose function has been impaired by chronic exposure to elevated FFA or glucose concentrations. We cultured rat pancreatic islets with or without FFA (2 mmol/l oleate/ palmitate 2:1) or high glucose (16.7 mmol/l) concentrations in the presence or absence of metformin (0.25-12.5 mu g/ml) and then measured insulin release, glucose utilization, glucose, and FFA oxidation. When compared with control islets, islets exposed to high FFA or glucose concentrations showed an increased basal and a decreased glucose-induced insulin release. In islets cultured for an additional 24 h with FFA or glucose in the presence of metformin (2.5 mu g/ml), both basal and glucose-induced insulin secretions were restored. Both glucose utilization and glucose oxidation were altered in islets pre-exposed to high FFA or glucose concentrations. In particular, regarding control islets, glucose utilization was increased at 2.8 mmol/l glucose and decreased at 16.7 mmol/l glucose; glucose oxidation was similar to control islets at 2.8 mmol/l glucose but decreased at 16.7 mmol/l glucose. In contrast, oleate oxidation was increased in islets pre-exposed to FFA. AU of these abnormalities were reversed in islets cultured for an additional 24 h with high FFA or glucose concentrations in the presence of metformin (2.5 mu g/ml). In conclusion, our data show that metformin is able to restore the intracellular abnormalities of glucose and FFA metabolism and to restore a normal secretory pattern in rat pancreatic islets whose secretors function has been impaired by chronic exposure to elevated FFA or glucose levels. These data raise the possibility that, in diabetic patients, metformin tin addition to its peripheral effects) may have a direct beneficial effect on the beta-cell secretory function.