Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients
Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients
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DOI：
10.1007/s00125-004-1627-9
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发表时间：
2005-02-01
期刊：
影响因子：
8.2
通讯作者：
Marchetti, P
中科院分区：
文献类型：
--
作者：
Anello, M;Lupi, R;Marchetti, P
目的/假设：关于从2型糖尿病受试者分离的胰岛的胰岛素释放特性的信息很少。由于线粒体代表了调节胰岛素分泌的重要代谢产物产生的位点，我们直接在从2型糖尿病患者分离的胰岛中研究了胰岛素释放以及线粒体功能和形态。研究方法：通过胶原酶消化和密度梯度纯化制备胰岛，并通过分批孵育法评估响应于葡萄糖和精氨酸的胰岛素分泌。腺嘌呤核苷酸，线粒体膜电位，UCP-2的表达，呼吸链的复合物I和复合物V，硝基酪氨酸水平进行了评估，并与胰岛素分泌。结果如下：与对照胰岛相比，糖尿病胰岛显示对葡萄糖的胰岛素分泌减少，并且这种缺陷与较低的ATP水平、较低的ATP/ ADP比率和受损的线粒体膜超极化相关。在2型糖尿病胰岛中还发现UCP- 2、呼吸链复合体I和复合体V的蛋白表达增加，以及硝基酪氨酸水平升高。形态学研究显示，对照和糖尿病β细胞具有相似数量的线粒体;然而，2型糖尿病β细胞中的线粒体密度体积显著更高。结论/解释：在来自2型糖尿病受试者的胰腺β细胞中，对葡萄糖的分泌反应受损与线粒体功能和形态的显著改变相关。特别地，UCP- 2表达增加（可能是由于燃料过载的状况），这导致较低的ATP，降低的ATP/ADP比率，从而减少胰岛素释放。
Aims/hypothesis: Little information is available on the insulin release properties of pancreatic islets isolated from type 2 diabetic subjects. Since mitochondria represent the site where important metabolites that regulate insulin secretion are generated, we studied insulin release as well as mitochondrial function and morphology directly in pancreatic islets isolated from type 2 diabetic patients. Methods: Islets were prepared by collagenase digestion and density gradient purification, and insulin secretion in response to glucose and arginine was assessed by the batch incubation method. Adenine nucleotides, mitochondrial membrane potential, the expression of UCP-2, complex I and complex V of the respiratory chain, and nitrotyrosine levels were evaluated and correlated with insulin secretion. Results: Compared to control islets, diabetic islets showed reduced insulin secretion in response to glucose, and this defect was associated with lower ATP levels, a lower ATP/ ADP ratio and impaired hyperpolarization of the mitochondrial membrane. Increased protein expression of UCP- 2, complex I and complex Vof the respiratory chain, and a higher level of nitrotyrosine were also found in type 2 diabetic islets. Morphology studies showed that control and diabetic beta cells had a similar number of mitochondria; however, mitochondrial density volume was significantly higher in type 2 diabetic beta cells. Conclusions/interpretation: In pancreatic beta cells from type 2 diabetic subjects, the impaired secretory response to glucose is associated with a marked alteration of mitochondrial function and morphology. In particular, UCP- 2 expression is increased ( probably due to a condition of fuel overload), which leads to lower ATP, decreased ATP/ADP ratio, with consequent reduction of insulin release.