Direct effect of cholesterol on insulin secretion -: A novel mechanism for pancreatic β-cell dysfunction
Direct effect of cholesterol on insulin secretion -: A novel mechanism for pancreatic β-cell dysfunction
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DOI：
10.2337/db07-0056
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发表时间：
2007-09-01
期刊：
影响因子：
7.7
通讯作者：
Piston, David W.
中科院分区：
文献类型：
--
作者：
Hao, Mingming;Head, W. Steven;Piston, David W.
2型糖尿病通常伴有血脂和脂蛋白水平异常，但大多数关于高脂血症和糖尿病之间联系的研究都集中在游离脂肪酸（FFA）上。在这项研究中，我们研究了胆固醇和胰岛素分泌之间的关系，从胰腺P-细胞是独立的FFAS.RESEARCH设计和方法的影响，几种方法被用来调节胆固醇水平在完整的胰岛和培养的P-细胞，包括最近开发的小鼠模型，表现出升高的胆固醇，但正常的FFA水平。胆固醇的急性和代谢性改变是使用药理学试剂完成的。结果-我们发现血清胆固醇升高和胰岛素分泌减少之间有直接联系，胆固醇消耗可恢复正常分泌。我们进一步证明，过量的胆固醇抑制分泌通过增加神经元型一氧化氮合酶二聚体的代谢下调。结论胆固醇对P细胞代谢的直接影响打开了一套新的机制，可能有助于P细胞功能障碍和肥胖患者糖尿病的发病。
OBJECTIVE-Type 2 diabetes is often accompanied by abnormal blood lipid and lipoprotein levels, but most studies on the link between hyperlipidemia and diabetes have focused on free fatty acids (FFAs). In this study, we examined the relationship between cholesterol and insulin secretion from pancreatic P-cells that is independent of the effects of FFAs.RESEARCH DESIGN AND METHODS-Several methods were used to modulate cholesterol levels in intact islets and cultured P-cells, including a recently developed mouse model that exhibits elevated cholesterol but normal FFA levels. Acute and metabolic alteration of cholesterol was done using pharmacological reagents.RESULTS-We found a direct link between elevated serum cholesterol and reduced insulin secretion, with normal secretion restored by cholesterol depletion. We further demonstrate that excess cholesterol inhibits secretion by downregulation of metabolism through increased neuronal nitric oxide synthase dimerization.CONCLUSIONS-This direct effect of cholesterol on P-cell metabolism opens a novel set of mechanisms that may contribute to P-cell dysfunction and the onset of diabetes in obese patients.