BETA-CELL LIPOTOXICITY IN THE PATHOGENESIS OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS OF OBESE RATS - IMPAIRMENT IN ADIPOCYTE-BETA-CELL RELATIONSHIPS
BETA-CELL LIPOTOXICITY IN THE PATHOGENESIS OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS OF OBESE RATS - IMPAIRMENT IN ADIPOCYTE-BETA-CELL RELATIONSHIPS
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DOI：
10.1073/pnas.91.23.10878
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发表时间：
1994-11-08
影响因子：
11.1
通讯作者：
UNGER, RH
中科院分区：
文献类型：
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作者：
LEE, Y;HIROSE, H;UNGER, RH
高胰岛素血症、葡萄糖刺激的胰岛素分泌（GSIS）的丧失和外周胰岛素抵抗在非胰岛素依赖型糖尿病（NIDDM）中共存。由于游离脂肪酸（FFA）可以诱导这些相同的异常，我们研究了它们在肥胖Zucker糖尿病脂肪（ZDP-drt）大鼠从5周龄（高血糖发作前）到14周龄的NIDDM发病机制中的作用。在高血糖发生前两周，血浆FFA开始逐渐升高，在高血糖发生时平均为1.9 +/- 0.06 mM（与对照组相比P < 0.001）。此时，GSIS不存在，β细胞GLUT-2葡萄糖转运蛋白降低。糖尿病前期胰岛三酰甘油含量升高至对照组的10倍，并与血浆FFA相关（r = 0.825; P < 0.001），而血浆FFA又与血糖浓度相关（r = 0.873; P < 0.001）。通过与瘦同窝仔配对喂养将高脂血症降低至1.3 +/- 0.07 mM，降低了所有β细胞异常并预防了高血糖症。在含有2 mM FFA的培养基中培养7天的正常大鼠胰岛在3 mM葡萄糖下表现出基础胰岛素分泌增加，第一阶段GSIS减少了68%;在糖尿病前期胰岛中，FPA使第一阶段GSIS减少了69%。结果表明高脂血症在NIDDM发病机制中的作用;对胰岛素介导的抗脂解作用的抵抗被用来解释高FFA，尽管高胰岛素血症，和β细胞对甘油三酯血症的敏感性被用来解释FFA诱导的GSIS损失。
Hyperinsulinemia, loss of glucose-stimulated insulin secretion (GSIS), and peripheral insulin resistance coexist in non-insulin-dependent diabetes mellitus (NIDDM). Because free fatty acids (FFA) can induce these same abnormalities, we studied their role in the pathogenesis of the NIDDM of obese Zucker diabetic fatty (ZDP-drt) rats from 5 weeks of age (before the onset of hyperglycemia) until 14 weeks. Two weeks prior to hyperglycemia, plasma FFA began to rise progressively, averaging 1.9 +/- 0.06 mM at the onset of hyperglycemia (P < 0.001 vs. controls). At this time GSIS was absent and beta-cell GLUT-2 glucose transporter was decreased. The triacylglycerol content of prediabetic islets rose to 10 times that of controls and was correlated with plasma FFA (r = 0.825; P < 0.001), which, in turn, was correlated with the plasma glucose concentration (r = 0.873; P < 0.001). Reduction of hyperlipacidemia to 1.3 +/- 0.07 mM by pair feeding with lean littermates reduced all beta-cell abnormalities and prevented hyperglycemia. Normal rat islets that had been cultured for 7 days in medium containing 2 mM FFA exhibited increased basal insulin secretion at 3 mM glucose, and first-phase GSIS was reduced by 68 %; in prediabetic islets, first-phase GSIS was reduced by 69 % by FPA. The results suggest a role for hyperlipacidemia in the pathogenesis of NIDDM; resistance to insulin mediated antilipolysis is invoked to explain the high FFA despite hyperinsulinemia, and sensitivity of beta cells to hyperlipacedemia is invoked to explain the FFA-induced loss of GSIS.