Early hepatic insulin resistance precedes the onset of diabetes in obese C57BLKS-db/db mice.
Early hepatic insulin resistance precedes the onset of diabetes in obese C57BLKS-db/db mice.
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作者：
Davis RC;Castellani LW;Hosseini M;Ben-Zeev O;Mao HZ;Weinstein MM;Jung DY;Jun JY;Kim JK;Lusis AJ;Péterfy M
鉴定瘦素受体缺陷型肥胖 C57BLKS/J-db/db (BKS-db) 小鼠品系中导致糖尿病易感性的代谢紊乱。年轻的 BKS-db 小鼠被用来识别导致糖尿病发生的代谢途径。使用抗糖尿病 B6-db 菌株作为比较，应用体内和体外方法来鉴定两种菌株之间的代谢和分子差异。尽管血浆胰岛素水平较高，但 BKS-db 小鼠表现出较低的脂肪生成基因表达、脂肪生成速率、肝甘油三酯和糖原含量以及糖异生基因的胰岛素抑制受损。 BKS-db 原代肝细胞中肝胰岛素受体底物 (IRS)-1 和 IRS-2 表达以及胰岛素刺激的 Akt 磷酸化降低。高胰岛素-正常血糖钳夹研究表明，与肝脏胰岛素抵抗相比，BKS-db 小鼠的骨骼肌比 B6-db 小鼠的骨骼肌对胰岛素更敏感。我们还证明，BKS-db 小鼠血浆甘油三酯水平升高与脂肪酶活性降低导致的甘油三酯清除率降低相关。我们的研究表明，在 β 细胞衰竭发生之前，BKS-db 中存在代谢紊乱，并确定早期肝脏胰岛素抵抗是 BKS-db 表型的一个组成部分。我们认为肝脏胰岛素信号传导缺陷导致 BKS-db 小鼠品系患上糖尿病。
To identify metabolic derangements contributing to diabetes susceptibility in the leptin receptor–deficient obese C57BLKS/J-db/db (BKS-db) mouse strain. Young BKS-db mice were used to identify metabolic pathways contributing to the development of diabetes. Using the diabetes-resistant B6-db strain as a comparison, in vivo and in vitro approaches were applied to identify metabolic and molecular differences between the two strains. Despite higher plasma insulin levels, BKS-db mice exhibit lower lipogenic gene expression, rate of lipogenesis, hepatic triglyceride and glycogen content, and impaired insulin suppression of gluconeogenic genes. Hepatic insulin receptor substrate (IRS)-1 and IRS-2 expression and insulin-stimulated Akt-phosphorylation are decreased in BKS-db primary hepatocytes. Hyperinsulinemic-euglycemic clamp studies indicate that in contrast to hepatic insulin resistance, skeletal muscle is more insulin sensitive in BKS-db than in B6-db mice. We also demonstrate that elevated plasma triglyceride levels in BKS-db mice are associated with reduced triglyceride clearance due to lower lipase activities. Our study demonstrates the presence of metabolic derangements in BKS-db before the onset of β-cell failure and identifies early hepatic insulin resistance as a component of the BKS-db phenotype. We propose that defects in hepatic insulin signaling contribute to the development of diabetes in the BKS-db mouse strain.
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影响因子：
8.2
作者：
LIKE, AA;CHICK, WL
通讯作者：
CHICK, WL
影响因子：
4.4
作者：
Haas JT;Biddinger SB
通讯作者：
Biddinger SB
影响因子：
4.8
作者：
Cao, GQ;Liang, Y;Etgen, GJ
通讯作者：
Etgen, GJ
影响因子：
15.9
作者：
Matsusue, K;Haluzik, M;Gonzalez, FJ
通讯作者：
Gonzalez, FJ
DOI：
10.1016/j.bbadis.2006.01.002
发表时间：
2006-04-01
影响因子：
6.2
作者：
Mao, HZ;Roussos, EI;Péterfy, M
通讯作者：
Péterfy, M