Increased p85α is a potent negative regulator of skeletal muscle insulin signaling and induces in vivo insulin resistance associated with growth hormone excess
Increased p85α is a potent negative regulator of skeletal muscle insulin signaling and induces in vivo insulin resistance associated with growth hormone excess
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DOI：
10.1074/jbc.m506967200
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发表时间：
2005-11-11
影响因子：
4.8
通讯作者：
Draznin, B
中科院分区：
文献类型：
--
作者：
Barbour, LA;Rahman, SM;Draznin, B
胰岛素抵抗是正常妊娠和生长激素过量（GH）状态的基本特征，但其潜在机制仍是谜。我们之前发现，在过表达胎盘生长激素的转基因动物的骨骼肌中，磷脂酰肌醇激酶（pi3激酶）的p85调控亚基显著增加，irs -1相关的pi3激酶活性显著降低。在本研究中，我们利用p85 α、p85 β或胰岛素样生长因子-1缺失的转基因小鼠，提供了新的证据，表明p85 α的过表达是骨骼肌胰岛素抵抗的主要机制。我们发现p85总量的增加完全是由p85 α特异性亚型的增加引起的。在肝脏特异性缺失胰岛素样生长因子-1的小鼠中，过量的生长激素引起胰岛素抵抗和骨骼肌p85 α的增加，使用GH释放激素拮抗剂完全可逆。为了了解p85 α在gh诱导的胰岛素抵抗中的作用，我们使用了p85 α或p85 β编码基因缺失的小鼠，分别为p85 α(+/-)和p85 β(-/-)。野生型和p85 β(-/-)小鼠在体内产生胰岛素抵抗，并表现出p85 α的过度表达和胰岛素刺激的骨骼肌PI 3激酶活性降低。相比之下，p85 α(+/-)小鼠保留了与p85 α表达降低相关的整体胰岛素敏感性和PI 3-激酶活性。这些发现证明了p85 α的增加在调节骨骼肌胰岛素抵抗中对生长激素的重要性，并提出了降低p85 α作为增强骨骼肌胰岛素敏感性的治疗策略的潜在作用。
Insulin resistance is a cardinal feature of normal pregnancy and excess growth hormone (GH) states, but its underlying mechanism remains enigmatic. We previously found a significant increase in the p85 regulatory subunit of phosphatidylinositol kinase ( PI3-kinase) and striking decrease in IRS-1-associated PI 3-kinase activity in the skeletal muscle of transgenic animals overexpressing human placental growth hormone. Herein, using transgenic mice bearing deletions in p85 alpha, p85 beta, or insulin-like growth factor-1, we provide novel evidence suggesting that overexpression of p85 alpha is a primary mechanism for skeletal muscle insulin resistance in response to GH. We found that the excess in total p85 was entirely accounted for by an increase in the free p85 alpha-specific isoform. In mice with a liver-specific deletion in insulin-like growth factor-1, excess GH caused insulin resistance and an increase in skeletal muscle p85 alpha, which was completely reversible using a GH-releasing hormone antagonist. To understand the role of p85 alpha in GH-induced insulin resistance, we used mice bearing deletions of the genes coding for p85 alpha or p85 beta, respectively (p85 alpha(+/-) and p85 beta(-/-)). Wild type and p85 beta(-/-) mice developed in vivo insulin resistance and demonstrated overexpression of p85 alpha and reduced insulin-stimulated PI 3-kinase activity in skeletal muscle in response to GH. In contrast, p85 alpha(+/-) mice retained global insulin sensitivity and PI 3-kinase activity associated with reduced p85 alpha expression. These findings demonstrated the importance of increased p85 alpha in mediating skeletal muscle insulin resistance in response to GH and suggested a potential role for reducing p85 alpha as a therapeutic strategy for enhancing insulin sensitivity in skeletal muscle.