Leptin Deficiency and Beta-Cell Dysfunction Underlie Type 2 Diabetes in Compound Akt Knockout Mice
Leptin Deficiency and Beta-Cell Dysfunction Underlie Type 2 Diabetes in Compound Akt Knockout Mice
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DOI：
10.1128/mcb.01792-08
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发表时间：
2009-06-01
影响因子：
5.3
通讯作者：
Hay, Nissim
中科院分区：
文献类型：
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作者：
Chen, William S.;Peng, Xiao-Ding;Hay, Nissim
对单个Akt同种型无效的小鼠的表型分析表明，它们在功能上是不同的，并且只有Akt 2在糖尿病中起作用。我们发现Akt亚型在葡萄糖稳态和糖尿病中起着补偿和补充作用。Pten单倍缺陷抑制了Akt 2（-/-）小鼠的胰岛素抵抗，表明其他Akt亚型可以补偿Akt 2功能。然而，Akt 2（-/-）小鼠中Akt 1的单倍缺陷将前驱糖尿病转化为明显的2型糖尿病，这也被Pten的单倍缺陷逆转。Akt 3似乎对糖尿病没有显著影响。Akt 1（+/-）Akt 2（-/-）小鼠中的显性2型糖尿病表现为由于β细胞功能障碍导致的高血糖症以及由于瘦素水平显著降低导致的葡萄糖稳态受损。在Akt 1（+/-）Akt 2（-/-）和Akt 2（-/-）小鼠中，恢复瘦素水平足以恢复正常的血糖和胰岛素水平，这表明瘦素缺乏是这些小鼠中糖尿病的主要原因。这些结果揭示了Akt与糖尿病联系的新机制，提供了治疗策略，并表明通过Akt抑制，作为癌症治疗的结果诱导的糖尿病可以通过瘦素治疗逆转。
Phenotypic analyses of mice null for the individual Akt isoforms suggested that they are functionally distinct and that only Akt2 plays a role in diabetes. We show here that Akt isoforms play compensatory and complementary roles in glucose homeostasis and diabetes. Insulin resistance in Akt2(-/-) mice was inhibited by haplodeficiency of Pten, suggesting that other Akt isoforms can compensate for Akt2 function. Haplodeficiency of Akt1 in Akt2(-/-) mice, however, converts prediabetes to overt type 2 diabetes, which is also reversed by haplodeficiency of Pten. Akt3 does not appear to contribute significantly to diabetes. Overt type 2 diabetes in Akt1(+/-) Akt2(-/-) mice is manifested by hyperglycemia due to beta-cell dysfunction combined with impaired glucose homeostasis due to markedly decreased leptin levels. Restoring leptin levels was sufficient to restore normal blood glucose and insulin levels in Akt1(+/-) Akt2(-/-) and Akt2(-/-) mice, suggesting that leptin-deficiency is the predominant cause of diabetes in these mice. These results uncover a new mechanism linking Akt to diabetes, provide a therapeutic strategy, and show that diabetes induced as a consequence of cancer therapy, via Akt inhibition, could be reversed by leptin therapy.