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Diabetes Res Clin Pract. 2017 Oct 28. pii: S0168-8227(17)30315-7. doi: 10.1016/j.diabres.2017.10.004. [Epub ahead of print]

Akt activation: A potential strategy to ameliorate insulin resistance.

Author information

1
Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
2
Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China. Electronic address: j.liu@mail.xjtu.edu.cn.

Abstract

Insulin resistance is a hallmark of type 2 diabetes and obesity while the mechanism remains unclear. Current therapy to treat type 2 diabetes is metformin, the 5'-monophosphate-activated protein kinase (AMPK) activator, owing to the ability to augment peripheral glucose uptake. However, metformin also displays limitations, as AMPK activation remains intact and regular in most type 2 diabetes and metformin does not seem to facilitate peripheral insulin resistance. Evidence has shown that PI3K-Akt/PKB pathway could be induced via insulin and act as an important effector. Akt/PKB is capable of inducing a great number of downstream molecules, such as translocating glucose transporters GLUTs to the cell membrane thus increase glucose uptake. Hence, any defect in Akt/PKB pathway along with the downstream molecules could lead to insulin resistance. Inositol pyrophosphates, synthesized by inositol hexakisphosphate (IP6) kinase 1 (IP6K1) and competitive with 3,4,5-bisphosphate (PIP3) to bind the PH domain of Akt/PKB, demonstrate the ability to inhibit Akt signaling. In addition, IP6K1 knockout mice present increased insulin sensitivity and obesity resistance, indicating a novel therapeutic target in confronting insulin resistance. Taken together, we conclude that Akt activation is another potential strategy to ameliorate insulin resistance.

KEYWORDS:

AMPK; Akt/PKB; IP6K1; Insulin resistance; Type 2 diabetes

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