Akt activation: A potential strategy to ameliorate insulin resistance

Diabetes Res Clin Pract. 2019 Oct;156:107092. doi: 10.1016/j.diabres.2017.10.004. Epub 2017 Oct 28.

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.

Publication types

  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / genetics*
  • Humans
  • Insulin Resistance / genetics*
  • Mice
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-akt / metabolism*

Substances

  • Proto-Oncogene Proteins c-akt