PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis

Abstract

New therapeutic approaches to counter the increasing prevalence of obesity and type 2 diabetes mellitus are in high demand. Deregulation of the phosphoinositide-3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (AKT), mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways, which are essential for glucose homeostasis, often results in obesity and diabetes. Thus, these pathways should be attractive therapeutic targets. However, with the exception of metformin, which is considered to function mainly by activating AMPK, no treatment for the metabolic syndrome based on targeting protein kinases has yet been developed. By contrast, therapies based on the inhibition of the PI3K/AKT and MAPK pathways are already successful in the treatment of diverse cancer types and inflammatory diseases. This contradiction prompted us to review the signal transduction mechanisms of PI3K/AKT, MAPK and AMPK and their roles in glucose homeostasis, and we also discuss current clinical implications.

General aspects of muscle glucose uptake

“…Besides the effects on the liver and skeletal muscle, studies have shown that metformin activates AMPK in aortic endothelial tissue in vivo (Zou et al 2004). Therefore, it can be stated that some of the mechanisms of action of metformin may be explained by AMPK activation (Schultze et al 2012, Viollet et al 2012.…”

Sirt2 Deacetylase Is a Novel AKT Binding Partner Critical for AKT Activation by Insulin

“…Activation of the phosphatidylinositol 3-kinase (PI3K)-AKT/PKB pathway is considered the main signaling component downstream of the insulin receptor (3,4). When activated, AKT regulates a multitude of targets by direct phosphorylation (5).…”

Dose-Finding Quantitative 18F-FDG PET Imaging Study with the Oral Pan-AKT Inhibitor GSK2141795 in Patients with Gynecologic Malignancies

“…The PI3K/AKT pathway also plays an evolutionarily conserved role in glucose metabolism where it acts to transduce intracellular signals downstream of insulin and the insulinlike-growth factor (3). The 3 AKT isoforms (AKT1, 2, and 3) are highly homologous yet differ in quantitative levels of tissuespecific expression, which determines the relative contribution of each isoform to glucose metabolism and insulin signaling (4)(5)(6).…”