The Anti-diabetic Drugs Rosiglitazone and Metformin Stimulate AMP-activated Protein Kinase through Distinct Signaling Pathways*

By L. Fryer, Asha Parbu-Patel, David Carling. Journal of Biological Chemistry, 2002

1,081 citations recorded by the source corpus.

AMP-activated protein kinase (AMPK) is activated within the cell in response to multiple stresses that increase the intracellular AMP:ATP ratio. Here we show that incubation of muscle cells with the thiazolidinedione, rosiglitazone, leads to a dramatic increase in this ratio with the concomitant activation of AMPK. This finding raises the possibility that a number of the beneficial effects of the thiazolidinediones could be mediated via activation of AMPK. Furthermore, we show that in addition to the classical activation pathway, AMPK can also be stimulated without changing the levels of adenine nucleotides. In muscle cells, both hyperosmotic stress and the anti-diabetic agent, metformin, activate AMPK in the absence of any increase in the AMP:ATP ratio. However, although activation is no longer dependent on this ratio, it still involves increased phosphorylation of threonine 172 within the catalytic (α) subunit. AMPK stimulation in response to hyperosmotic stress does not appear to involve phosphatidylinositol 3-phosphate kinase, protein kinase C, mitogen-activated protein (MAP) kinase kinase, or p38 MAP kinase α or β. Our results demonstrate that AMPK can be activated by at least two distinct signaling mechanisms and suggest that it may play a wider role in the cellular stress response than was previously understood.

Subfields: Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3fbcef45d11b6f6d902282ccb8ed0664e64012ab

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Citations in the corpus

Metformin Induces a Dietary Restriction–Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1, and SKN-1 (2010, background): “In mammalian models, metformin and other biguanides activate AMPK in reactions needed for some metformin-associated outcomes [20,21,65].”
The AMP-activated protein kinase cascade--a unifying system for energy control. (2004, background): “It is not clear how these conditions signal activation of AMPK, but they do lead to increased phosphorylation of AMPK by its upstream kinase [ 12 ,13].”
AMPK - a nutrient and energy sensor that maintains energy homeostasis (2012, background): “AMPK is also switched on by numerous drugs and xenobiotics, including antidiabetic drugs (such as metformin, phenformin and thiazolidinedione”
Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site (2004, background): “Several drugs, including metformin (Hawley et al. 2002) and rosiglitazone (Fryer et al. 2002), used extensively for the treatment of type II diabetes, activate AMPK, supporting the view that AMPK actions protect the body from developing diabetes.”
Adiponectin: A novel adipokine linking adipocytes and vascular function. (2004, positive): “Interestingly, AMP kinase has recently been implicated in the mechanism of action of metformin in the liver (47) and potentially in the action of the thiazolidinedione insulin sensitizers (48, 49), suggesting that it may be an important mediator of antidiabetic metabolic effects, consistent with the”
Molecular mediators of hepatic steatosis and liver injury. (2004, positive): “A second class of antidiabetic drugs, the thiazolidinediones, are principally recognized as drugs that activate PPAR-γ ; however, recent data suggest that they also can activate AMPK (55, 56).”
Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade (2003, background): “The anti-diabetic drug metformin activates AMPK in intact cells by a mechanism that is not known, although it does not involve changes in cellular adenine nucleotide content [25-27].”