Metabolic stress and altered glucose transport: activation of AMP-activated protein kinase as a unifying coupling mechanism

• Published in: Diabetes (New York, N.Y.) Vol. 49; no. 4; pp. 527 - 531
• Main Authors: Hayashi, T, Hirshman, M F, Fujii, N, Habinowski, S A, Witters, L A, Goodyear, L J
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01-04-2000
• Subjects: 2,4-Dinitrophenol - pharmacology; Adenosine Monophosphate - pharmacology; Adenosine Triphosphate - metabolism; Animals; Biological Transport - drug effects; Creatine - metabolism; Enzyme Activation - drug effects; Glucose - metabolism; Kinetics; Male; Muscle Contraction; Muscle, Skeletal - metabolism; Osmolar Concentration; Phosphocreatine - metabolism; Protein Kinases - metabolism; Rats; Rats, Sprague-Dawley; Rotenone - pharmacology; Stress, Physiological - metabolism; Uncoupling Agents - pharmacology
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.49.4.527

Metabolic stress and altered glucose transport: activation of AMP-activated protein kinase as a unifying coupling mechanism.
T Hayashi ,
M F Hirshman ,
N Fujii ,
S A Habinowski ,
L A Witters and
L J Goodyear
Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
02215, USA.
Abstract
5'AMP-activated protein kinase (AMPK) can be activated in response to cellular fuel depletion and leads to switching off ATP-consuming
pathways and switching on ATP-regenerating pathways in many cell types. We have hypothesized that AMPK is a central mediator
of insulin-independent glucose transport, which enables fuel-depleted muscle cells to take up glucose for ATP regeneration
under conditions of metabolic stress. To test this hypothesis, rat epitrochlearis muscles were isolated and incubated in vitro
under several conditions that evoke metabolic stress accompanied by intracellular fuel depletion. Rates of glucose transport
in the isolated muscles were increased by all of these conditions, including contraction (5-fold above basal), hypoxia (8-fold),
2,4-dinotrophenol (11-fold), rotenone (7-fold), and hyperosmolarity (8-fold). All of these stimuli simultaneously increased
both alpha1 and alpha2 isoform-specific AMPK activity. There was close correlation between alpha1 (r2 = 0.72) and alpha2 (r2
= 0.67) AMPK activities and the rate of glucose transport, irrespective of the metabolic stress used, all of which compromised
muscle fuel status as judged by ATP, phosphocreatine, and glycogen content. 5-Aminoimidazole-4-carboxamide ribonucleoside,
a pharmacological AMPK activator that is metabolized to an AMP-mimetic ZMP, also increased both glucose transport and AMPK
activity but did not change fuel status. Insulin stimulated glucose transport by 6.5-fold above basal but did not affect AMPK
activity. These results suggest that the activation of AMPK may be a common mechanism leading to insulin-independent glucose
transport in skeletal muscle under conditions of metabolic stress.