Stimulation of AMP-Activated Protein Kinase (AMPK) Is Associated with Enhancement of Glut1-Mediated Glucose Transport

doi:10.1006/abbi.2000.1935

Archives of Biochemistry and Biophysics

Volume 380, Issue 2, 15 August 2000, Pages 347-352

https://doi.org/10.1006/abbi.2000.1935 Get rights and content

Abstract

In cells expressing only the Glut1 isoform of glucose transporters, we have shown that glucose transport is markedly stimulated in response to hypoxia or inhibition of oxidative phosphorylation, conditions that would be expected to cause a stimulation of AMP-activated protein kinase (AMPK) activity. In the present study we tested the hypothesis that the stimulation of AMPK activity might be accompanied by an enhancement of Glut1-mediated glucose transport. Exposure of Clone 9 cells, 3T3-L1 preadipocytes, and C₂C₁₂ myoblasts (cells that express only the Glut1 isoform) to 5-aminoimidazole-4-carboxamideribonucleoside (AICAR), an adenosine analog that stimulates AMPK activity, resulted in a marked increase in the rate of glucose transport (ranging from four- to sixfold) that was accompanied by activation of AMPK. This stimulation of AMPK activity was associated with an increase in the phosphorylation of threonine 172 on the activation loop of its alpha subunit, with the predominant change being in the alpha-2 isoform. Exposure of Clone 9 cells to 5-iodotubercidin, an inhibitor of adenosine kinase, abolished the accumulation of AICAR-5′-monophosphate (ZMP), stimulation of AMPK, and the enhancement of glucose transport in response to AICAR. There was no significant increase in the content of Glut1 in plasma membranes of Clone 9 cells exposed to AICAR. We conclude that stimulation of AMPK activity is associated with enhancement of Glut1-mediated glucose transport, and that the glucose transport response is mediated by activation of Glut1 transporters preexisting in the plasma membrane.

References (31)

B.E. Kemp et al.
Trends Biochem. Sci.
(1999)
L.A. Witters et al.
Biochem. Biophys. Res. Commun.
(1991)
P.A. Hansen et al.
J. Biol. Chem.
(1998)
G. Sweeney et al.
J. Biol. Chem.
(1999)
L.A. Witters et al.
J. Biol. Chem.
(1992)
R.K. Prasad et al.
Arch. Biochem. Biophys.
(1999)
H.R. Samari et al.
J. Biol. Chem.
(1998)
B.E. Crute et al.
J. Biol. Chem.
(1998)
A. Behrooz et al.
J. Biol. Chem.
(1997)
D.G. Hardie et al.
Eur. J. Biochem.
(1997)

D.G. Hardie et al.

Annu. Rev. Biochem.

(1998)

R. Sato et al.

Proc. Natl. Acad. Sci. USA

(1993)

W.W. Winder et al.

Am. J. Physiol.

(1996)

J.M. Corton et al.

Eur. J. Biochem.

(1995)

G.F. Merrill et al.

Am. J. Physiol.

(1997)

Cited by (147)

Microgels-Encapsulated Magnesium/Emodin-based metal organic framework nanorods for diabetic bone regeneration
2024, Chemical Engineering Journal
Diabetic bone defect repair is one of the major challenges in clinic, because the pathological microenvironments such as hyperglycemia, oxidative stress, and inflammation exist in the bone defect area of diabetes mellitus. Although the current tissue-engineered bone has achieved favorable bone regeneration and functional reconstruction, it is still unsatisfactory for diabetic bone defect repair only by correcting a single pathological factor. In this study, we develop a multifunctional nano-releasing system of GelMA/HAMA microgels-encapsulated Mg²⁺/Emodin (MgEm) nanorods based on MOF design principle (denoted as MEGH) for reversing the diabetic pathological microenvironment. For the slow-release system of MEGH microgels, Emodin exert the hypoglycemic, antioxidant, and anti-inflammatory function, while Mg²⁺ ions could promote angiogenesis for bone regeneration. Subsequently, we combine decalcified bone matrix with the bone regenerative units based on BMSCs-loaded MEGH microgels (BMSCs@MEGH-D) for the construction of tissue-engineered bone. Finally, the pre-constructed BMSCs@MEGH-D scaffolds successfully promote the vascularized bone regeneration in diabetic rabbit skull models due to the effective correction of diabetic pathological microenvironment. The underlying mechanism indicates a synergetic efficacy of regulate glucose, inflammation, oxygen-related bioprocesses, as well as osteogenesis-related pathways. Our findings provide a promising treatment for reversing the diabetic pathological microenvironment to accelerate bone defect repair.
Adipose organ dysfunction and type 2 diabetes: Role of nitric oxide
2024, Biochemical Pharmacology
Adipose organ, historically known as specialized lipid-handling tissue serving as the long-term fat depot, is now appreciated as the largest endocrine organ composed of two main compartments, i.e., subcutaneous and visceral adipose tissue (AT), madding up white and beige/brown adipocytes. Adipose organ dysfunction manifested as maldistribution of the compartments, hypertrophic, hypoxic, inflamed, and insulin-resistant AT, contributes to the development of type 2 diabetes (T2D). Here, we highlight the role of nitric oxide (NO·) in AT (dys)function in relation to developing T2D. The key aspects determining lipid and glucose homeostasis in AT depend on the physiological levels of the NO· produced via endothelial NO· synthases (eNOS). In addition to decreased NO· bioavailability (via decreased expression/activity of eNOS or scavenging NO·), excessive NO· produced by inducible NOS (iNOS) in response to hypoxia and AT inflammation may be a critical interfering factor diverting NO· signaling to the formation of reactive oxygen and nitrogen species, resulting in AT and whole-body metabolic dysfunction. Pharmacological approaches boosting AT-NO· availability at physiological levels (by increasing NO· production and its stability), as well as suppression of iNOS-NO· synthesis, are potential candidates for developing NO·-based therapeutics in T2D.
Bicalutamide may enhance kidney injury in diabetes by concomitantly damaging energy production from OXPHOS and glycolysis
2022, Chemico-Biological Interactions
Citation Excerpt :
Apigenin (at 100 μM), an inhibitor of glucose uptake, showed remarkable inhibition of glucose uptake as a comparable positive control, and similarly, glucose uptake was fully suppressed by Bic (p < 0.001) (Fig. 4b). Generally, stimulation of AMPK activity is associated with enhancement of GLUT-1-mediated glucose transport [37] and glycolysis implying cellular adaptive responses to hypoxia [38]. Under a hypoxic status, HIF-1α triggers GLUT-1 expression, thereby enhancing glucose uptake for glycolysis [11,13].
Bicalutamide (Bic), frequently used in androgen-deprivation therapy for treating prostate cancer, was demonstrated to induce multiple apoptosis and fibrosis pathways and mitochondrial dysfunction in renal mesangial cells. Whether Bic also damages the glycolytic pathway has never been cited. To investigate this, we performed an in vitro model study with mesangial cells, and at the same time, collected data from an in vivo experiment. Bic induced hypoxia-inducible factor (HIF)-1 which upregulates phosphorylated-5′-AMP-activated protein kinase (p-AMPK) and severely suppresses the rate of adenosine triphosphate (ATP) production in both the oxidative phosphorylation and glycolysis pathways. Bic suppressed the oxygen consumption rate, extracellular acidification rate, and mitochondrial proton efflux rate, downregulated in vivo but upregulated in vitro glucose transporter (GLUT)-1, reduced glucose uptake, inhibited key glycolytic enzymes, including phosphofructokinase (PFK), pyruvate kinase (PK), and pyruvate dehydrogenase (PDH), and upregulated hexokinase II (HKII) and lactic dehydrogenase A (LDHA). In vivo, Bic downregulated renal cubilin levels, thereby disrupting the glomerular reabsorption function. Conclusively, Bic can damage bioenergenesis from both mitochondria and glycolysis. It was suggested that long-term administration of Bic can initiate renal damage depending on the duration and dose of treatment, which requires cautious follow-up.
Dictyostelium Differentiation-Inducing Factor 1 Promotes Glucose Uptake via Direct Inhibition of Mitochondrial Malate Dehydrogenase in Mouse 3T3-L1 Cells
2024, International Journal of Molecular Sciences
Pharmacological Evidence That Dictyostelium Differentiation-Inducing Factor 1 Promotes Glucose Uptake Partly via an Increase in Intracellular cAMP Content in Mouse 3T3-L1 Cells
2023, Molecules
Genetic preservation of SLC22A3 in the Admixed and Xhosa populations living in the Western Cape
2023, Molecular Biology Reports

View all citing articles on Scopus

¹: To whom correspondence should be addressed. Fax: (216) 368-5824. E-mail: [email protected].

View full text

Regular ArticleStimulation of AMP-Activated Protein Kinase (AMPK) Is Associated with Enhancement of Glut1-Mediated Glucose Transport

Abstract

Trends Biochem. Sci.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Arch. Biochem. Biophys.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Eur. J. Biochem.

Annu. Rev. Biochem.

Proc. Natl. Acad. Sci. USA

Am. J. Physiol.

Eur. J. Biochem.

Am. J. Physiol.

Regular Article
Stimulation of AMP-Activated Protein Kinase (AMPK) Is Associated with Enhancement of Glut1-Mediated Glucose Transport