Methotrexate Increases Skeletal Muscle GLUT4 Expression and Improves Metabolic Control in Experimental Diabetes

@article{Russo2012MethotrexateIS,
  title={Methotrexate Increases Skeletal Muscle GLUT4 Expression and Improves Metabolic Control in Experimental Diabetes},
  author={Giuseppina T Russo and Letteria Minutoli and Alessandra Bitto and Domenica Altavilla and E. Alessi and Annalisa Giandalia and Elisabetta L. Romeo and Maria Francesca Stagno and Francesco Squadrito and Domenico Cucinotta and Jacob Selhub},
  journal={Journal of Nutrition and Metabolism},
  year={2012},
  volume={2012}
}
Long-term administration of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) mimics the effects of endurance exercise by activating AMP kinase and by increasing skeletal muscle expression of GLUT4 glucose transporter. AICAR is an intermediate in the purine de novo synthesis, and its tissue concentrations can be increased, in vivo, by low doses of methotrexate (MTX) through the inhibition of the enzyme AICAR transformylase. We report here the first evidence that, in experimental type 2… 

Figures and Tables from this paper

Methotrexate Promotes Glucose Uptake and Lipid Oxidation in Skeletal Muscle via AMPK Activation
TLDR
It is found MTX markedly reduced the threshold for AICAR-induced AMPK activation and potentiated glucose uptake and lipid oxidation, which underscore a role for AMPK as a direct molecular link between MTX and energy metabolism in skeletal muscle.
Methotrexate reduces HbA1c concentration but does not produce chronic accumulation of ZMP in patients with rheumatoid or psoriatic arthritis
TLDR
The data do not support the hypothesis that MTX improves glucose homeostasis through chronic accumulation of ZMP, and MTX therapy probably does not produce a chronic increase in erythrocyte ZMP or urinary AICAR concentrations.
ATIC as a link between antirheumatic drugs and regulation of energy metabolism in skeletal muscle
TLDR
This work reviews antirheumatic drugs that inhibit ATIC, the final enzyme in the de novo purine biosynthesis, responsible for conversion of ZMP to IMP and discusses whether these drugs might improve systemic glucose homeostasis by inhibiting ATIC and activating AMPK in skeletal muscle.
Browning of adipose tissue and increased thermogenesis induced by Methotrexate
TLDR
Novel evidence is presented that MTX treatment increases the gene expression of thermogenic genes in brown and beige adipose tissues in a fat cell autonomous manner and it is shown that treatment of mice with MTX is associated with cold resistance, improved glucose homeostasis, decreased inflammation, and reduced hepatosteatosis in high‐fat diet states.
Soc . Physiol . Sci . 34 ( 2 ) , 386-403 L-carnitine Increases Skeletal Muscle GLUT 4 Expression and Improves Metabolic Control in Type 2 Diabetes
TLDR
The results of this study demonstrate that carnitine supplementation ameliorates insulin resistance in type 2 diabetic rats and up-regulating GLUT4 protein expression in the skeletal muscles through increasing the activity of AMPK.
Effects of Ghrelin on Triglyceride Accumulation and Glucose Uptake in Primary Cultured Rat Myoblasts under Palmitic Acid-Induced High Fat Conditions
TLDR
Assessment of the effects of acylated ghrelin on glucose and triglyceride metabolism in rat myoblasts under palmitic acid- (PA-) induced high fat conditions concluded that these effects may involve fatty acid oxidation.
Cardiovascular inflammation is reduced with methotrexate in diabetes
TLDR
It is reported that db/db mice concomitantly fed the Western diet and treated with the anti-inflammatory agent methotrexate display a less aggressive inflammatory profile than their saline-treated counterpart, lending support to the notion that alterations in the inflammatory system may be involved in the macrovascular benefits observed in type 2 diabetes trials.
Is Osteocalcin Implicated in the Regulation Of Energy Metabolism in Active Rheumatoid Arthritis
TLDR
The present study suggests that inflammatory factors may modify in distinct ways the relationship between osteocalcin and carbohydrate metabolism in patients with RA.
A marriage of two “Methusalem” drugs for the treatment of psoriasis?
TLDR
Arguments that the “antidiabetic” drug metformin could be useful as an add-on therapy to methotrexate for the treatment of psoriasis and, perhaps, for rheumatoid arthritis as well are presented.
...
1
2
...

References

SHOWING 1-10 OF 56 REFERENCES
Acute and chronic treatment of ob/ob and db/db mice with AICAR decreases blood glucose concentrations.
Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome.
TLDR
Evidence is provided that long-term administration of AICAR improves glucose tolerance, improves the lipid profile, and reduces systolic blood pressure in an insulin-resistant animal model and gives additional support to the hypothesis that AMPK activation might be a potential future pharmacological strategy for treating the insulin resistance syndrome.
Chronic treatment with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside increases insulin-stimulated glucose uptake and GLUT4 translocation in rat skeletal muscles in a fiber type-specific manner.
TLDR
5 days of AICAR administration induces a pronounced fiber type-specific increase in insulin-stimulated glucose uptake and GLUT4 cell surface content in rat skeletal muscle with the greatest effect observed on white fast-twitch glycolytic muscles (EPI).
Glycemic improvement in diabetic db/db mice by overexpression of the human insulin-regulatable glucose transporter (GLUT4).
TLDR
It is demonstrated that GLUT4 upregulation overcomes the glucose transporter translocation defect and alleviates insulin resistance in genetically diabetic mice, thus resulting in markedly improved glycemic control.
5' AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle.
TLDR
Evidence is provided that the increased glucose uptake observed with AMPK activation by AICA-riboside in perfused rat hindlimb muscles is due to an increase in the translocation of GLUT4 to surface membranes.
Effect of AMPK activation on muscle glucose metabolism in conscious rats.
TLDR
The activation of AMPK by AICAR increases skeletal muscle glucose transport activity both in vivo and in vitro, and this cellular pathway may play an important role in exercise-induced increase in glucose Transport activity.
Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance
TLDR
To determine the importance of glucose uptake into muscle for glucose homeostasis, disruption of GLUT4 selectively in mouse muscles resulted in a profound reduction in basal glucose transport and near-absence of stimulation by insulin or contraction.
AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle.
TLDR
Evidence is provided that decreases in muscle content of malonyl-CoA can increase the rate of fatty acid oxidation, and perfusion with medium containing AICAR was found to activate AMPK in skeletal muscle, inactivate ACC, and decrease malony l-coA.
Kinetics of Contraction-Induced GLUT4 Translocation in Skeletal Muscle Fibers From Living Mice
TLDR
A novel imaging system is developed to study contraction-stimulated GLUT4 translocation in living mice and determine the function of AMP-activated protein kinase α2 (AMPKα2) in this process.
Methotrexate prevents renal injury in experimental diabetic rats via anti-inflammatory actions.
TLDR
The results indicate that intermittent administration of MTX prevented renal injuries without changes in blood glucose level and BP in experimental diabetic rats, suggesting that anti-inflammatory agents might be beneficial for the treatment of diabetic nephropathy.
...
1
2
3
4
5
...