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Impact of insulin deprivation and treatment on sphingolipid distribution in different muscle subcellular compartments of streptozotocin-diabetic C57Bl/6 mice
- Source :
- American Journal of Physiology-Endocrinology and Metabolism. 306:E529-E542
- Publication Year :
- 2014
- Publisher :
- American Physiological Society, 2014.
-
Abstract
- Insulin deprivation in type 1 diabetes (T1D) individuals increases lipolysis and plasma free fatty acids (FFA) concentration, which can stimulate synthesis of intramyocellular bioactive lipids such as ceramides (Cer) and long-chain fatty acid-CoAs (LCFa-CoAs). Ceramide was shown to decrease muscle insulin sensitivity, and at mitochondrial levels it stimulates reactive oxygen species production. Here, we show that insulin deprivation in streptozotocin diabetic C57BL/6 mice increases quadriceps muscle Cer content, which was correlated with a concomitant decrease in the body fat and increased plasma FFA, glycosylated hemoglobin level (%Hb A1c), and muscular LCFa-CoA content. The alternations were accompanied by an increase in protein expression in LCFa-CoA and Cer synthesis (FATP1/ACSVL5, CerS1, CerS5), a decrease in the expression of genes implicated in muscle insulin sensitivity (GLUT4, GYS1), and inhibition of insulin signaling cascade by Aktα and GYS3β phosphorylation under acute insulin stimulation. Both the content and composition of sarcoplasmic fraction sphingolipids were most affected by insulin deprivation, whereas mitochondrial fraction sphingolipids remained stable. The observed effects of insulin deprivation were reversed, except for content and composition of LCFa-CoA, CerS protein expression, GYS1 gene expression, and phosphorylation status of Akt and GYS3β when exogenous insulin was provided by subcutaneous insulin implants. Principal component analysis and Pearson's correlation analysis revealed close relationships between the features of the diabetic phenotype, the content of LCFa-CoAs and Cers containing C18-fatty acids in sarcoplasm, but not in mitochondria. Insulin replacement did not completely rescue the phenotype, especially regarding the content of LCFa-CoA, or proteins implicated in Cer synthesis and muscle insulin sensitivity. These persistent changes might contribute to muscle insulin resistance observed in T1D individuals.
- Subjects :
- Male
medicine.medical_specialty
Ceramide
Physiology
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
Ceramides
Diabetes Mellitus, Experimental
Mice
chemistry.chemical_compound
Insulin resistance
Physiology (medical)
Internal medicine
medicine
Animals
Insulin
Phosphorylation
Muscle, Skeletal
Protein kinase B
Sphingolipids
Type 1 diabetes
Glucose Transporter Type 4
biology
Skeletal muscle
Articles
medicine.disease
Insulin receptor
Endocrinology
medicine.anatomical_structure
chemistry
biology.protein
lipids (amino acids, peptides, and proteins)
Reactive Oxygen Species
Proto-Oncogene Proteins c-akt
GLUT4
Signal Transduction
Subcellular Fractions
Subjects
Details
- ISSN :
- 15221555 and 01931849
- Volume :
- 306
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Endocrinology and Metabolism
- Accession number :
- edsair.doi.dedup.....9231d944ed89e11c7e18bd9a3c818bf9