Lipids Activate Skeletal Muscle Mitochondrial Fission and Quality Control Networks to Induce Insulin Resistance in Humans
| Autor: | Melissa L. Erickson, Hisashi Fujioka, Gangarao Davuluri, Ciaran E. Fealy, Bartolome Burguera, Jacob T. Mey, Christopher L. Axelrod, Kathryn Pergola, Anny Mulya, Charles L. Hoppel, Emily Huang, Daniel Hsia, William T. King, Wagner S Dantas, Bernard Tandler, John P. Kirwan |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Adult Male medicine.medical_specialty Endocrinology Diabetes and Metabolism Biopsy Cell Respiration 030209 endocrinology & metabolism PINK1 Oxidative phosphorylation Mitochondrion Mitochondrial Dynamics Article 03 medical and health sciences DNM1L 0302 clinical medicine Endocrinology Insulin resistance Lipid droplet Internal medicine medicine Humans Insulin Infusions Intravenous Muscle Skeletal Phospholipids Chemistry Fatty Acids Skeletal muscle medicine.disease Lipid Metabolism Lipids Healthy Volunteers Mitochondria Muscle Soybean Oil 030104 developmental biology medicine.anatomical_structure Glucose Clamp Technique Mitochondrial fission Emulsions Female Insulin Resistance Metabolic Networks and Pathways |
| Zdroj: | Metabolism |
| Popis: | Background and aims A diminution in skeletal muscle mitochondrial function due to ectopic lipid accumulation and excess nutrient intake is thought to contribute to insulin resistance and the development of type 2 diabetes. However, the functional integrity of mitochondria in insulin-resistant skeletal muscle remains highly controversial. Methods 19 healthy adults (age:28.4 ± 1.7 years; BMI:22.7 ± 0.3 kg/m2) received an overnight intravenous infusion of lipid (20% Intralipid) or saline followed by a hyperinsulinemic-euglycemic clamp to assess insulin sensitivity using a randomized crossover design. Skeletal muscle biopsies were obtained after the overnight lipid infusion to evaluate activation of mitochondrial dynamics proteins, ex-vivo mitochondrial membrane potential, ex-vivo oxidative phosphorylation and electron transfer capacity, and mitochondrial ultrastructure. Results Overnight lipid infusion increased dynamin related protein 1 (DRP1) phosphorylation at serine 616 and PTEN-induced kinase 1 (PINK1) expression (P = 0.003 and P = 0.008, respectively) in skeletal muscle while reducing mitochondrial membrane potential (P = 0.042). The lipid infusion also increased mitochondrial-associated lipid droplet formation (P = 0.011), the number of dilated cristae, and the presence of autophagic vesicles without altering mitochondrial number or respiratory capacity. Additionally, lipid infusion suppressed peripheral glucose disposal (P = 0.004) and hepatic insulin sensitivity (P = 0.014). Conclusions These findings indicate that activation of mitochondrial fission and quality control occur early in the onset of insulin resistance in human skeletal muscle. Targeting mitochondrial dynamics and quality control represents a promising new pharmacological approach for treating insulin resistance and type 2 diabetes. Clinical trial registration NCT02697201 , ClinicalTrials.gov |
| Databáze: | OpenAIRE |
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