Lipids activate skeletal muscle mitochondrial fission and quality control networks to induce insulin resistance in humans.

Christopher L Axelrod, Ciaran E Fealy, Melissa L Erickson, Gangarao Davuluri, Hisashi Fujioka, Wagner S Dantas, Emily Huang, Kathryn Pergola, Jacob T Mey, William T King, Anny Mulya, Daniel Hsia, Bartolome Burguera, Bernard Tandler, Charles L Hoppel, John P Kirwan

Journal: Metabolism: clinical and experimental 2021;121():154803

PMID: 34090870

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Plain Language Summary

Insulin resistance is a key pathophysiological mechanism in the development and progression of type 2 diabetes. Abnormalities in lipid metabolism and ectopic lipid accumulation are known to directly contribute to the onset of insulin resistance. Authors hypothesised that lipid infusion would increase dynamin related protein 1 [a type of protein]-mediated mitochondrial fission in skeletal muscle independent of function and content, consequently reducing peripheral insulin sensitivity. The study included sedentary but otherwise healthy adults who were prospectively randomized to receive either lipid or saline infusion to isolate the direct contribution of fatty acids to skeletal muscle mitochondrial dynamics. Results show that mitochondrial fission and quality control networks are activated in response to lipid infusion which occurs independent of changes in mitochondrial content or capacity and contributes to the onset of insulin resistance in healthy humans. Authors conclude that treatments that limit lipid-induced activation of mitochondrial fission and/or quality control processes may have therapeutic value in the treatment of insulin resistance.

Abstract

[{"label":"BACKGROUND AND AIMS","text":"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."},{"label":"METHODS","text":"19 healthy adults (age:28.4\u202f\u00b1\u202f1.7\u202fyears; BMI:22.7\u202f\u00b1\u202f0.3\u202fkg\/m) 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."},{"label":"RESULTS","text":"Overnight lipid infusion increased dynamin related protein 1 (DRP1) phosphorylation at serine 616 and PTEN-induced kinase 1 (PINK1) expression (P\u202f=\u202f0.003 and P\u202f=\u202f0.008, respectively) in skeletal muscle while reducing mitochondrial membrane potential (P\u202f=\u202f0.042). The lipid infusion also increased mitochondrial-associated lipid droplet formation (P\u202f=\u202f0.011), 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\u202f=\u202f0.004) and hepatic insulin sensitivity (P\u202f=\u202f0.014)."},{"label":"CONCLUSIONS","text":"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."},{"label":"CLINICAL TRIAL REGISTRATION","text":"NCT02697201, ClinicalTrials.gov."},{"copyright":"Copyright \u00a9 2021 Elsevier Inc. All rights reserved."}]

Address: Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; Department of Translational Services, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; Sarcopenia and Malnutrition Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.; Cryo-Electron Microscopy Core, Case Western Reserve University, Cleveland, OH 44109, USA; Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; Department of Translational Services, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.; Clinical Trials Unit, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.; Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.; Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH 44106, USA.; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44109, USA.; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: [email protected].

DOI: 10.1016/j.metabol.2021.154803

Patient Centred Factor

Mediators: Insulin resistance

Clinical Imbalances

Immune and inflammation Structural Integrity and Musculoskeletal

Laboratory Testing

Blood Tissue biopsy Imaging

Modifiable Lifestyle Factors

Diet Exercise and movement

Jadad Score

Nutrition Evidence Keywords

Insulin resistance Obesity Exercise Type 2 diabetes Lipids Fatty acids Insulin sensitivity Metabolic rate Mitochondria

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MeSH Terms: Adult, Biopsy, Cell Respiration, Emulsions, Fatty Acids, Female, Glucose Clamp Technique, Healthy Volunteers, Humans, Infusions, Intravenous, Insulin, Insulin Resistance, Lipid Metabolism, Lipids, Male, Metabolic Networks and Pathways, Mitochondria, Muscle, Mitochondrial Dynamics, Muscle, Skeletal, Phospholipids, Soybean Oil