TY - JOUR
T1 - Insulin Resistance and Increased Muscle Cytokine Levels in Patients With Mitochondrial Myopathy
AU - Rue, Nana
AU - Vissing, John
AU - Galbo, Henrik
PY - 2014/10/1
Y1 - 2014/10/1
N2 - CONTEXT: Mitochondrial dysfunction has been proposed to cause insulin resistance and that might stimulate cytokine production.OBJECTIVE: The objective of the study was to elucidate the association between mitochondrial myopathy, insulin sensitivity, and cytokine levels in muscle.DESIGN AND SETTING: This was an experimental, controlled study in outpatients.PARTICIPANTS: Eight overnight-fasted patients (P) with various inherited mitochondrial myopathies and eight healthy subjects (C) matched for sex, age, weight, height, and physical activity participated in the study.INTERVENTIONS: The intervention included a 120-minute hyperinsulinemic, euglycemic clamp. Another morning, microdialysis of both vastus lateralis muscles for 4 hours, including one-legged, knee extension exercise for 30 minutes, was performed.MAIN OUTCOME MEASURES: Glucose infusion rate during 90-120 minutes of insulin infusion was measured. Cytokine concentrations in dialysate were also measured.RESULTS: Muscle strength, percentage fat mass, and creatine kinase in plasma did not differ between groups. The maximal oxygen uptake was 21 ± 3 (SE) (P) and 36 ± 3(C) mL/kg·min (2P < .05). Basal insulin, C-peptide, and glucagon were higher in P (55 ± 10, 980 ± 92, and 102 ± 13 pM) than in C (36 ± 12, 712 ± 98, and 44 ± 10 pM) (two-sided significance testing [2P ]< .05). The homeostasis model assessment insulin sensitivity index and glucose infusion rate (6.8 ± 1.0 vs 9.4 ± 1.3 mg/min·kg) were lower, and free fatty acids and glycerol at 120 minutes were higher in P vs C (2P < .05). Dialysate concentrations of TNF-α, IL-6, IL-8, IL-10, and monocyte chemoattractant protein-1 were higher in P vs C (2P < .05). Dialysate concentrations of these cytokines and of IL-1 receptor antagonist increased during exercise (2P < .05), identically in P and C. No differences existed in plasma cytokine concentrations.CONCLUSIONS: In patients with a variety of mitochondrial myopathies, insulin sensitivity of muscle, adipose tissue, and pancreatic A cells is reduced, supporting that mitochondrial function influences insulin action. Furthermore, a local, low-grade inflammation of potential clinical importance exists in the muscle of these patients.
AB - CONTEXT: Mitochondrial dysfunction has been proposed to cause insulin resistance and that might stimulate cytokine production.OBJECTIVE: The objective of the study was to elucidate the association between mitochondrial myopathy, insulin sensitivity, and cytokine levels in muscle.DESIGN AND SETTING: This was an experimental, controlled study in outpatients.PARTICIPANTS: Eight overnight-fasted patients (P) with various inherited mitochondrial myopathies and eight healthy subjects (C) matched for sex, age, weight, height, and physical activity participated in the study.INTERVENTIONS: The intervention included a 120-minute hyperinsulinemic, euglycemic clamp. Another morning, microdialysis of both vastus lateralis muscles for 4 hours, including one-legged, knee extension exercise for 30 minutes, was performed.MAIN OUTCOME MEASURES: Glucose infusion rate during 90-120 minutes of insulin infusion was measured. Cytokine concentrations in dialysate were also measured.RESULTS: Muscle strength, percentage fat mass, and creatine kinase in plasma did not differ between groups. The maximal oxygen uptake was 21 ± 3 (SE) (P) and 36 ± 3(C) mL/kg·min (2P < .05). Basal insulin, C-peptide, and glucagon were higher in P (55 ± 10, 980 ± 92, and 102 ± 13 pM) than in C (36 ± 12, 712 ± 98, and 44 ± 10 pM) (two-sided significance testing [2P ]< .05). The homeostasis model assessment insulin sensitivity index and glucose infusion rate (6.8 ± 1.0 vs 9.4 ± 1.3 mg/min·kg) were lower, and free fatty acids and glycerol at 120 minutes were higher in P vs C (2P < .05). Dialysate concentrations of TNF-α, IL-6, IL-8, IL-10, and monocyte chemoattractant protein-1 were higher in P vs C (2P < .05). Dialysate concentrations of these cytokines and of IL-1 receptor antagonist increased during exercise (2P < .05), identically in P and C. No differences existed in plasma cytokine concentrations.CONCLUSIONS: In patients with a variety of mitochondrial myopathies, insulin sensitivity of muscle, adipose tissue, and pancreatic A cells is reduced, supporting that mitochondrial function influences insulin action. Furthermore, a local, low-grade inflammation of potential clinical importance exists in the muscle of these patients.
KW - Adipose Tissue
KW - Adult
KW - Chemokine CCL2
KW - Cytokines
KW - Exercise
KW - Female
KW - Glucagon-Secreting Cells
KW - Glucose Clamp Technique
KW - Humans
KW - Hyperinsulinism
KW - Insulin Resistance
KW - Interleukin-10
KW - Interleukin-6
KW - Interleukin-8
KW - Male
KW - Middle Aged
KW - Mitochondria
KW - Mitochondrial Myopathies
KW - Muscle, Skeletal
KW - Outpatients
KW - Tumor Necrosis Factor-alpha
U2 - 10.1210/jc.2014-1831
DO - 10.1210/jc.2014-1831
M3 - Journal article
C2 - 25057876
SN - 0021-972X
VL - 99
SP - 3757
EP - 3765
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 10
ER -