Insulin Resistance and Increased Muscle Cytokine Levels in Patients With Mitochondrial Myopathy

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 -