Skeletal Muscle Insulin Resistance and Absence of Inflammation Characterize Insulin-Resistant Grade I Obese Women.
Obesity is associated with insulin-resistance (IR), the key feature of type 2 diabetes. Although chronic low-grade inflammation has been identified as a central effector of IR development, it has never been investigated simultaneously at systemic level and locally in skeletal muscle and adipose tissue in obese humans characterized for their insulin sensitivity.



We compared metabolic parameters and inflammation at systemic and tissue levels in normal-weight and obese subjects with different insulin sensitivity to better understand the mechanisms involved in IR development.



30 post-menopausal women were classified as normal-weight insulin-sensitive (controls, CT) and obese (grade I) insulin-sensitive (OIS) or insulin-resistant (OIR) according to their body mass index and homeostasis model assessment of IR index. They underwent a hyperinsulinemic-euglycemic clamp, blood sampling, skeletal muscle and subcutaneous adipose tissue biopsies, an activity questionnaire and a self-administrated dietary recall. We analyzed insulin sensitivity, inflammation and IR-related parameters at the systemic level. In tissues, insulin response was assessed by P-Akt/Akt expression and inflammation by macrophage infiltration as well as cytokines and IκBα expression.



Systemic levels of lipids, adipokines, inflammatory cytokines, and lipopolysaccharides were equivalent between OIS and OIR subjects. In subcutaneous adipose tissue, the number of anti-inflammatory macrophages was higher in OIR than in CT and OIS and was associated with higher IL-6 level. Insulin induced Akt phosphorylation to the same extent in CT, OIS and OIR. In skeletal muscle, we could not detect any inflammation even though IκBα expression was lower in OIR compared to CT. However, while P-Akt/Akt level increased following insulin stimulation in CT and OIS, it remained unchanged in OIR.



Our results show that systemic IR occurs without any change in systemic and tissues inflammation. We identified a muscle defect in insulin response as an early mechanism of IR development in grade I obese post-menopausal women.
PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.
Cacylde
C
Amouzou
PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.|Centre Hospitalier Régional Universitaire (CHRU) Montpellier, Montpellier, France.
Cyril
C
Breuker
PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.
Odile
O
Fabre
PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.
Annick
A
Bourret
PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.
Karen
K
Lambert
Faculty of Health, York University, York, Ontario, Canada.
Olivier
O
Birot
PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.|Centre Hospitalier Régional Universitaire (CHRU) Montpellier, Montpellier, France.
Christine
C
Fédou
Centre Hospitalier Régional Universitaire (CHRU) Montpellier, Montpellier, France.
Anne-Marie
AM
Dupuy
PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.|Centre Hospitalier Régional Universitaire (CHRU) Montpellier, Montpellier, France.
Jean-Paul
JP
Cristol
PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.|Centre Hospitalier Régional Universitaire (CHRU) Montpellier, Montpellier, France.
Thibault
T
Sutra
PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.|Centre Hospitalier Régional Universitaire (CHRU) Montpellier, Montpellier, France.
Nicolas
N
Molinari
PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.|Centre Hospitalier Régional Universitaire (CHRU) Montpellier, Montpellier, France.
Laurent
L
Maimoun
PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.|Centre Hospitalier Régional Universitaire (CHRU) Montpellier, Montpellier, France.
Denis
D
Mariano-Goulart
Centre Hospitalier Régional Universitaire (CHRU) Montpellier, Montpellier, France.
Florence
F
Galtier
PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.|Centre Hospitalier Régional Universitaire (CHRU) Montpellier, Montpellier, France.
Antoine
A
Avignon
University of Grenoble Alpes, INSERM U1042, HP2, Grenoble, CHU Albert Michalon, Grenoble, France.
Françoise
F
Stanke-Labesque
PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.|Centre Hospitalier Régional Universitaire (CHRU) Montpellier, Montpellier, France.
Jacques
J
Mercier
PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.|Centre Hospitalier Régional Universitaire (CHRU) Montpellier, Montpellier, France.
Ariane
A
Sultan
PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.
Catherine
C
Bisbal
D001786:Blood Glucose / Q000378:metabolism*; D002097:C-Reactive Protein; D016022:Case-Control Studies; D002465:Cell Movement / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004032:Diet; D005260:Female; D005786:Gene Expression Regulation; D015309:Glucose Clamp Technique; D006801:Humans; D007249:Inflammation; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism*; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017698:Postmenopause / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D050151:Subcutaneous Fat / Q000378:metabolism / Q000503:physiopathology; D011795:Surveys and Questionnaires
D001786:Blood Glucose; C508600:IL6 protein, human; D007328:Insulin; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000072000:NF-KappaB Inhibitor alpha; D002097:C-Reactive Protein; D051057:Proto-Oncogene Proteins c-akt