Insulin resistance in striated muscle-specific integrin receptor beta1-deficient mice.
Integrin receptor plays key roles in mediating both inside-out and outside-in signaling between cells and the extracellular matrix. We have observed that the tissue-specific loss of the integrin beta1 subunit in striated muscle results in a near complete loss of integrin beta1 subunit protein expression concomitant with a loss of talin and to a lesser extent, a reduction in F-actin content. Muscle-specific integrin beta1-deficient mice had no significant difference in food intake, weight gain, fasting glucose, and insulin levels with their littermate controls. However, dynamic analysis of glucose homeostasis using euglycemichyperinsulinemic clamps demonstrated a 44 and 48% reduction of insulin-stimulated glucose infusion rate and glucose clearance, respectively. The whole body insulin resistance resulted from a specific inhibition of skeletal muscle glucose uptake and glycogen synthesis without any significant effect on the insulin suppression of hepatic glucose output or insulin-stimulated glucose uptake in adipose tissue. The reduction in skeletal muscle insulin responsiveness occurred without any change in GLUT4 protein expression levels but was associated with an impairment of the insulin-stimulated protein kinase B/Akt serine 473 phosphorylation but not threonine 308. The inhibition of insulin-stimulated serine 473 phosphorylation occurred concomitantly with a decrease in integrin-linked kinase expression but with no change in the mTOR.Rictor.LST8 complex (mTORC2). These data demonstrate an in vivo crucial role of integrin beta1 signaling events in mediating cross-talk to that of insulin action.
Zong
Haihong
H
Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Bastie
Claire C
CC
Xu
Jun
J
Fassler
Reinhard
R
Campbell
Kevin P
KP
Kurland
Irwin J
IJ
Pessin
Jeffrey E
JE
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004435:Eating / Q000502:physiology; D005215:Fasting / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006003:Glycogen / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D054792:Muscle, Striated; D009928:Organ Specificity / Q000235:genetics; D010766:Phosphorylation / Q000502:physiology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D016608:Talin / Q000235:genetics / Q000378:metabolism
D000199:Actins; D002352:Carrier Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D019012:Integrin beta1; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C495693:Slc2a4 protein, mouse; D016608:Talin; C525637:rictor protein, mouse; D006003:Glycogen; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose