Abnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction.
OBJECTIVE
Whole body and myocardial insulin resistance are features of non-insulin-dependent diabetes mellitus (NIDDM) and left-ventricular dysfunction (LVD). We determined whether abnormalities of insulin receptor substrate-1 (IRS1), IRS1-associated PI3K (IRS1-PI3K), and glucose transporter 4 (GLUT4) contribute to tissue-specific insulin resistance.


RESULTS
We collected skeletal muscle (n = 27) and myocardial biopsies (n = 24) from control patients (n = 7), patients with NIDDM (n = 9) and patients with LVD (n = 8), who were characterized by euglycaemic-hyperinsulinaemic clamp and positron emission tomography. Comparative studies were carried out in three mouse models. We demonstrate an unrecognized reduction of IRS1 in skeletal muscle of LVD patients and an unexpected increase in cardiac IRS1-PI3K activity in NIDDM and LVD patients. In NIDDM, there was a concomitant reduction in sarcolemmal GLUT4, whereas in patients with LVD sarcolemmal GLUT4 was increased. We confirm activation of IRS1-PI3K and reduction in sarcolemmal GLUT4 in the insulin resistant ob/ob mouse heart where we also demonstrate perturbation of GLUT4 docking and fusion. A direct relationship between PI3K and GLUT4 was demonstrated in mice expressing activated PI3K in the heart and increased GLUT4 at the sarcolemma was confirmed in a mouse model of LVD.


CONCLUSIONS
Our data show that the mechanisms of myocardial insulin resistance are different between NIDDM and LVD.
Medical Research Council Clinical Sciences Centre, Imperial College, Hammersmith Hospital Campus, London W12 0NN, UK.
Stuart A
SA
Cook
Anabel
A
Varela-Carver
Marco
M
Mongillo
Christina
C
Kleinert
Muhammad T
MT
Khan
Lucia
L
Leccisotti
Nicola
N
Strickland
Takashi
T
Matsui
Saumya
S
Das
Anthony
A
Rosenzweig
Prakash
P
Punjabi
Paolo G
PG
Camici
D000328:Adult; D000368:Aged; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000378:metabolism*; D005260:Female; D015309:Glucose Clamp Technique; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D018810:Magnetic Resonance Angiography; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D018487:Ventricular Dysfunction, Left / Q000378:metabolism*
D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases