TY - JOUR
T1 - Abnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction
AU - Cook, Stuart A.
AU - Varela-Carver, Anabel
AU - Mongillo, Marco
AU - Kleinert, Christina
AU - Khan, Muhammad T.
AU - Leccisotti, Lucia
AU - Strickland, Nicola
AU - Matsui, Takashi
AU - Das, Saumya
AU - Rosenzweig, Anthony
AU - Punjabi, Prakash
AU - Camici, Paolo G.
PY - 2010/1
Y1 - 2010/1
N2 - AimsWhole 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.Methods and resultsWe 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.ConclusionOur data show that the mechanisms of myocardial insulin resistance are different between NIDDM and LVD.
AB - AimsWhole 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.Methods and resultsWe 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.ConclusionOur data show that the mechanisms of myocardial insulin resistance are different between NIDDM and LVD.
KW - Congestive heart failure
KW - Diabetes
KW - Imaging
KW - Insulin
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U2 - 10.1093/eurheartj/ehp396
DO - 10.1093/eurheartj/ehp396
M3 - Article
C2 - 19797329
AN - SCOPUS:73949160605
VL - 31
SP - 100
EP - 111
JO - European Heart Journal
JF - European Heart Journal
SN - 0195-668X
IS - 1
ER -