Abnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction

Area of Science:

• Biochemistry
• Physiology
• Endocrinology

Background:

• Whole body and myocardial insulin resistance are key features of non-insulin-dependent diabetes mellitus (NIDDM) and left-ventricular dysfunction (LVD).
• Understanding the molecular mechanisms underlying tissue-specific insulin resistance is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the roles of insulin receptor substrate-1 (IRS1), IRS1-associated PI3K (IRS1-PI3K), and glucose transporter 4 (GLUT4) in contributing to insulin resistance in NIDDM and LVD.

Main Methods:

• Biopsies of skeletal muscle and myocardium were collected from control subjects, patients with NIDDM, and patients with LVD.
• Euglycaemic-hyperinsulinaemic clamp and positron emission tomography were used for patient characterization.
• Comparative studies were performed in three mouse models of insulin resistance.

Main Results:

• Skeletal muscle showed reduced IRS1 in LVD patients, while cardiac IRS1-PI3K activity increased in both NIDDM and LVD patients.
• NIDDM patients exhibited reduced sarcolemmal GLUT4, whereas LVD patients showed increased sarcolemmal GLUT4.
• Mouse models confirmed IRS1-PI3K activation and GLUT4 reduction in insulin-resistant hearts, with evidence of GLUT4 trafficking defects.

Conclusions:

• The molecular mechanisms driving myocardial insulin resistance are distinct in NIDDM compared to LVD.
• Abnormalities in IRS1, IRS1-PI3K, and GLUT4 play significant, yet different, roles in the development of insulin resistance in these conditions.